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  1. Maria Nikodemova, Alissa L Small, Stephanie M C Smith, Gordon S Mitchell and Jyoti J Watters.
    Spinal but not cortical microglia acquire an atypical phenotype with high VEGF, galectin-3 and osteopontin, and blunted inflammatory responses in ALS rats.. Neurobiology of disease 69:43–53, September 2014.
    Abstract Activation of microglia, CNS resident immune cells, is a pathological hallmark of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder affecting motor neurons. Despite evidence that microglia contribute to disease progression, the exact role of these cells in ALS pathology remains unknown. We immunomagnetically isolated microglia from different CNS regions of SOD1(G93A) rats at three different points in disease progression: presymptomatic, symptom onset and end-stage. We observed no differences in microglial number or phenotype in presymptomatic rats compared to wild-type controls. Although after disease onset there was no macrophage infiltration, there were significant increases in microglial numbers in the spinal cord, but not cortex. At disease end-stage, microglia were characterized by high expression of galectin-3, osteopontin and VEGF, and concomitant downregulated expression of TNF$\alpha$, IL-6, BDNF and arginase-1. Flow cytometry revealed the presence of at least two phenotypically distinct microglial populations in the spinal cord. Immunohistochemistry showed that galectin-3/osteopontin positive microglia were restricted to the ventral horns of the spinal cord, regions with severe motor neuron degeneration. End-stage SOD1(G93A) microglia from the cortex, a less affected region, displayed similar gene expression profiles to microglia from wild-type rats, and displayed normal responses to systemic inflammation induced by LPS. On the other hand, end-stage SOD1(G93A) spinal microglia had blunted responses to systemic LPS suggesting that in addition to their phenotypic changes, they may also be functionally impaired. Thus, after disease onset, microglia acquired unique characteristics that do not conform to typical M1 (inflammatory) or M2 (anti-inflammatory) phenotypes. This transformation was observed only in the most affected CNS regions, suggesting that overexpression of mutated hSOD1 is not sufficient to trigger these changes in microglia. These novel observations suggest that microglial regional and phenotypic heterogeneity may be an important consideration when designing new therapeutic strategies targeting microglia and neuroinflammation in ALS.
    URL, DOI BibTeX

    @article{Nikodemova2014,
    	abstract = "Activation of microglia, CNS resident immune cells, is a pathological hallmark of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder affecting motor neurons. Despite evidence that microglia contribute to disease progression, the exact role of these cells in ALS pathology remains unknown. We immunomagnetically isolated microglia from different CNS regions of SOD1(G93A) rats at three different points in disease progression: presymptomatic, symptom onset and end-stage. We observed no differences in microglial number or phenotype in presymptomatic rats compared to wild-type controls. Although after disease onset there was no macrophage infiltration, there were significant increases in microglial numbers in the spinal cord, but not cortex. At disease end-stage, microglia were characterized by high expression of galectin-3, osteopontin and VEGF, and concomitant downregulated expression of TNF$\alpha$, IL-6, BDNF and arginase-1. Flow cytometry revealed the presence of at least two phenotypically distinct microglial populations in the spinal cord. Immunohistochemistry showed that galectin-3/osteopontin positive microglia were restricted to the ventral horns of the spinal cord, regions with severe motor neuron degeneration. End-stage SOD1(G93A) microglia from the cortex, a less affected region, displayed similar gene expression profiles to microglia from wild-type rats, and displayed normal responses to systemic inflammation induced by LPS. On the other hand, end-stage SOD1(G93A) spinal microglia had blunted responses to systemic LPS suggesting that in addition to their phenotypic changes, they may also be functionally impaired. Thus, after disease onset, microglia acquired unique characteristics that do not conform to typical M1 (inflammatory) or M2 (anti-inflammatory) phenotypes. This transformation was observed only in the most affected CNS regions, suggesting that overexpression of mutated hSOD1 is not sufficient to trigger these changes in microglia. These novel observations suggest that microglial regional and phenotypic heterogeneity may be an important consideration when designing new therapeutic strategies targeting microglia and neuroinflammation in ALS.",
    	author = "Nikodemova, Maria and Small, Alissa L and Smith, Stephanie M C and Mitchell, Gordon S and Watters, Jyoti J",
    	doi = "10.1016/j.nbd.2013.11.009",
    	issn = "1095-953X",
    	journal = "Neurobiology of disease",
    	month = "sep",
    	pages = "43--53",
    	pmid = 24269728,
    	title = "{Spinal but not cortical microglia acquire an atypical phenotype with high VEGF, galectin-3 and osteopontin, and blunted inflammatory responses in ALS rats.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24269728",
    	volume = 69,
    	year = 2014
    }
    
  2. Sahar Soliman, Tauheed Ishrat, Anilkumar Pillai, Payaningal R Somanath, Adviye Ergul, Azza B El-Remessy and Susan C Fagan.
    Candesartan induces a prolonged proangiogenic effect and augments endothelium-mediated neuroprotection after oxygen and glucose deprivation: role of vascular endothelial growth factors A and B.. The Journal of pharmacology and experimental therapeutics 349(3):444–57, June 2014.
    Abstract Angiogenesis is a key component of recovery after stroke. Angiotensin II receptor blocker (ARB) treatment improves neurobehavioral outcome and is associated with enhanced angiogenesis after stroke. The purpose of this study is to investigate the temporal pattern of the ARB proangiogenic effect in the ischemic brain and its association with vascular endothelial growth factors VEGF-A and VEGF-B. Wistar rats were exposed to 90-minute middle cerebral artery occlusion and treated with candesartan (1 mg/kg) at reperfusion. The proangiogenic potential of the cerebrospinal fluid was determined at 8, 24, 48, and 72 hours using an in vitro Matrigel tube formation assay. In addition, the expression of VEGF-A and VEGF-B was measured in brain homogenates using Western blotting at the same time points. A single candesartan dose induced a prolonged proangiogenic effect and a prolonged upregulation of VEGF-A and VEGF-B in vivo. In the ischemic hemisphere, candesartan treatment was associated with stabilization of hypoxia-inducible factor-1$\alpha$ and preservation of angiopoietin-1. The effect of ARB treatment on endothelial cells was studied in vitro. Our results identified brain endothelial cells as one target for the action of ARBs and a source of the upregulated VEGF-A and VEGF-B, which exerted an autocrine angiogenic response, in addition to a paracrine neuroprotective effect. Taken together, this study highlights the potential usefulness of augmenting the endogenous restorative capacity of the brain through the administration of ARBs.
    URL, DOI BibTeX

    @article{Soliman2014,
    	abstract = "Angiogenesis is a key component of recovery after stroke. Angiotensin II receptor blocker (ARB) treatment improves neurobehavioral outcome and is associated with enhanced angiogenesis after stroke. The purpose of this study is to investigate the temporal pattern of the ARB proangiogenic effect in the ischemic brain and its association with vascular endothelial growth factors VEGF-A and VEGF-B. Wistar rats were exposed to 90-minute middle cerebral artery occlusion and treated with candesartan (1 mg/kg) at reperfusion. The proangiogenic potential of the cerebrospinal fluid was determined at 8, 24, 48, and 72 hours using an in vitro Matrigel tube formation assay. In addition, the expression of VEGF-A and VEGF-B was measured in brain homogenates using Western blotting at the same time points. A single candesartan dose induced a prolonged proangiogenic effect and a prolonged upregulation of VEGF-A and VEGF-B in vivo. In the ischemic hemisphere, candesartan treatment was associated with stabilization of hypoxia-inducible factor-1$\alpha$ and preservation of angiopoietin-1. The effect of ARB treatment on endothelial cells was studied in vitro. Our results identified brain endothelial cells as one target for the action of ARBs and a source of the upregulated VEGF-A and VEGF-B, which exerted an autocrine angiogenic response, in addition to a paracrine neuroprotective effect. Taken together, this study highlights the potential usefulness of augmenting the endogenous restorative capacity of the brain through the administration of ARBs.",
    	author = "Soliman, Sahar and Ishrat, Tauheed and Pillai, Anilkumar and Somanath, Payaningal R and Ergul, Adviye and El-Remessy, Azza B and Fagan, Susan C",
    	doi = "10.1124/jpet.113.212613",
    	issn = "1521-0103",
    	journal = "The Journal of pharmacology and experimental therapeutics",
    	keywords = "Angiopoietin-1,Angiopoietin-1: metabolism,Animals,Benzimidazoles,Benzimidazoles: administration \& dosage,Benzimidazoles: therapeutic use,Cell Culture Techniques,Cell Line,Cell Movement,Cell Movement: drug effects,Cell Proliferation,Cell Proliferation: drug effects,Disease Models, Animal,Dose-Response Relationship, Drug,Endothelial Cells,Endothelial Cells: drug effects,Endothelium, Vascular,Endothelium, Vascular: drug effects,Endothelium, Vascular: metabolism,Endothelium, Vascular: physiopathology,Glucose,Glucose: metabolism,Hypoxia-Inducible Factor 1, alpha Subunit,Hypoxia-Inducible Factor 1, alpha Subunit: metabol,Male,Neovascularization, Physiologic,Neovascularization, Physiologic: drug effects,Neuroprotective Agents,Neuroprotective Agents: administration \& dosage,Neuroprotective Agents: therapeutic use,Oxygen,Oxygen: metabolism,Rats,Rats, Wistar,Stroke,Stroke: metabolism,Stroke: physiopathology,Stroke: prevention \& control,Tetrazoles,Tetrazoles: administration \& dosage,Tetrazoles: therapeutic use,Up-Regulation,Vascular Endothelial Growth Factor A,Vascular Endothelial Growth Factor A: biosynthesis,Vascular Endothelial Growth Factor B,Vascular Endothelial Growth Factor B: biosynthesis",
    	month = "jun",
    	number = 3,
    	pages = "444--57",
    	pmid = 24681872,
    	title = "{Candesartan induces a prolonged proangiogenic effect and augments endothelium-mediated neuroprotection after oxygen and glucose deprivation: role of vascular endothelial growth factors A and B.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24681872",
    	volume = 349,
    	year = 2014
    }
    
  3. Gladys Yacila and Youssef Sari.
    Potential Therapeutic Drugs and Methods for the Treatment of Amyotrophic Lateral Sclerosis.. Current medicinal chemistry, June 2014.
    Abstract Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder caused by damage of motoneurons leading to paralysis state and long term disability. Riluzole is currently the only FDA-approved drug for the treatment of ALS. The proposed mechanisms of ALS include glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, protein aggregation, SOD1 accumulations, and neuronal death. In this review, we discuss potential biomarkers for the identification of patients with ALS. We further emphasize potential therapy involving the uses of neurotrophic factors such as IGF-I, GDNF, VEGF, ADNF-9, colivelin and angiogenin in the treatment of ALS. Moreover, we described several existing drugs such as talampanel, ceftriaxone, pramipexole, dexpramipexole and arimoclomol potential compounds for the treatment of ALS. Interestingly, the uses of stem cell therapy and immunotherapy are promising for the treatment of ALS.
    URL BibTeX

    @article{Yacila2014,
    	abstract = "Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder caused by damage of motoneurons leading to paralysis state and long term disability. Riluzole is currently the only FDA-approved drug for the treatment of ALS. The proposed mechanisms of ALS include glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, protein aggregation, SOD1 accumulations, and neuronal death. In this review, we discuss potential biomarkers for the identification of patients with ALS. We further emphasize potential therapy involving the uses of neurotrophic factors such as IGF-I, GDNF, VEGF, ADNF-9, colivelin and angiogenin in the treatment of ALS. Moreover, we described several existing drugs such as talampanel, ceftriaxone, pramipexole, dexpramipexole and arimoclomol potential compounds for the treatment of ALS. Interestingly, the uses of stem cell therapy and immunotherapy are promising for the treatment of ALS.",
    	author = "Yacila, Gladys and Sari, Youssef",
    	issn = "1875-533X",
    	journal = "Current medicinal chemistry",
    	month = "jun",
    	pmid = 24934355,
    	title = "{Potential Therapeutic Drugs and Methods for the Treatment of Amyotrophic Lateral Sclerosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24934355",
    	year = 2014
    }
    
  4. Lei Yang, Liang Yang, Wencong Tian, Jing Li, Jie Liu, Mengmeng Zhu, Yan Zhang, Yinan Yang, Fei Liu, Qiong Zhang, Qianqian Liu, Yanna Shen and Zhi Qi.
    Resveratrol plays dual roles in pancreatic cancer cells.. Journal of cancer research and clinical oncology 140(5):749–55, May 2014.
    Abstract PURPOSE: Although the potential anticancer effect of resveratrol (RSV) on pancreatic cancer has been reported, its mechanism was not fully understood. The role of vascular endothelial growth factor B (VEGF-B) in cancer remains controversial. Herein, we aimed to examine whether the anticancer effect of RSV was related to the VEGF-B. METHODS: The effect of RSV on pancreatic cancer cell line (capan-2 cells) was evaluated by CCK-8 assay, Hoechst 33342 staining, and flow cytometry. The mRNA level of VEGF-B was measured by real-time PCR. VEGF-B expression was knockdown by small interfering RNA (siRNA).The protein levels of VEGF-B, glycogen synthase kinase-3 beta (GSK-3$\beta$), and Bax were measured by Western blot. RESULTS: Resveratrol treatment inhibited tumor growth, induced apoptosis, and up-regulated Bax expression in capan-2 cells. The mRNA and protein levels of VEGF-B were up-regulated after RSV treatment. However, VEGF-B siRNA treatment increased the apoptotic rate, and inhibited tumor activator GSK-3$\beta$, while Bax expression was not affected. The combination of RSV and VEGF-B siRNA showed significantly higher apoptotic rate in comparison with RSV or VEGF-B siRNA mono-treatment group. CONCLUSIONS: Resveratrol plays dual roles in pancreatic cancer: as a tumor suppressor via the up-regulation of Bax; as a tumor activator via the up-regulation of VEGF-B; and the anticancer effect of RSV is much stronger than the cancer promotion effect. The combination of RSV with pharmacological inhibitor of VEGF-B might, therefore, be a promising modality for clinical pancreatic cancer therapy.
    URL, DOI BibTeX

    @article{Yang2014,
    	abstract = "PURPOSE: Although the potential anticancer effect of resveratrol (RSV) on pancreatic cancer has been reported, its mechanism was not fully understood. The role of vascular endothelial growth factor B (VEGF-B) in cancer remains controversial. Herein, we aimed to examine whether the anticancer effect of RSV was related to the VEGF-B. METHODS: The effect of RSV on pancreatic cancer cell line (capan-2 cells) was evaluated by CCK-8 assay, Hoechst 33342 staining, and flow cytometry. The mRNA level of VEGF-B was measured by real-time PCR. VEGF-B expression was knockdown by small interfering RNA (siRNA).The protein levels of VEGF-B, glycogen synthase kinase-3 beta (GSK-3$\beta$), and Bax were measured by Western blot. RESULTS: Resveratrol treatment inhibited tumor growth, induced apoptosis, and up-regulated Bax expression in capan-2 cells. The mRNA and protein levels of VEGF-B were up-regulated after RSV treatment. However, VEGF-B siRNA treatment increased the apoptotic rate, and inhibited tumor activator GSK-3$\beta$, while Bax expression was not affected. The combination of RSV and VEGF-B siRNA showed significantly higher apoptotic rate in comparison with RSV or VEGF-B siRNA mono-treatment group. CONCLUSIONS: Resveratrol plays dual roles in pancreatic cancer: as a tumor suppressor via the up-regulation of Bax; as a tumor activator via the up-regulation of VEGF-B; and the anticancer effect of RSV is much stronger than the cancer promotion effect. The combination of RSV with pharmacological inhibitor of VEGF-B might, therefore, be a promising modality for clinical pancreatic cancer therapy.",
    	author = "Yang, Lei and Yang, Liang and Tian, Wencong and Li, Jing and Liu, Jie and Zhu, Mengmeng and Zhang, Yan and Yang, Yinan and Liu, Fei and Zhang, Qiong and Liu, Qianqian and Shen, Yanna and Qi, Zhi",
    	doi = "10.1007/s00432-014-1624-4",
    	issn = "1432-1335",
    	journal = "Journal of cancer research and clinical oncology",
    	keywords = "Apoptosis,Apoptosis: drug effects,Cell Line, Tumor,Gene Expression Regulation, Neoplastic,Gene Expression Regulation, Neoplastic: drug effec,Glycogen Synthase Kinase 3,Glycogen Synthase Kinase 3: biosynthesis,Humans,Pancreatic Neoplasms,Pancreatic Neoplasms: drug therapy,Pancreatic Neoplasms: genetics,Pancreatic Neoplasms: pathology,RNA, Small Interfering,Stilbenes,Stilbenes: administration \& dosage,Vascular Endothelial Growth Factor B,Vascular Endothelial Growth Factor B: biosynthesis,Vascular Endothelial Growth Factor B: genetics,bcl-2-Associated X Protein,bcl-2-Associated X Protein: biosynthesis",
    	month = "may",
    	number = 5,
    	pages = "749--55",
    	pmid = 24604347,
    	title = "{Resveratrol plays dual roles in pancreatic cancer cells.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24604347",
    	volume = 140,
    	year = 2014
    }
    
  5. Philippe Corcia, Hélène Blasco and William Camu.
    [Genetics of amyotrophic lateral sclerosis].. Presse médicale (Paris, France : 1983) 43(5):555–62, May 2014.
    Abstract Although the pathophysiology of amyotrophic lateral sclerosis remains currently unknown, involvement of genetic factors is worldwide accepted as a key clue in the motor neuron death. Since 1993 and the discovery of mutation in the SOD1 gene, number of genes linked to or promoting ALS had always growing. Among them, only four (SOD1, TARDBP, FUS and C9ORF72 genes) are unanimously recognized as convincing causative genetic factors for more than 60% of familial and probably 10% of sporadic ALS cases. Geographic origin of the studied populations tends to become one of the major items in the gene-ALS relationship: this was extremely stressed for C9ORF72. Concerning susceptibility genes factors, an increase of the risk of ALS is clearly shown for SMN1 and ATXN2 genes and accepted for some VEGF haplotypes. Finally, some modulating effects might also exist as underline for the relationships between ApoE and ALS that differ between European and North American studies. In inherited ALS, The European Federation of Neurological Societies (EFNS) edited rules that gave a legal frame to situations for which research of mutations were justified. Progress in the field of genetic raises major questions concerning the relevance of genetic studies from asymptomatic relatives. This first implies that the mutation identified in the proband case is perfectly characterized as a pathogenic mutation.
    URL, DOI BibTeX

    @article{Corcia2014,
    	abstract = "Although the pathophysiology of amyotrophic lateral sclerosis remains currently unknown, involvement of genetic factors is worldwide accepted as a key clue in the motor neuron death. Since 1993 and the discovery of mutation in the SOD1 gene, number of genes linked to or promoting ALS had always growing. Among them, only four (SOD1, TARDBP, FUS and C9ORF72 genes) are unanimously recognized as convincing causative genetic factors for more than 60\% of familial and probably 10\% of sporadic ALS cases. Geographic origin of the studied populations tends to become one of the major items in the gene-ALS relationship: this was extremely stressed for C9ORF72. Concerning susceptibility genes factors, an increase of the risk of ALS is clearly shown for SMN1 and ATXN2 genes and accepted for some VEGF haplotypes. Finally, some modulating effects might also exist as underline for the relationships between ApoE and ALS that differ between European and North American studies. In inherited ALS, The European Federation of Neurological Societies (EFNS) edited rules that gave a legal frame to situations for which research of mutations were justified. Progress in the field of genetic raises major questions concerning the relevance of genetic studies from asymptomatic relatives. This first implies that the mutation identified in the proband case is perfectly characterized as a pathogenic mutation.",
    	author = "Corcia, Philippe and Blasco, H\'{e}l\`{e}ne and Camu, William",
    	doi = "10.1016/j.lpm.2014.01.012",
    	issn = "0755-4982",
    	journal = "Presse m\'{e}dicale (Paris, France : 1983)",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Humans",
    	month = "may",
    	number = 5,
    	pages = "555--62",
    	pmid = 24703222,
    	title = "{[Genetics of amyotrophic lateral sclerosis].}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24703222",
    	volume = 43,
    	year = 2014
    }
    
  6. Anton Valavanis, Urs Schwarz, Christian R Baumann, Michael Weller and Michael Linnebank.
    Amyotrophic lateral sclerosis after embolization of cerebral arterioveneous malformations.. Journal of neurology 261(4):732–7, April 2014.
    Abstract Cerebral arterioveneous malformations (AVM) can cause neurological symptoms and carry a risk of hemorrhage. Therapeutic options to cure or reduce AVM include surgery, embolization, irradiation, and combinations thereof. Prompted by three index cases treated in our center, we studied whether AVM embolization is associated with an increased risk of subsequent amyotrophic lateral sclerosis (ALS). In a monocenter series, we retrospectively analyzed the new development of ALS in patients who had been treated with embolization of cerebral AVM from 1986 to 2010 (n = 1,114). After a median follow-up of 11 years (range, 0-25 years) after first embolization, seven patients developed ALS with a median latency of 14 years (range, 12-17 years) and a median age of ALS onset of 38 years (range, 28-52 years). In all cases, the initial limb of ALS symptom onset was ipsilateral to the AVM. Five patients died within the follow-up period, with a range of 1-4 years after the onset of ALS symptoms. The seven patients belonged to a subgroup of 34 patients who had in common a rare AVM architecture characterized by significant perinidal angiogenesis. All cases were partially treated by at least three embolization sessions. As there is no known association between AVM and ALS, AVM embolization must be taken into account to have contributed to the development of ALS in the seven patients with this rare AVM architecture. Searching for underlying mechanisms, we compared frozen serum samples that were available from four of the patients who developed ALS, from eight patients with AVM of other architecture, and less than three embolizations who did not develop ALS, and of 20 controls. The concentration of vascular endothelial growth factor (VEGF) in the serum was lowest in AVM patients who developed ALS (245 ± 154 pmol/l) and highest in controls (409 ± 178 pmol/l). Although this difference was not statistically significant in the small sample, it suggests that low VEGF production by AVM with significant angiogenesis, possibly due to multiple embolization procedures, might have contributed to ALS development. ALS should be considered as a late complication of multiple embolizations of cerebral AVM characterized by significant perinidal angiogenesis.
    URL, DOI BibTeX

    @article{Valavanis2014,
    	abstract = "Cerebral arterioveneous malformations (AVM) can cause neurological symptoms and carry a risk of hemorrhage. Therapeutic options to cure or reduce AVM include surgery, embolization, irradiation, and combinations thereof. Prompted by three index cases treated in our center, we studied whether AVM embolization is associated with an increased risk of subsequent amyotrophic lateral sclerosis (ALS). In a monocenter series, we retrospectively analyzed the new development of ALS in patients who had been treated with embolization of cerebral AVM from 1986 to 2010 (n = 1,114). After a median follow-up of 11 years (range, 0-25 years) after first embolization, seven patients developed ALS with a median latency of 14 years (range, 12-17 years) and a median age of ALS onset of 38 years (range, 28-52 years). In all cases, the initial limb of ALS symptom onset was ipsilateral to the AVM. Five patients died within the follow-up period, with a range of 1-4 years after the onset of ALS symptoms. The seven patients belonged to a subgroup of 34 patients who had in common a rare AVM architecture characterized by significant perinidal angiogenesis. All cases were partially treated by at least three embolization sessions. As there is no known association between AVM and ALS, AVM embolization must be taken into account to have contributed to the development of ALS in the seven patients with this rare AVM architecture. Searching for underlying mechanisms, we compared frozen serum samples that were available from four of the patients who developed ALS, from eight patients with AVM of other architecture, and less than three embolizations who did not develop ALS, and of 20 controls. The concentration of vascular endothelial growth factor (VEGF) in the serum was lowest in AVM patients who developed ALS (245 ± 154 pmol/l) and highest in controls (409 ± 178 pmol/l). Although this difference was not statistically significant in the small sample, it suggests that low VEGF production by AVM with significant angiogenesis, possibly due to multiple embolization procedures, might have contributed to ALS development. ALS should be considered as a late complication of multiple embolizations of cerebral AVM characterized by significant perinidal angiogenesis.",
    	author = "Valavanis, Anton and Schwarz, Urs and Baumann, Christian R and Weller, Michael and Linnebank, Michael",
    	doi = "10.1007/s00415-014-7260-8",
    	issn = "1432-1459",
    	journal = "Journal of neurology",
    	month = "apr",
    	number = 4,
    	pages = "732--7",
    	pmid = 24509642,
    	title = "{Amyotrophic lateral sclerosis after embolization of cerebral arterioveneous malformations.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24509642",
    	volume = 261,
    	year = 2014
    }
    
  7. C Lunetta, V A Sansone, S Penco, L Mosca, C Tarlarini, F Avemaria, E Maestri, M G Melazzini, G Meola and M Corbo.
    Amyotrophic lateral sclerosis in pregnancy is associated with a vascular endothelial growth factor promoter genotype.. European journal of neurology : the official journal of the European Federation of Neurological Societies 21(4):594–8, April 2014.
    Abstract BACKGROUND AND PURPOSE: The occurrence of amyotrophic lateral sclerosis (ALS) during pregnancy is uncommon and the effect of one on the other is not well described. METHODS: The clinical and genetic features of five cases of ALS are reported with an onset during pregnancy or within 1 month from delivery. Charts from 239 women with a diagnosis of ALS attending the neuromuscular clinics at the Neuromuscular Omnicentre (NEMO) and at IRCCS Policlinico San Donato from 2008 to 2011 were reviewed. RESULTS: Of these, 12.8% of the women in child-bearing age had a diagnosis of ALS during pregnancy or immediately after delivery. Genetic screening of the major causative genes revealed two mutations in superoxide dismutase 1 (SOD1) gene; the analysis of vascular endothelial growth factor (VEGF) promoter variation showed a segregation of the haplotype CA/AG (-2578C/A; -1190A/G) in patients developing ALS related to pregnancy. No effects on foetal development or neonatal course were observed. CONCLUSIONS: Pregnancy may unmask ALS but whether this is coincidental is unclear. Hormonal and inflammatory modifications might trigger ALS in subjects with increased susceptibility to oxidative stress related to the toxic function of SOD1 or in subjects with a reduction of neuroprotective molecules such as VEGF.
    URL, DOI BibTeX

    @article{Lunetta2014,
    	abstract = "BACKGROUND AND PURPOSE: The occurrence of amyotrophic lateral sclerosis (ALS) during pregnancy is uncommon and the effect of one on the other is not well described. METHODS: The clinical and genetic features of five cases of ALS are reported with an onset during pregnancy or within 1 month from delivery. Charts from 239 women with a diagnosis of ALS attending the neuromuscular clinics at the Neuromuscular Omnicentre (NEMO) and at IRCCS Policlinico San Donato from 2008 to 2011 were reviewed. RESULTS: Of these, 12.8\% of the women in child-bearing age had a diagnosis of ALS during pregnancy or immediately after delivery. Genetic screening of the major causative genes revealed two mutations in superoxide dismutase 1 (SOD1) gene; the analysis of vascular endothelial growth factor (VEGF) promoter variation showed a segregation of the haplotype CA/AG (-2578C/A; -1190A/G) in patients developing ALS related to pregnancy. No effects on foetal development or neonatal course were observed. CONCLUSIONS: Pregnancy may unmask ALS but whether this is coincidental is unclear. Hormonal and inflammatory modifications might trigger ALS in subjects with increased susceptibility to oxidative stress related to the toxic function of SOD1 or in subjects with a reduction of neuroprotective molecules such as VEGF.",
    	author = "Lunetta, C and Sansone, V A and Penco, S and Mosca, L and Tarlarini, C and Avemaria, F and Maestri, E and Melazzini, M G and Meola, G and Corbo, M",
    	doi = "10.1111/ene.12345",
    	issn = "1468-1331",
    	journal = "European journal of neurology : the official journal of the European Federation of Neurological Societies",
    	month = "apr",
    	number = 4,
    	pages = "594--8",
    	pmid = 24471417,
    	title = "{Amyotrophic lateral sclerosis in pregnancy is associated with a vascular endothelial growth factor promoter genotype.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24471417",
    	volume = 21,
    	year = 2014
    }
    
  8. K Vijayalakshmi, Piyush Ostwal, R Sumitha, S Shruthi, Anu Mary Varghese, Poojashree Mishra, Gowri S Manohari, B C Sagar, T N Sathyaprabha, A Nalini, T R Raju and Phalguni Anand Alladi.
    Role of VEGF and VEGFR2 Receptor in Reversal of ALS-CSF Induced Degeneration of NSC-34 Motor Neuron Cell Line.. Molecular neurobiology, 2014.
    Abstract Vascular endothelial growth factor (VEGF), the well-known angiogenic factor is both neurotrophic and neuroprotective. Altered VEGF signalling is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal degenerative disease of motor neurons. We have shown earlier that VEGF protects NSC-34 motor neuronal cell line, when exposed to cerebrospinal fluid (CSF) from sporadic ALS patients (ALS-CSF). Here, we have investigated the consequences of ALS-CSF and VEGF supplementation on the VEGFR2 receptor and endogenous VEGF expression. ALS-CSF caused significant down-regulation of VEGFR2 as well as the Calbindin-D28K levels, but not endogenous VEGF. Exogenous supplementation restored the depletion of VEGFR2 and Calbindin-D28K with a concomitant up-regulation of endogenous VEGF. The up-regulated caspase 3 in the ALS-CSF group was reinstated to basal levels along with a significant reduction in the number of TUNEL-positive cells. Electron photomicrographs of ALS-CSF-exposed cells divulged presence of cytoplasmic vacuoles alongside severe damage to organelles like mitochondria, endoplasmic reticulum, etc. Substantial recovery of most of the damaged organelles was noted in response to VEGF supplementation. While the enhancement in endogenous VEGF levels highlights the autocrine functions, the up-regulation of VEGFR2 receptor emphasizes the paracrine functions of VEGF in modulating its neuroprotective effect against ALS-CSF. The revival of cellular organellar structure, increased calbindin expression and enhanced survival in response to VEGF supplementation consolidates the opinion that VEGF indeed has a therapeutic potential in sporadic ALS.
    URL, DOI BibTeX

    @article{Vijayalakshmi2014,
    	abstract = "Vascular endothelial growth factor (VEGF), the well-known angiogenic factor is both neurotrophic and neuroprotective. Altered VEGF signalling is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal degenerative disease of motor neurons. We have shown earlier that VEGF protects NSC-34 motor neuronal cell line, when exposed to cerebrospinal fluid (CSF) from sporadic ALS patients (ALS-CSF). Here, we have investigated the consequences of ALS-CSF and VEGF supplementation on the VEGFR2 receptor and endogenous VEGF expression. ALS-CSF caused significant down-regulation of VEGFR2 as well as the Calbindin-D28K levels, but not endogenous VEGF. Exogenous supplementation restored the depletion of VEGFR2 and Calbindin-D28K with a concomitant up-regulation of endogenous VEGF. The up-regulated caspase 3 in the ALS-CSF group was reinstated to basal levels along with a significant reduction in the number of TUNEL-positive cells. Electron photomicrographs of ALS-CSF-exposed cells divulged presence of cytoplasmic vacuoles alongside severe damage to organelles like mitochondria, endoplasmic reticulum, etc. Substantial recovery of most of the damaged organelles was noted in response to VEGF supplementation. While the enhancement in endogenous VEGF levels highlights the autocrine functions, the up-regulation of VEGFR2 receptor emphasizes the paracrine functions of VEGF in modulating its neuroprotective effect against ALS-CSF. The revival of cellular organellar structure, increased calbindin expression and enhanced survival in response to VEGF supplementation consolidates the opinion that VEGF indeed has a therapeutic potential in sporadic ALS.",
    	author = "Vijayalakshmi, K and Ostwal, Piyush and Sumitha, R and Shruthi, S and Varghese, Anu Mary and Mishra, Poojashree and Manohari, S Gowri and Sagar, B C and Sathyaprabha, T N and Nalini, A and Raju, T R and Alladi, Phalguni Anand",
    	doi = "10.1007/s12035-014-8757-y",
    	issn = "1559-1182",
    	journal = "Molecular neurobiology",
    	month = "",
    	pmid = 24880751,
    	title = "{Role of VEGF and VEGFR2 Receptor in Reversal of ALS-CSF Induced Degeneration of NSC-34 Motor Neuron Cell Line.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24880751",
    	year = 2014
    }
    
  9. Luis B Tovar-Y-Romo, Uri Nimrod Ram\'ırez-Jarqu\'ın, Rafael Lazo-Gómez and Ricardo Tapia.
    Trophic factors as modulators of motor neuron physiology and survival: implications for ALS therapy.. Frontiers in cellular neuroscience 8:61, January 2014.
    Abstract Motor neuron physiology and development depend on a continuous and tightly regulated trophic support from a variety of cellular sources. Trophic factors guide the generation and positioning of motor neurons during every stage of the developmental process. As well, they are involved in axon guidance and synapse formation. Even in the adult spinal cord an uninterrupted trophic input is required to maintain neuronal functioning and protection from noxious stimuli. Among the trophic factors that have been demonstrated to participate in motor neuron physiology are vascular endothelial growth factor (VEGF), glial-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF) and insulin-like growth factor 1 (IGF-1). Upon binding to membrane receptors expressed in motor neurons or neighboring glia, these trophic factors activate intracellular signaling pathways that promote cell survival and have protective action on motor neurons, in both in vivo and in vitro models of neuronal degeneration. For these reasons these factors have been considered a promising therapeutic method for amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, although their efficacy in human clinical trials have not yet shown the expected protection. In this minireview we summarize experimental data on the role of these trophic factors in motor neuron function and survival, as well as their mechanisms of action. We also briefly discuss the potential therapeutic use of the trophic factors and why these therapies may have not been yet successful in the clinical use.
    URL, DOI BibTeX

    @article{Tovar-Y-Romo2014,
    	abstract = "Motor neuron physiology and development depend on a continuous and tightly regulated trophic support from a variety of cellular sources. Trophic factors guide the generation and positioning of motor neurons during every stage of the developmental process. As well, they are involved in axon guidance and synapse formation. Even in the adult spinal cord an uninterrupted trophic input is required to maintain neuronal functioning and protection from noxious stimuli. Among the trophic factors that have been demonstrated to participate in motor neuron physiology are vascular endothelial growth factor (VEGF), glial-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF) and insulin-like growth factor 1 (IGF-1). Upon binding to membrane receptors expressed in motor neurons or neighboring glia, these trophic factors activate intracellular signaling pathways that promote cell survival and have protective action on motor neurons, in both in vivo and in vitro models of neuronal degeneration. For these reasons these factors have been considered a promising therapeutic method for amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, although their efficacy in human clinical trials have not yet shown the expected protection. In this minireview we summarize experimental data on the role of these trophic factors in motor neuron function and survival, as well as their mechanisms of action. We also briefly discuss the potential therapeutic use of the trophic factors and why these therapies may have not been yet successful in the clinical use.",
    	author = "Tovar-Y-Romo, Luis B and Ram\'{\i}rez-Jarqu\'{\i}n, Uri Nimrod and Lazo-G\'{o}mez, Rafael and Tapia, Ricardo",
    	doi = "10.3389/fncel.2014.00061",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Tovar-Y-Romo et al. - 2014 - Trophic factors as modulators of motor neuron physiology and survival implications for ALS therapy.pdf:pdf",
    	issn = "1662-5102",
    	journal = "Frontiers in cellular neuroscience",
    	month = "jan",
    	pages = 61,
    	pmid = 24616665,
    	title = "{Trophic factors as modulators of motor neuron physiology and survival: implications for ALS therapy.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3937589\&tool=pmcentrez\&rendertype=abstract",
    	volume = 8,
    	year = 2014
    }
    
  10. Ana Catarina Pronto-Laborinho, Susana Pinto and Mamede Carvalho.
    Roles of Vascular Endothelial Growth Factor in Amyotrophic Lateral Sclerosis.. BioMed research international 2014:947513, January 2014.
    Abstract Amyotrophic lateral sclerosis (ALS) is a fatal devastating neurodegenerative disorder, involving progressive degeneration of motor neurons in spinal cord, brainstem, and motor cortex. Riluzole is the only drug approved in ALS but it only confers a modest improvement in survival. In spite of a high number of clinical trials no other drug has proved effectiveness. Recent studies support that vascular endothelial growth factor (VEGF), originally described as a key angiogenic factor, also plays a key role in the nervous system, including neurogenesis, neuronal survival, neuronal migration, and axon guidance. VEGF has been used in exploratory clinical studies with promising results in ALS and other neurological disorders. Although VEGF is a very promising compound, translating the basic science breakthroughs into clinical practice is the major challenge ahead. VEGF-B, presenting a single safety profile, protects motor neurons from degeneration in ALS animal models and, therefore, it will be particularly interesting to test its effects in ALS patients. In the present paper the authors make a brief description of the molecular properties of VEGF and its receptors and review its different features and therapeutic potential in the nervous system/neurodegenerative disease, particularly in ALS.
    URL, DOI BibTeX

    @article{Pronto-Laborinho2014,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is a fatal devastating neurodegenerative disorder, involving progressive degeneration of motor neurons in spinal cord, brainstem, and motor cortex. Riluzole is the only drug approved in ALS but it only confers a modest improvement in survival. In spite of a high number of clinical trials no other drug has proved effectiveness. Recent studies support that vascular endothelial growth factor (VEGF), originally described as a key angiogenic factor, also plays a key role in the nervous system, including neurogenesis, neuronal survival, neuronal migration, and axon guidance. VEGF has been used in exploratory clinical studies with promising results in ALS and other neurological disorders. Although VEGF is a very promising compound, translating the basic science breakthroughs into clinical practice is the major challenge ahead. VEGF-B, presenting a single safety profile, protects motor neurons from degeneration in ALS animal models and, therefore, it will be particularly interesting to test its effects in ALS patients. In the present paper the authors make a brief description of the molecular properties of VEGF and its receptors and review its different features and therapeutic potential in the nervous system/neurodegenerative disease, particularly in ALS.",
    	author = "Pronto-Laborinho, Ana Catarina and Pinto, Susana and de Carvalho, Mamede",
    	doi = "10.1155/2014/947513",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Pronto-Laborinho, Pinto, de Carvalho - 2014 - Roles of Vascular Endothelial Growth Factor in Amyotrophic Lateral Sclerosis.pdf:pdf",
    	issn = "2314-6141",
    	journal = "BioMed research international",
    	month = "jan",
    	pages = 947513,
    	pmid = 24987705,
    	title = "{Roles of Vascular Endothelial Growth Factor in Amyotrophic Lateral Sclerosis.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4022172\&tool=pmcentrez\&rendertype=abstract",
    	volume = 2014,
    	year = 2014
    }
    
  11. Chengyuan Ma, Yang Li, Xianfeng Zhang, Gang Zhao and Haiyang Xu.
    Levels of vascular endothelial growth factor and matrix metalloproteinase-9 proteins in patients with glioma.. The Journal of international medical research 42(1):198–204, 2014.
    Abstract OBJECTIVE: To investigate the levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) proteins in patients with glioma, in order to determine if either protein has prognostic value. METHOD: The presence of VEGF and MMP-9 proteins in paraffin-embedded tumour specimens from patients with glioma was detected using immunohistochemistry. The correlation between the levels of VEGF and MMP-9 proteins and tumour grade was analysed. RESULTS: A total of 32 patients with low-grade gliomas (World Health Organization [WHO] grade II) and 48 patients with high-grade gliomas (WHO grades III-IV) participated in the study. Positive immunohistochemical staining of VEGF and MMP-9 proteins was detected in 58/80 (72.5%) and 60/80 (75.0%) of patients, respectively. The level of VEGF immunostaining was significantly positively correlated with the level of MMP-9 immunostaining (r = 0.78). Significantly more high-grade gliomas (grades III-IV) demonstrated positive VEGF and MMP-9 immunostaining compared with the low grade gliomas (grades I-II). CONCLUSIONS: These data suggest that VEGF and MMP-9 play an important role in the malignant behaviour of gliomas.
    URL, DOI BibTeX

    @article{Ma2014,
    	abstract = "OBJECTIVE: To investigate the levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) proteins in patients with glioma, in order to determine if either protein has prognostic value. METHOD: The presence of VEGF and MMP-9 proteins in paraffin-embedded tumour specimens from patients with glioma was detected using immunohistochemistry. The correlation between the levels of VEGF and MMP-9 proteins and tumour grade was analysed. RESULTS: A total of 32 patients with low-grade gliomas (World Health Organization [WHO] grade II) and 48 patients with high-grade gliomas (WHO grades III-IV) participated in the study. Positive immunohistochemical staining of VEGF and MMP-9 proteins was detected in 58/80 (72.5\%) and 60/80 (75.0\%) of patients, respectively. The level of VEGF immunostaining was significantly positively correlated with the level of MMP-9 immunostaining (r = 0.78). Significantly more high-grade gliomas (grades III-IV) demonstrated positive VEGF and MMP-9 immunostaining compared with the low grade gliomas (grades I-II). CONCLUSIONS: These data suggest that VEGF and MMP-9 play an important role in the malignant behaviour of gliomas.",
    	author = "Ma, Chengyuan and Li, Yang and Zhang, Xianfeng and Zhao, Gang and Xu, Haiyang",
    	doi = "10.1177/0300060513481924",
    	issn = "1473-2300",
    	journal = "The Journal of international medical research",
    	month = "",
    	number = 1,
    	pages = "198--204",
    	pmid = 24398760,
    	title = "{Levels of vascular endothelial growth factor and matrix metalloproteinase-9 proteins in patients with glioma.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24398760",
    	volume = 42,
    	year = 2014
    }
    
  12. Orion P Keifer, Deirdre M O'Connor and Nicholas M Boulis.
    Gene and protein therapies utilizing VEGF for ALS.. Pharmacology & therapeutics 141(3):261–71, 2014.
    Abstract Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is usually fatal within 2-5years. Unfortunately, the only treatment currently available is riluzole, which has a limited efficacy. As a redress, there is an expanding literature focusing on other potential treatments. One such potential treatment option utilizes the vascular endothelial growth factor (VEGF) family, which includes factors that are primarily associated with angiogenesis but are now increasingly recognized to have neurotrophic effects. Reduced expression of a member of this family, VEGF-A, in mice results in neurodegeneration similar to that of ALS, while treatment of animal models of ALS with either VEGF-A gene therapy or VEGF-A protein has yielded positive therapeutic outcomes. These basic research findings raise the potential for a VEGF therapy to be translated to the clinic for the treatment of ALS. This review covers the VEGF family, its receptors and neurotrophic effects as well as VEGF therapy in animal models of ALS and advances towards clinical trials.
    URL, DOI BibTeX

    @article{Keifer2014,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is usually fatal within 2-5years. Unfortunately, the only treatment currently available is riluzole, which has a limited efficacy. As a redress, there is an expanding literature focusing on other potential treatments. One such potential treatment option utilizes the vascular endothelial growth factor (VEGF) family, which includes factors that are primarily associated with angiogenesis but are now increasingly recognized to have neurotrophic effects. Reduced expression of a member of this family, VEGF-A, in mice results in neurodegeneration similar to that of ALS, while treatment of animal models of ALS with either VEGF-A gene therapy or VEGF-A protein has yielded positive therapeutic outcomes. These basic research findings raise the potential for a VEGF therapy to be translated to the clinic for the treatment of ALS. This review covers the VEGF family, its receptors and neurotrophic effects as well as VEGF therapy in animal models of ALS and advances towards clinical trials.",
    	author = "Keifer, Orion P and O'Connor, Deirdre M and Boulis, Nicholas M",
    	doi = "10.1016/j.pharmthera.2013.10.009",
    	issn = "1879-016X",
    	journal = "Pharmacology \& therapeutics",
    	month = "",
    	number = 3,
    	pages = "261--71",
    	pmid = 24177067,
    	title = "{Gene and protein therapies utilizing VEGF for ALS.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24177067",
    	volume = 141,
    	year = 2014
    }
    
  13. Rita Carilho, Mamede Carvalho, Michael Swash, Susana Pinto, Anabela Pinto and Júlia Costa.
    Vascular endothelial growth factor and amyotrophic lateral sclerosis: the interplay with exercise and noninvasive ventilation.. Muscle & nerve 49(4):545–50, 2014.
    Abstract INTRODUCTION: We evaluated plasma vascular endothelial growth factor (VEGF) levels in patients with amyotrophic lateral sclerosis (ALS) with reference to the effects of respiratory failure, noninvasive ventilation (NIV), and exercise. METHODS: We studied plasma VEGF levels in 83 ALS patients, 20 healthy controls, and 10 patients with other disorders. There were 4 groups of ALS patients: G1, 27 patients without respiratory problems; G2, 14 patients stabilized on nocturnal NIV; G3, 30 patients presenting with respiratory failure; G4, 12 patients on an aerobic exercise protocol. RESULTS: VEGF plasma levels did not differ significantly between ALS patients and controls, or between ALS groups. In G3, the mean VEGF levels increased 75% during NIV. In G4, the mean VEGF level increased by 300% during the exercise program. VEGF levels did not change during the course of the disease. CONCLUSIONS: VEGF levels in ALS depend on changes in ventilation and exercise but are probably not affected by the disease process itself.
    URL, DOI BibTeX

    @article{Carilho2014,
    	abstract = "INTRODUCTION: We evaluated plasma vascular endothelial growth factor (VEGF) levels in patients with amyotrophic lateral sclerosis (ALS) with reference to the effects of respiratory failure, noninvasive ventilation (NIV), and exercise. METHODS: We studied plasma VEGF levels in 83 ALS patients, 20 healthy controls, and 10 patients with other disorders. There were 4 groups of ALS patients: G1, 27 patients without respiratory problems; G2, 14 patients stabilized on nocturnal NIV; G3, 30 patients presenting with respiratory failure; G4, 12 patients on an aerobic exercise protocol. RESULTS: VEGF plasma levels did not differ significantly between ALS patients and controls, or between ALS groups. In G3, the mean VEGF levels increased 75\% during NIV. In G4, the mean VEGF level increased by 300\% during the exercise program. VEGF levels did not change during the course of the disease. CONCLUSIONS: VEGF levels in ALS depend on changes in ventilation and exercise but are probably not affected by the disease process itself.",
    	author = "Carilho, Rita and de Carvalho, Mamede and Swash, Michael and Pinto, Susana and Pinto, Anabela and Costa, J\'{u}lia",
    	doi = "10.1002/mus.23955",
    	issn = "1097-4598",
    	journal = "Muscle \& nerve",
    	keywords = "Aged,Aged, 80 and over,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: blood,Amyotrophic Lateral Sclerosis: diagnosis,Amyotrophic Lateral Sclerosis: therapy,Biological Markers,Biological Markers: blood,Exercise,Exercise Test,Exercise Test: methods,Exercise: physiology,Female,Humans,Male,Middle Aged,Noninvasive Ventilation,Noninvasive Ventilation: methods,Vascular Endothelial Growth Factor A,Vascular Endothelial Growth Factor A: blood",
    	month = "",
    	number = 4,
    	pages = "545--50",
    	pmid = 23868282,
    	title = "{Vascular endothelial growth factor and amyotrophic lateral sclerosis: the interplay with exercise and noninvasive ventilation.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23868282",
    	volume = 49,
    	year = 2014
    }
    
  14. Yuko Nagara, Takahisa Tateishi, Ryo Yamasaki, Shintaro Hayashi, Mami Kawamura, Hitoshi Kikuchi, Kyoko Motomura Iinuma, Masahito Tanaka, Toru Iwaki, Takuya Matsushita, Yasumasa Ohyagi and Jun-ichi Kira.
    Impaired cytoplasmic-nuclear transport of hypoxia-inducible factor-1$\alpha$ in amyotrophic lateral sclerosis.. Brain pathology (Zurich, Switzerland) 23(5):534–46, September 2013.
    Abstract We investigated the mechanisms underlying abnormal vascular endothelial growth factor (VEGF) production in amyotrophic lateral sclerosis (ALS). We immunohistochemically studied VEGF, its receptors VEGFR1 and 2, and hypoxia-inducible factor-1$\alpha$ (HIF-1$\alpha$) in autopsied ALS spinal cords. We also chronologically assessed the expression of HIF-1$\alpha$, karyopherin $\beta$1, karyopherin $\beta$-cargo protein complex inhibitors and nuclear pore complex proteins in G93A mutant superoxide dismutase 1 (mSOD1) transgenic mice at presymptomatic, symptomatic and end stages. In ALS patients, compared with controls, HIF-1$\alpha$ immunoreactivity in the cytoplasm of anterior horn cells (AHCs) was significantly increased, while immunoreactivities for VEGF and VEGFRs were significantly decreased. Similar changes in HIF-1$\alpha$ and VEGF levels were observed in mSOD1 transgenic mice. HIF-1$\alpha$ co-localized with karyopherin $\beta$1 in the cytoplasm of AHCs and karyopherin $\beta$1 co-localized with nucleoporin 62 (Nup62) on the nuclear envelope. From the presymptomatic stage of mSOD1 transgenic mice, karyopherin $\beta$1 immunoreactivity in AHC nuclei significantly decreased and morphological irregularities of the Nup62-immunostained nuclear envelope became more pronounced with disease progression. Thus, in AHCs from mSOD1 transgenic mice, transport of cytoplasmic HIF-1$\alpha$ to the nuclear envelope and into the nucleus is impaired from the presymptomatic stage, suggesting that impaired cytoplasmic-nuclear transport of HIF-1$\alpha$ through the nuclear pore might precede motor neuron degeneration.
    URL, DOI BibTeX

    @article{Nagara2013,
    	abstract = "We investigated the mechanisms underlying abnormal vascular endothelial growth factor (VEGF) production in amyotrophic lateral sclerosis (ALS). We immunohistochemically studied VEGF, its receptors VEGFR1 and 2, and hypoxia-inducible factor-1$\alpha$ (HIF-1$\alpha$) in autopsied ALS spinal cords. We also chronologically assessed the expression of HIF-1$\alpha$, karyopherin $\beta$1, karyopherin $\beta$-cargo protein complex inhibitors and nuclear pore complex proteins in G93A mutant superoxide dismutase 1 (mSOD1) transgenic mice at presymptomatic, symptomatic and end stages. In ALS patients, compared with controls, HIF-1$\alpha$ immunoreactivity in the cytoplasm of anterior horn cells (AHCs) was significantly increased, while immunoreactivities for VEGF and VEGFRs were significantly decreased. Similar changes in HIF-1$\alpha$ and VEGF levels were observed in mSOD1 transgenic mice. HIF-1$\alpha$ co-localized with karyopherin $\beta$1 in the cytoplasm of AHCs and karyopherin $\beta$1 co-localized with nucleoporin 62 (Nup62) on the nuclear envelope. From the presymptomatic stage of mSOD1 transgenic mice, karyopherin $\beta$1 immunoreactivity in AHC nuclei significantly decreased and morphological irregularities of the Nup62-immunostained nuclear envelope became more pronounced with disease progression. Thus, in AHCs from mSOD1 transgenic mice, transport of cytoplasmic HIF-1$\alpha$ to the nuclear envelope and into the nucleus is impaired from the presymptomatic stage, suggesting that impaired cytoplasmic-nuclear transport of HIF-1$\alpha$ through the nuclear pore might precede motor neuron degeneration.",
    	author = "Nagara, Yuko and Tateishi, Takahisa and Yamasaki, Ryo and Hayashi, Shintaro and Kawamura, Mami and Kikuchi, Hitoshi and Iinuma, Kyoko Motomura and Tanaka, Masahito and Iwaki, Toru and Matsushita, Takuya and Ohyagi, Yasumasa and Kira, Jun-ichi",
    	doi = "10.1111/bpa.12040",
    	issn = "1750-3639",
    	journal = "Brain pathology (Zurich, Switzerland)",
    	keywords = "Active Transport, Cell Nucleus,Aged,Aged, 80 and over,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Amyotrophic Lateral Sclerosis: physiopathology,Animals,Female,Gene Expression Regulation,Gene Expression Regulation: genetics,Glial Fibrillary Acidic Protein,Glial Fibrillary Acidic Protein: metabolism,Humans,Hypoxia-Inducible Factor 1, alpha Subunit,Hypoxia-Inducible Factor 1, alpha Subunit: metabol,Male,Membrane Glycoproteins,Membrane Glycoproteins: metabolism,Mice,Mice, Transgenic,Middle Aged,Mutation,Mutation: genetics,Nerve Tissue Proteins,Nerve Tissue Proteins: metabolism,Nuclear Pore Complex Proteins,Nuclear Pore Complex Proteins: metabolism,Phosphopyruvate Hydratase,Phosphopyruvate Hydratase: metabolism,Spinal Cord,Spinal Cord: metabolism,Spinal Cord: pathology,Superoxide Dismutase,Superoxide Dismutase: genetics,Vascular Endothelial Growth Factor A,Vascular Endothelial Growth Factor A: metabolism,Vascular Endothelial Growth Factor Receptor-1,Vascular Endothelial Growth Factor Receptor-1: gen,Vascular Endothelial Growth Factor Receptor-1: met,Vascular Endothelial Growth Factor Receptor-2,Vascular Endothelial Growth Factor Receptor-2: gen,Vascular Endothelial Growth Factor Receptor-2: met,beta Karyopherins,beta Karyopherins: metabolism",
    	month = "sep",
    	number = 5,
    	pages = "534--46",
    	pmid = 23368766,
    	title = "{Impaired cytoplasmic-nuclear transport of hypoxia-inducible factor-1$\alpha$ in amyotrophic lateral sclerosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23368766",
    	volume = 23,
    	year = 2013
    }
    
  15. M Kittaka, H Shiba, M Kajiya, K Ouhara, K Takeda, K Kanbara, T Fujita, H Kawaguchi, H Komatsuzawa and H Kurihara.
    Antimicrobial peptide LL37 promotes vascular endothelial growth factor-A expression in human periodontal ligament cells.. Journal of periodontal research 48(2):228–34, April 2013.
    Abstract BACKGROUND AND OBJECTIVE: LL37, originally found in the innate immune system, is a robust antimicrobial peptide. LL37 exhibits multiple bio-functions in various cell types, such as migration, cytokine production, apoptosis, and angiogenesis besides its antimicrobial activity Periodontal ligament (PL) cells play a pivotal role in periodontal tissue regeneration. Based on these findings, we hypothesized that LL37 can regulate PL cell function to promote regeneration of periodontal tissue. To prove this hypothesis, we investigated the effect of LL37 on the potent angiogenic inducer vascular endothelial growth factor (VEGF) expression in cultures of human PL (HPL) cells because neovascularization is indispensable for the progress of tissue regeneration. Moreover, we investigated the signaling cascade associated with LL37-induced VEGF expression. MATERIAL AND METHOD: HPL cells were treated with synthesized LL37 in the presence or absence of PD98059, a MEK-ERK inhibitor, or PDTC, an NF-$\kappa$B inhibitor. VEGF expression levels were assessed by real-time polymerase chain reaction analysis and an enzyme-linked immunoassay. Phosphorylation levels of ERK1/2 or NF-$\kappa$B p65 were determined by Western blotting. RESULTS: LL37 upregulated VEGF-A expression at the mRNA and protein levels in HPL cells, while VEGF-B mRNA expression was not affected. Both ERK and NF-$\kappa$B inhibitors clearly abrogated the increase in VEGF-A levels induced by LL37 in HPL cells. Importantly, LL37 increased phosphorylated levels of ERK1/2 and NF-$\kappa$B p65 in HPL cells. CONCLUSION: LL37 induces VEGF-A production in HPL cells via ERK and NF-$\kappa$B signaling cascades, which may result in angiogenesis, thereby contributing to periodontal regeneration.
    URL, DOI BibTeX

    @article{Kittaka2013,
    	abstract = "BACKGROUND AND OBJECTIVE: LL37, originally found in the innate immune system, is a robust antimicrobial peptide. LL37 exhibits multiple bio-functions in various cell types, such as migration, cytokine production, apoptosis, and angiogenesis besides its antimicrobial activity Periodontal ligament (PL) cells play a pivotal role in periodontal tissue regeneration. Based on these findings, we hypothesized that LL37 can regulate PL cell function to promote regeneration of periodontal tissue. To prove this hypothesis, we investigated the effect of LL37 on the potent angiogenic inducer vascular endothelial growth factor (VEGF) expression in cultures of human PL (HPL) cells because neovascularization is indispensable for the progress of tissue regeneration. Moreover, we investigated the signaling cascade associated with LL37-induced VEGF expression. MATERIAL AND METHOD: HPL cells were treated with synthesized LL37 in the presence or absence of PD98059, a MEK-ERK inhibitor, or PDTC, an NF-$\kappa$B inhibitor. VEGF expression levels were assessed by real-time polymerase chain reaction analysis and an enzyme-linked immunoassay. Phosphorylation levels of ERK1/2 or NF-$\kappa$B p65 were determined by Western blotting. RESULTS: LL37 upregulated VEGF-A expression at the mRNA and protein levels in HPL cells, while VEGF-B mRNA expression was not affected. Both ERK and NF-$\kappa$B inhibitors clearly abrogated the increase in VEGF-A levels induced by LL37 in HPL cells. Importantly, LL37 increased phosphorylated levels of ERK1/2 and NF-$\kappa$B p65 in HPL cells. CONCLUSION: LL37 induces VEGF-A production in HPL cells via ERK and NF-$\kappa$B signaling cascades, which may result in angiogenesis, thereby contributing to periodontal regeneration.",
    	author = "Kittaka, M and Shiba, H and Kajiya, M and Ouhara, K and Takeda, K and Kanbara, K and Fujita, T and Kawaguchi, H and Komatsuzawa, H and Kurihara, H",
    	doi = "10.1111/j.1600-0765.2012.01524.x",
    	issn = "1600-0765",
    	journal = "Journal of periodontal research",
    	keywords = "Anti-Bacterial Agents,Anti-Bacterial Agents: pharmacology,Calcium-Calmodulin-Dependent Protein Kinases,Calcium-Calmodulin-Dependent Protein Kinases: anta,Cathelicidins,Cathelicidins: pharmacology,Cell Culture Techniques,Cells, Cultured,Dose-Response Relationship, Drug,Flavonoids,Flavonoids: pharmacology,Humans,MAP Kinase Signaling System,MAP Kinase Signaling System: drug effects,Mitogen-Activated Protein Kinase 1,Mitogen-Activated Protein Kinase 1: analysis,NF-kappa B,NF-kappa B: analysis,NF-kappa B: antagonists \& inhibitors,Neovascularization, Physiologic,Neovascularization, Physiologic: drug effects,Periodontal Ligament,Periodontal Ligament: cytology,Periodontal Ligament: drug effects,Phosphorylation,Protein Kinase Inhibitors,Protein Kinase Inhibitors: pharmacology,Pyrrolidines,Pyrrolidines: pharmacology,Regeneration,Regeneration: drug effects,Signal Transduction,Signal Transduction: drug effects,Thiocarbamates,Thiocarbamates: pharmacology,Up-Regulation,Vascular Endothelial Growth Factor A,Vascular Endothelial Growth Factor A: antagonists ,Vascular Endothelial Growth Factor A: drug effects,eIF-2 Kinase,eIF-2 Kinase: analysis,p38 Mitogen-Activated Protein Kinases,p38 Mitogen-Activated Protein Kinases: analysis",
    	month = "apr",
    	number = 2,
    	pages = "228--34",
    	pmid = 22943069,
    	title = "{Antimicrobial peptide LL37 promotes vascular endothelial growth factor-A expression in human periodontal ligament cells.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/22943069",
    	volume = 48,
    	year = 2013
    }
    
  16. Robert Ringseis, Susann Rosenbaum, Denise K Gessner, Lea Herges, Johanna F Kubens, Frank-Christoph Mooren, Karsten Krüger and Klaus Eder.
    Supplementing obese Zucker rats with niacin induces the transition of glycolytic to oxidative skeletal muscle fibers.. The Journal of nutrition 143(2):125–31, February 2013.
    Abstract In the present study, we tested the hypothesis that niacin increases the oxidative capacity of muscle by increasing the oxidative type I muscle fiber content. Twenty-four obese Zucker rats were assigned to 2 groups of 12 rats that were fed either a control diet (O group) or a diet supplemented with 750 mg/kg diet niacin (O+N group) for 4 wk. In addition, one group of lean rats (L group) was included in the experiment and fed the control diet for 4 wk. Plasma and liver concentrations of TG were markedly greater in obese groups than in the L group but markedly lower in the O+N group than in the O group (P < 0.05). Rats of the O+N group had a higher percentage of oxidative type I fibers and higher mRNA levels of genes encoding regulators of muscle fiber composition (Ppard, Ppargc1a, Ppargc1b), angiogenic factors (Vegfa, Vegfb), and genes involved in fatty acid utilization (Cpt1b, Slc25a20, Slc22a4, Slc22a5, Slc27a1) and oxidative phosphorylation (Cox4i1, Cox6a2) and a higher activity of the mitochondrial oxidative enzyme succinate dehydrogenase in muscle than rats of the O and L groups (P < 0.05). These niacin-induced changes in muscle metabolic phenotype are indicative of an increased capacity of muscle for oxidative utilization of fatty acids and are likely mediated by the upregulation of Ppard, Ppargc1a, and Ppargc1b, which are key regulators of muscle fiber composition, mitochondrial biogenesis, angiogenesis, and genes involved in fatty acid catabolism and oxidative phosphorylation. The increased utilization of fatty acids by muscle might contribute to the strong TG-lowering effect of niacin treatment.
    URL, DOI BibTeX

    @article{Ringseis2013,
    	abstract = "In the present study, we tested the hypothesis that niacin increases the oxidative capacity of muscle by increasing the oxidative type I muscle fiber content. Twenty-four obese Zucker rats were assigned to 2 groups of 12 rats that were fed either a control diet (O group) or a diet supplemented with 750 mg/kg diet niacin (O+N group) for 4 wk. In addition, one group of lean rats (L group) was included in the experiment and fed the control diet for 4 wk. Plasma and liver concentrations of TG were markedly greater in obese groups than in the L group but markedly lower in the O+N group than in the O group (P < 0.05). Rats of the O+N group had a higher percentage of oxidative type I fibers and higher mRNA levels of genes encoding regulators of muscle fiber composition (Ppard, Ppargc1a, Ppargc1b), angiogenic factors (Vegfa, Vegfb), and genes involved in fatty acid utilization (Cpt1b, Slc25a20, Slc22a4, Slc22a5, Slc27a1) and oxidative phosphorylation (Cox4i1, Cox6a2) and a higher activity of the mitochondrial oxidative enzyme succinate dehydrogenase in muscle than rats of the O and L groups (P < 0.05). These niacin-induced changes in muscle metabolic phenotype are indicative of an increased capacity of muscle for oxidative utilization of fatty acids and are likely mediated by the upregulation of Ppard, Ppargc1a, and Ppargc1b, which are key regulators of muscle fiber composition, mitochondrial biogenesis, angiogenesis, and genes involved in fatty acid catabolism and oxidative phosphorylation. The increased utilization of fatty acids by muscle might contribute to the strong TG-lowering effect of niacin treatment.",
    	author = {Ringseis, Robert and Rosenbaum, Susann and Gessner, Denise K and Herges, Lea and Kubens, Johanna F and Mooren, Frank-Christoph and Kr\"{u}ger, Karsten and Eder, Klaus},
    	doi = "10.3945/jn.112.164038",
    	issn = "1541-6100",
    	journal = "The Journal of nutrition",
    	keywords = "Animals,Dietary Supplements,Gene Expression Regulation,Glycolysis,Hypolipidemic Agents,Hypolipidemic Agents: therapeutic use,Lipid Mobilization,Liver,Liver: metabolism,Male,Mitochondrial Turnover,Muscle Fibers, Slow-Twitch,Muscle Fibers, Slow-Twitch: enzymology,Muscle Fibers, Slow-Twitch: metabolism,Muscle Fibers, Slow-Twitch: pathology,Muscle Proteins,Muscle Proteins: genetics,Muscle Proteins: metabolism,Niacin,Niacin: therapeutic use,Obesity,Obesity: diet therapy,Obesity: metabolism,Obesity: pathology,Oxidation-Reduction,Oxidative Phosphorylation,RNA, Messenger,RNA, Messenger: metabolism,Random Allocation,Rats,Rats, Zucker,Triglycerides,Triglycerides: blood,Triglycerides: metabolism",
    	month = "feb",
    	number = 2,
    	pages = "125--31",
    	pmid = 23256146,
    	title = "{Supplementing obese Zucker rats with niacin induces the transition of glycolytic to oxidative skeletal muscle fibers.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23256146",
    	volume = 143,
    	year = 2013
    }
    
  17. M A Mukhamedyarov, A A Rizvanov, Z Z Safiullov, A A Izmailov, G A Sharifullina, V V Solovieva, Yu V Fedotova, I I Salafutdinov, E E Cherenkova, F V Bashirov, M S Kaligin, S R Abdulkhakov, M M Shmarov, Yu D Logunov, B S Naroditsky, A P Kiyasov, A L Zefirov and R R Islamov.
    Analysis of the efficiency of gene-cell therapy in transgenic mice with amyotrophic lateral sclerosis phenotype.. Bulletin of experimental biology and medicine 154(4):558–61, February 2013.
    Abstract Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by progressive death of cerebral and spinal motorneurons. Using behavioral tests we studied the efficiency of gene-cell therapy in SOD1 G93A transgenic mice receiving xenotransplantation of human umbilical cord blood mononuclear cells genetically modified with adenoviral vectors encoding vascular endothelial growth factor (VEGF) and reporter green fluorescent protein (EGFP) genes. The cells were transplanted to mice on week 27 of life (preclinical stage of the disease). Behavioral tests (open field, grip strength test) showed that transplantation of umbilical cord blood mononuclear cells expressing VEGF significantly improved the parameters of motor and explorative activity, grip strength, and animal survival. Thus, gene-cell therapy based on genetically modified mononuclear cells expressing VEGF can be efficient for the treatment of amyotrophic lateral sclerosis.
    URL BibTeX

    @article{Mukhamedyarov2013,
    	abstract = "Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by progressive death of cerebral and spinal motorneurons. Using behavioral tests we studied the efficiency of gene-cell therapy in SOD1 G93A transgenic mice receiving xenotransplantation of human umbilical cord blood mononuclear cells genetically modified with adenoviral vectors encoding vascular endothelial growth factor (VEGF) and reporter green fluorescent protein (EGFP) genes. The cells were transplanted to mice on week 27 of life (preclinical stage of the disease). Behavioral tests (open field, grip strength test) showed that transplantation of umbilical cord blood mononuclear cells expressing VEGF significantly improved the parameters of motor and explorative activity, grip strength, and animal survival. Thus, gene-cell therapy based on genetically modified mononuclear cells expressing VEGF can be efficient for the treatment of amyotrophic lateral sclerosis.",
    	author = "Mukhamedyarov, M A and Rizvanov, A A and Safiullov, Z Z and Izmailov, A A and Sharifullina, G A and Solovieva, V V and Fedotova, V Yu and Salafutdinov, I I and Cherenkova, E E and Bashirov, F V and Kaligin, M S and Abdulkhakov, S R and Shmarov, M M and Logunov, D Yu and Naroditsky, B S and Kiyasov, A P and Zefirov, A L and Islamov, R R",
    	issn = "1573-8221",
    	journal = "Bulletin of experimental biology and medicine",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: physiopathology,Amyotrophic Lateral Sclerosis: therapy,Animals,Cell- and Tissue-Based Therapy,Cell- and Tissue-Based Therapy: methods,Genetic Therapy,Genetic Therapy: methods,Humans,Mice,Mice, Transgenic,Superoxide Dismutase,Superoxide Dismutase: genetics,Superoxide Dismutase: metabolism,Transplantation, Heterologous,Vascular Endothelial Growth Factor A,Vascular Endothelial Growth Factor A: genetics,Vascular Endothelial Growth Factor A: metabolism",
    	month = "feb",
    	number = 4,
    	pages = "558--61",
    	pmid = 23486603,
    	title = "{Analysis of the efficiency of gene-cell therapy in transgenic mice with amyotrophic lateral sclerosis phenotype.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23486603",
    	volume = 154,
    	year = 2013
    }
    
  18. Diana Wiesner, Irma Merdian, Jan Lewerenz, Albert C Ludolph, Luc Dupuis and Anke Witting.
    Fumaric acid esters stimulate astrocytic VEGF expression through HIF-1$\alpha$ and Nrf2.. PloS one 8(10):e76670, January 2013.
    Abstract Fumaric acid esters (FAE) are oral analogs of fumarate that have recently been shown to decrease relapse rate and disease progression in multiple sclerosis (MS), prompting to investigate their protective potential in other neurological diseases such as amyotrophic lateral sclerosis (ALS). Despite efficacy in MS, mechanisms of action of FAEs are still largely unknown. FAEs are known to activate the transcription factor Nrf2 and downstream anti-oxidant responses through the succination of Nrf2 inhibitor KEAP1. However, fumarate is also a known inhibitor of prolyl-hydroxylases domain enzymes (PhD), and PhD inhibition might lead to stabilization of the HIF-1$\alpha$ transcription factor under normoxic conditions and subsequent activation of a pseudo hypoxic response. Whether Nrf2 activation is associated with HIF-1$\alpha$ stabilization in response to FAEs in cell types relevant to MS or ALS remains unknown. Here, we show that FAEs elicit HIF-1$\alpha$ accumulation, and VEGF release as its expected consequence, in astrocytes but not in other cell types of the central nervous system. Reporter assays demonstrated that increased astrocytic VEGF release in response to FAEs was dependent upon both HIF-1$\alpha$ and Nrf2 activation. Last, astrocytes of transgenic mice expressing SOD1(G93A), an animal model of ALS, displayed reduced VEGF release in response to FAEs. These studies show that FAEs elicit different signaling pathways in cell types from the central nervous system, in particular a pseudo-hypoxic response in astrocytes. Disease relevant mutations might affect this response.
    URL, DOI BibTeX

    @article{Wiesner2013,
    	abstract = "Fumaric acid esters (FAE) are oral analogs of fumarate that have recently been shown to decrease relapse rate and disease progression in multiple sclerosis (MS), prompting to investigate their protective potential in other neurological diseases such as amyotrophic lateral sclerosis (ALS). Despite efficacy in MS, mechanisms of action of FAEs are still largely unknown. FAEs are known to activate the transcription factor Nrf2 and downstream anti-oxidant responses through the succination of Nrf2 inhibitor KEAP1. However, fumarate is also a known inhibitor of prolyl-hydroxylases domain enzymes (PhD), and PhD inhibition might lead to stabilization of the HIF-1$\alpha$ transcription factor under normoxic conditions and subsequent activation of a pseudo hypoxic response. Whether Nrf2 activation is associated with HIF-1$\alpha$ stabilization in response to FAEs in cell types relevant to MS or ALS remains unknown. Here, we show that FAEs elicit HIF-1$\alpha$ accumulation, and VEGF release as its expected consequence, in astrocytes but not in other cell types of the central nervous system. Reporter assays demonstrated that increased astrocytic VEGF release in response to FAEs was dependent upon both HIF-1$\alpha$ and Nrf2 activation. Last, astrocytes of transgenic mice expressing SOD1(G93A), an animal model of ALS, displayed reduced VEGF release in response to FAEs. These studies show that FAEs elicit different signaling pathways in cell types from the central nervous system, in particular a pseudo-hypoxic response in astrocytes. Disease relevant mutations might affect this response.",
    	author = "Wiesner, Diana and Merdian, Irma and Lewerenz, Jan and Ludolph, Albert C and Dupuis, Luc and Witting, Anke",
    	doi = "10.1371/journal.pone.0076670",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Wiesner et al. - 2013 - Fumaric acid esters stimulate astrocytic VEGF expression through HIF-1$\alpha$ and Nrf2.pdf:pdf",
    	issn = "1932-6203",
    	journal = "PloS one",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Animals,Astrocytes,Astrocytes: drug effects,Astrocytes: metabolism,Astrocytes: pathology,Cells, Cultured,Disease Models, Animal,Female,Fumarates,Fumarates: pharmacology,Gene Expression Regulation,Gene Expression Regulation: drug effects,Hypoxia-Inducible Factor 1, alpha Subunit,Hypoxia-Inducible Factor 1, alpha Subunit: genetic,Hypoxia-Inducible Factor 1, alpha Subunit: metabol,Male,Mice,Mice, Transgenic,Mutation,NF-E2-Related Factor 2,NF-E2-Related Factor 2: genetics,NF-E2-Related Factor 2: metabolism,Organ Specificity,Signal Transduction,Superoxide Dismutase,Superoxide Dismutase: genetics,Superoxide Dismutase: metabolism,Vascular Endothelial Growth Factor A,Vascular Endothelial Growth Factor A: agonists,Vascular Endothelial Growth Factor A: genetics,Vascular Endothelial Growth Factor A: metabolism",
    	month = "jan",
    	number = 10,
    	pages = "e76670",
    	pmid = 24098549,
    	title = "{Fumaric acid esters stimulate astrocytic VEGF expression through HIF-1$\alpha$ and Nrf2.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3789659\&tool=pmcentrez\&rendertype=abstract",
    	volume = 8,
    	year = 2013
    }
    
  19. Hui Sun, Karelle Bénardais, Nancy Stanslowsky, Nadine Thau-Habermann, Niko Hensel, Dongya Huang, Peter Claus, Reinhard Dengler, Martin Stangel and Susanne Petri.
    Therapeutic potential of mesenchymal stromal cells and MSC conditioned medium in Amyotrophic Lateral Sclerosis (ALS)–in vitro evidence from primary motor neuron cultures, NSC-34 cells, astrocytes and microglia.. PloS one 8(9):e72926, January 2013.
    Abstract Administration of mesenchymal stromal cells (MSC) improves functional outcome in the SOD1G93A mouse model of the degenerative motor neuron disorder amyotrophic lateral sclerosis (ALS) as well as in models of other neurological disorders. We have now investigated the effect of the interaction between MSC and motor neurons (derived from both non-transgenic and mutant SOD1G93A transgenic mice), NSC-34 cells and glial cells (astrocytes, microglia) (derived again from both non-transgenic and mutant SOD1G93A ALS transgenic mice) in vitro. In primary motor neurons, NSC-34 cells and astrocytes, MSC conditioned medium (MSC CM) attenuated staurosporine (STS) - induced apoptosis in a concentration-dependent manner. Studying MSC CM-induced expression of neurotrophic factors in astrocytes and NSC-34 cells, we found that glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) gene expression in astrocytes were significantly enhanced by MSC CM, with differential responses of non-transgenic and mutant astrocytes. Expression of Vascular Endothelial Growth Factor (VEGF) in NSC-34 cells was significantly upregulated upon MSC CM-treatment. MSC CM significantly reduced the expression of the cytokines TNF$\alpha$ and IL-6 and iNOS both in transgenic and non-transgenic astrocytes. Gene expression of the neuroprotective chemokine Fractalkine (CX3CL1) was also upregulated in mutant SOD1G93A transgenic astrocytes by MSC CM treatment. Correspondingly, MSC CM increased the respective receptor, CX3CR1, in mutant SOD1G93A transgenic microglia. Our data demonstrate that MSC modulate motor neuronal and glial response to apoptosis and inflammation. MSC therefore represent an interesting candidate for further preclinical and clinical evaluation in ALS.
    URL, DOI BibTeX

    @article{Sun2013,
    	abstract = "Administration of mesenchymal stromal cells (MSC) improves functional outcome in the SOD1G93A mouse model of the degenerative motor neuron disorder amyotrophic lateral sclerosis (ALS) as well as in models of other neurological disorders. We have now investigated the effect of the interaction between MSC and motor neurons (derived from both non-transgenic and mutant SOD1G93A transgenic mice), NSC-34 cells and glial cells (astrocytes, microglia) (derived again from both non-transgenic and mutant SOD1G93A ALS transgenic mice) in vitro. In primary motor neurons, NSC-34 cells and astrocytes, MSC conditioned medium (MSC CM) attenuated staurosporine (STS) - induced apoptosis in a concentration-dependent manner. Studying MSC CM-induced expression of neurotrophic factors in astrocytes and NSC-34 cells, we found that glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) gene expression in astrocytes were significantly enhanced by MSC CM, with differential responses of non-transgenic and mutant astrocytes. Expression of Vascular Endothelial Growth Factor (VEGF) in NSC-34 cells was significantly upregulated upon MSC CM-treatment. MSC CM significantly reduced the expression of the cytokines TNF$\alpha$ and IL-6 and iNOS both in transgenic and non-transgenic astrocytes. Gene expression of the neuroprotective chemokine Fractalkine (CX3CL1) was also upregulated in mutant SOD1G93A transgenic astrocytes by MSC CM treatment. Correspondingly, MSC CM increased the respective receptor, CX3CR1, in mutant SOD1G93A transgenic microglia. Our data demonstrate that MSC modulate motor neuronal and glial response to apoptosis and inflammation. MSC therefore represent an interesting candidate for further preclinical and clinical evaluation in ALS.",
    	author = "Sun, Hui and B\'{e}nardais, Karelle and Stanslowsky, Nancy and Thau-Habermann, Nadine and Hensel, Niko and Huang, Dongya and Claus, Peter and Dengler, Reinhard and Stangel, Martin and Petri, Susanne",
    	doi = "10.1371/journal.pone.0072926",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Sun et al. - 2013 - Therapeutic potential of mesenchymal stromal cells and MSC conditioned medium in Amyotrophic Lateral Sclerosis (ALS).pdf:pdf",
    	issn = "1932-6203",
    	journal = "PloS one",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: metabolism,Animals,Apoptosis,Apoptosis: drug effects,Astrocytes,Astrocytes: drug effects,Astrocytes: metabolism,Cells, Cultured,Chemokine CX3CL1,Chemokine CX3CL1: metabolism,Ciliary Neurotrophic Factor,Ciliary Neurotrophic Factor: metabolism,Culture Media, Conditioned,Culture Media, Conditioned: pharmacology,Glial Cell Line-Derived Neurotrophic Factors,Glial Cell Line-Derived Neurotrophic Factors: meta,Humans,Mesenchymal Stromal Cells,Mesenchymal Stromal Cells: drug effects,Mesenchymal Stromal Cells: metabolism,Mice,Microglia,Microglia: drug effects,Microglia: metabolism,Motor Neurons,Motor Neurons: drug effects,Motor Neurons: metabolism,Staurosporine,Staurosporine: pharmacology",
    	month = "jan",
    	number = 9,
    	pages = "e72926",
    	pmid = 24069165,
    	title = "{Therapeutic potential of mesenchymal stromal cells and MSC conditioned medium in Amyotrophic Lateral Sclerosis (ALS)--in vitro evidence from primary motor neuron cultures, NSC-34 cells, astrocytes and microglia.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3771979\&tool=pmcentrez\&rendertype=abstract",
    	volume = 8,
    	year = 2013
    }
    
  20. Jerònia Lladó, Laia Tolosa and Gabriel Olmos.
    Cellular and molecular mechanisms involved in the neuroprotective effects of VEGF on motoneurons.. Frontiers in cellular neuroscience 7:181, January 2013.
    Abstract Vascular endothelial growth factor (VEGF), originally described as a factor with a regulatory role in vascular growth and development, it is also known for its direct effects on neuronal cells. The discovery in the past decade that transgenic mice expressing reduced levels of VEGF developed late-onset motoneuron pathology, reminiscent of amyotrophic lateral sclerosis (ALS), opened a new field of research on this disease. VEGF has been shown to protect motoneurons from excitotoxic death, which is a relevant mechanism involved in motoneuron degeneration in ALS. Thus, VEGF delays motoneuron degeneration and increases survival in animal models of ALS. VEGF exerts its anti-excitotoxic effects on motoneurons through molecular mechanisms involving the VEGF receptor-2 resulting in the activation of the PI3-K/Akt signaling pathway, upregulation of GluR2 subunit of AMPA receptors, inhibition of p38MAPK, and induction of the anti-apoptotic molecule Bcl-2. In addition, VEGF acts on astrocytes to reduce astroglial activation and to induce the release of growth factors. The potential use of VEGF as a therapeutic tool in ALS is counteracted by its vascular effects and by its short effective time frame. More studies are needed to assess the optimal isoform, route of administration, and time frame for using VEGF in the treatment of ALS.
    URL, DOI BibTeX

    @article{Llado2013,
    	abstract = "Vascular endothelial growth factor (VEGF), originally described as a factor with a regulatory role in vascular growth and development, it is also known for its direct effects on neuronal cells. The discovery in the past decade that transgenic mice expressing reduced levels of VEGF developed late-onset motoneuron pathology, reminiscent of amyotrophic lateral sclerosis (ALS), opened a new field of research on this disease. VEGF has been shown to protect motoneurons from excitotoxic death, which is a relevant mechanism involved in motoneuron degeneration in ALS. Thus, VEGF delays motoneuron degeneration and increases survival in animal models of ALS. VEGF exerts its anti-excitotoxic effects on motoneurons through molecular mechanisms involving the VEGF receptor-2 resulting in the activation of the PI3-K/Akt signaling pathway, upregulation of GluR2 subunit of AMPA receptors, inhibition of p38MAPK, and induction of the anti-apoptotic molecule Bcl-2. In addition, VEGF acts on astrocytes to reduce astroglial activation and to induce the release of growth factors. The potential use of VEGF as a therapeutic tool in ALS is counteracted by its vascular effects and by its short effective time frame. More studies are needed to assess the optimal isoform, route of administration, and time frame for using VEGF in the treatment of ALS.",
    	author = "Llad\'{o}, Jer\`{o}nia and Tolosa, Laia and Olmos, Gabriel",
    	doi = "10.3389/fncel.2013.00181",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Llad\'{o}, Tolosa, Olmos - 2013 - Cellular and molecular mechanisms involved in the neuroprotective effects of VEGF on motoneurons.pdf:pdf",
    	issn = "1662-5102",
    	journal = "Frontiers in cellular neuroscience",
    	month = "jan",
    	pages = 181,
    	pmid = 24155688,
    	title = "{Cellular and molecular mechanisms involved in the neuroprotective effects of VEGF on motoneurons.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3803143\&tool=pmcentrez\&rendertype=abstract",
    	volume = 7,
    	year = 2013
    }
    
  21. Dan Krakora, Patrick Mulcrone, Michael Meyer, Christina Lewis, Ksenija Bernau, Genevieve Gowing, Chad Zimprich, Patrick Aebischer, Clive N Svendsen and Masatoshi Suzuki.
    Synergistic effects of GDNF and VEGF on lifespan and disease progression in a familial ALS rat model.. Molecular therapy : the journal of the American Society of Gene Therapy 21(8):1602–10, 2013.
    Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons in the brain and spinal cord. We have recently shown that human mesenchymal stem cells (hMSCs) modified to release glial cell line-derived neurotrophic factor (GDNF) decrease disease progression in a rat model of ALS when delivered to skeletal muscle. In the current study, we determined whether or not this effect could be enhanced by delivering GDNF in concert with other trophic factors. hMSC engineered to secrete GDNF (hMSC-GDNF), vascular endothelial growth factor (hMSC-VEGF), insulin-like growth factor-I (hMSC-IGF-I), or brain-derived neurotrophic factor (hMSC-BDNF), were prepared and transplanted bilaterally into three muscle groups. hMSC-GDNF and hMSC-VEGF prolonged survival and slowed the loss of motor function, but hMSC-IGF-I and hMSC-BDNF did not have any effect. We then tested the efficacy of a combined ex vivo delivery of GDNF and VEGF in extending survival and protecting neuromuscular junctions (NMJs) and motor neurons. Interestingly, the combined delivery of these neurotrophic factors showed a strong synergistic effect. These studies further support ex vivo gene therapy approaches for ALS that target skeletal muscle.
    URL, DOI BibTeX

    @article{Krakora2013,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons in the brain and spinal cord. We have recently shown that human mesenchymal stem cells (hMSCs) modified to release glial cell line-derived neurotrophic factor (GDNF) decrease disease progression in a rat model of ALS when delivered to skeletal muscle. In the current study, we determined whether or not this effect could be enhanced by delivering GDNF in concert with other trophic factors. hMSC engineered to secrete GDNF (hMSC-GDNF), vascular endothelial growth factor (hMSC-VEGF), insulin-like growth factor-I (hMSC-IGF-I), or brain-derived neurotrophic factor (hMSC-BDNF), were prepared and transplanted bilaterally into three muscle groups. hMSC-GDNF and hMSC-VEGF prolonged survival and slowed the loss of motor function, but hMSC-IGF-I and hMSC-BDNF did not have any effect. We then tested the efficacy of a combined ex vivo delivery of GDNF and VEGF in extending survival and protecting neuromuscular junctions (NMJs) and motor neurons. Interestingly, the combined delivery of these neurotrophic factors showed a strong synergistic effect. These studies further support ex vivo gene therapy approaches for ALS that target skeletal muscle.",
    	author = "Krakora, Dan and Mulcrone, Patrick and Meyer, Michael and Lewis, Christina and Bernau, Ksenija and Gowing, Genevieve and Zimprich, Chad and Aebischer, Patrick and Svendsen, Clive N and Suzuki, Masatoshi",
    	doi = "10.1038/mt.2013.108",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Krakora et al. - 2013 - Synergistic effects of GDNF and VEGF on lifespan and disease progression in a familial ALS rat model.pdf:pdf",
    	issn = "1525-0024",
    	journal = "Molecular therapy : the journal of the American Society of Gene Therapy",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: mortality,Animals,Cell Survival,Cell Survival: genetics,Disease Models, Animal,Disease Progression,Female,Gene Expression,Gene Transfer Techniques,Genetic Therapy,Glial Cell Line-Derived Neurotrophic Factor,Glial Cell Line-Derived Neurotrophic Factor: genet,Humans,Longevity,Longevity: genetics,Male,Mesenchymal Stem Cell Transplantation,Mesenchymal Stromal Cells,Mesenchymal Stromal Cells: metabolism,Motor Neurons,Motor Neurons: metabolism,Muscle, Skeletal,Muscle, Skeletal: metabolism,Neuromuscular Junction,Neuromuscular Junction: metabolism,Rats,Vascular Endothelial Growth Factor A,Vascular Endothelial Growth Factor A: genetics",
    	month = "",
    	number = 8,
    	pages = "1602--10",
    	pmid = 23712039,
    	title = "{Synergistic effects of GDNF and VEGF on lifespan and disease progression in a familial ALS rat model.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3734670\&tool=pmcentrez\&rendertype=abstract",
    	volume = 21,
    	year = 2013
    }
    
  22. Akshay Anand, Keshav Thakur and Pawan Kumar Gupta.
    ALS and oxidative stress: the neurovascular scenario.. Oxidative medicine and cellular longevity 2013:635831, 2013.
    Abstract Oxidative stress and angiogenic factors have been placed as the prime focus of scientific investigations after an establishment of link between vascular endothelial growth factor promoter (VEGF), hypoxia, and amyotrophic lateral sclerosis (ALS) pathogenesis. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter and mutant superoxide dismutase 1 (SOD1) which are characterised by atrophy and muscle weakness resulted in phenotype resembling human ALS in mice. This results in lower motor neurodegeneration thus establishing an important link between motor neuron degeneration, vasculature, and angiogenic molecules. In this review, we have presented human, animal, and in vitro studies which suggest that molecules like VEGF have a therapeutic, diagnostic, and prognostic potential in ALS. Involvement of vascular growth factors and hypoxia response elements also highlights the converging role of oxidative stress and neurovascular network for understanding and treatment of various neurodegenerative disorders like ALS.
    URL, DOI BibTeX

    @article{Anand2013,
    	abstract = "Oxidative stress and angiogenic factors have been placed as the prime focus of scientific investigations after an establishment of link between vascular endothelial growth factor promoter (VEGF), hypoxia, and amyotrophic lateral sclerosis (ALS) pathogenesis. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter and mutant superoxide dismutase 1 (SOD1) which are characterised by atrophy and muscle weakness resulted in phenotype resembling human ALS in mice. This results in lower motor neurodegeneration thus establishing an important link between motor neuron degeneration, vasculature, and angiogenic molecules. In this review, we have presented human, animal, and in vitro studies which suggest that molecules like VEGF have a therapeutic, diagnostic, and prognostic potential in ALS. Involvement of vascular growth factors and hypoxia response elements also highlights the converging role of oxidative stress and neurovascular network for understanding and treatment of various neurodegenerative disorders like ALS.",
    	author = "Anand, Akshay and Thakur, Keshav and Gupta, Pawan Kumar",
    	doi = "10.1155/2013/635831",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Anand, Thakur, Gupta - 2013 - ALS and oxidative stress the neurovascular scenario.pdf:pdf",
    	issn = "1942-0994",
    	journal = "Oxidative medicine and cellular longevity",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: pathology,Animals,Blood-Brain Barrier,Blood-Brain Barrier: metabolism,Blood-Brain Barrier: pathology,Humans,Motor Neurons,Motor Neurons: metabolism,Motor Neurons: pathology,Nervous System,Nervous System: blood supply,Nervous System: pathology,Oxidative Stress,Vascular Endothelial Growth Factor A,Vascular Endothelial Growth Factor A: metabolism",
    	month = "",
    	pages = 635831,
    	pmid = 24367722,
    	title = "{ALS and oxidative stress: the neurovascular scenario.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3866720\&tool=pmcentrez\&rendertype=abstract",
    	volume = 2013,
    	year = 2013
    }
    
  23. Kota Sato, Nobutoshi Morimoto, Tomoko Kurata, Takafumi Mimoto, Kazunori Miyazaki, Yoshio Ikeda and Koji Abe.
    Impaired response of hypoxic sensor protein HIF-1$\alpha$ and its downstream proteins in the spinal motor neurons of ALS model mice.. Brain research 1473:55–62, September 2012.
    Abstract We have recently reported spinal blood flow-metabolism uncoupling in an amyotrophic lateral sclerosis (ALS) animal model using Cu/Zn-superoxide dismutase 1 (SOD1)-transgenic (Tg) mice, suggesting a relative hypoxia in the spinal cord. However, the hypoxic stress sensor pathway has not been well studied in ALS. Here, we examined temporal and spatial changes of the hypoxic stress sensor proteins HIF-1$\alpha$ and its downstream proteins (VEGF, HO-1, and EPO) during the normoxiccourse of motor neuron (MN) degeneration in the spinal cord of these ALS model mice. We found that HIF-1$\alpha$ protein expression progressively increased both in the anterior large MNs and the surrounding glial cells in Tg mice from early symptomatic 14 week (W) and end stage 18 W. Double immunofluorescence analysis revealed that HIF-1$\alpha$, plus GFAP and Iba-1 double-positive surrounding glial cells, progressively increased from 14 W to 18 W, although the immunohistochemistry in large MNs did not change. Expression levels of VEGF and HO-1 also showed a progressive increase but were significant only in the surrounding glial cells at 18 W. In contrast, EPO protein expression was decreased in the surrounding glial cells of Tg mice at 18 W. Because HIF1-$\alpha$ serves as an important mediator of the hypoxic response, these findings indicate that MNs lack the neuroprotective response to hypoxic stress through the HIF-1$\alpha$ system, which could be an important mechanism of neurodegeneration in ALS.
    URL, DOI BibTeX

    @article{Sato2012,
    	abstract = "We have recently reported spinal blood flow-metabolism uncoupling in an amyotrophic lateral sclerosis (ALS) animal model using Cu/Zn-superoxide dismutase 1 (SOD1)-transgenic (Tg) mice, suggesting a relative hypoxia in the spinal cord. However, the hypoxic stress sensor pathway has not been well studied in ALS. Here, we examined temporal and spatial changes of the hypoxic stress sensor proteins HIF-1$\alpha$ and its downstream proteins (VEGF, HO-1, and EPO) during the normoxiccourse of motor neuron (MN) degeneration in the spinal cord of these ALS model mice. We found that HIF-1$\alpha$ protein expression progressively increased both in the anterior large MNs and the surrounding glial cells in Tg mice from early symptomatic 14 week (W) and end stage 18 W. Double immunofluorescence analysis revealed that HIF-1$\alpha$, plus GFAP and Iba-1 double-positive surrounding glial cells, progressively increased from 14 W to 18 W, although the immunohistochemistry in large MNs did not change. Expression levels of VEGF and HO-1 also showed a progressive increase but were significant only in the surrounding glial cells at 18 W. In contrast, EPO protein expression was decreased in the surrounding glial cells of Tg mice at 18 W. Because HIF1-$\alpha$ serves as an important mediator of the hypoxic response, these findings indicate that MNs lack the neuroprotective response to hypoxic stress through the HIF-1$\alpha$ system, which could be an important mechanism of neurodegeneration in ALS.",
    	author = "Sato, Kota and Morimoto, Nobutoshi and Kurata, Tomoko and Mimoto, Takafumi and Miyazaki, Kazunori and Ikeda, Yoshio and Abe, Koji",
    	doi = "10.1016/j.brainres.2012.07.040",
    	issn = "1872-6240",
    	journal = "Brain research",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Animals,Blotting, Western,Cell Hypoxia,Cell Hypoxia: physiology,Disease Models, Animal,Erythropoietin,Erythropoietin: biosynthesis,Fluorescent Antibody Technique,Heme Oxygenase-1,Heme Oxygenase-1: biosynthesis,Hypoxia-Inducible Factor 1, alpha Subunit,Hypoxia-Inducible Factor 1, alpha Subunit: biosynt,Mice,Mice, Transgenic,Motor Neurons,Motor Neurons: metabolism,Motor Neurons: pathology,Neuroglia,Neuroglia: metabolism,Neuroglia: pathology,Spinal Cord,Spinal Cord: metabolism,Spinal Cord: pathology,Superoxide Dismutase,Superoxide Dismutase: genetics,Vascular Endothelial Growth Factor A,Vascular Endothelial Growth Factor A: biosynthesis",
    	month = "sep",
    	pages = "55--62",
    	pmid = 22871270,
    	title = "{Impaired response of hypoxic sensor protein HIF-1$\alpha$ and its downstream proteins in the spinal motor neurons of ALS model mice.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/22871270",
    	volume = 1473,
    	year = 2012
    }
    
  24. Claudia Colombrita, Elisa Onesto, Francesca Megiorni, Antonio Pizzuti, Francisco E Baralle, Emanuele Buratti, Vincenzo Silani and Antonia Ratti.
    TDP-43 and FUS RNA-binding proteins bind distinct sets of cytoplasmic messenger RNAs and differently regulate their post-transcriptional fate in motoneuron-like cells.. The Journal of biological chemistry 287(19):15635–47, May 2012.
    Abstract The RNA-binding proteins TDP-43 and FUS form abnormal cytoplasmic aggregates in affected tissues of patients with amyotrophic lateral sclerosis and frontotemporal lobar dementia. TDP-43 and FUS localize mainly in the nucleus where they regulate pre-mRNA splicing, but they are also involved in mRNA transport, stability, and translation. To better investigate their cytoplasmic activities, we applied an RNA immunoprecipitation and chip analysis to define the mRNAs associated to TDP-43 and FUS in the cytoplasmic ribonucleoprotein complexes from motoneuronal NSC-34 cells. We found that they bind different sets of mRNAs although converging on common cellular pathways. Bioinformatics analyses identified the (UG)(n) consensus motif in 80% of 3'-UTR sequences of TDP-43 targets, whereas for FUS the binding motif was less evident. By in vitro assays we validated binding to selected target 3'-UTRs, including Vegfa and Grn for TDP-43, and Vps54, Nvl, and Taf15 for FUS. We showed that TDP-43 has a destabilizing activity on Vegfa and Grn mRNAs and may ultimately affect progranulin protein content, whereas FUS does not affect mRNA stability/translation of its targets. We also demonstrated that three different point mutations in TDP-43 did not change the binding affinity for Vegfa and Grn mRNAs or their protein level. Our data indicate that TDP-43 and FUS recognize distinct sets of mRNAs and differently regulate their fate in the cytoplasm of motoneuron-like cells, therefore suggesting complementary roles in neuronal RNA metabolism and neurodegeneration.
    URL, DOI BibTeX

    @article{Colombrita2012,
    	abstract = "The RNA-binding proteins TDP-43 and FUS form abnormal cytoplasmic aggregates in affected tissues of patients with amyotrophic lateral sclerosis and frontotemporal lobar dementia. TDP-43 and FUS localize mainly in the nucleus where they regulate pre-mRNA splicing, but they are also involved in mRNA transport, stability, and translation. To better investigate their cytoplasmic activities, we applied an RNA immunoprecipitation and chip analysis to define the mRNAs associated to TDP-43 and FUS in the cytoplasmic ribonucleoprotein complexes from motoneuronal NSC-34 cells. We found that they bind different sets of mRNAs although converging on common cellular pathways. Bioinformatics analyses identified the (UG)(n) consensus motif in 80\% of 3'-UTR sequences of TDP-43 targets, whereas for FUS the binding motif was less evident. By in vitro assays we validated binding to selected target 3'-UTRs, including Vegfa and Grn for TDP-43, and Vps54, Nvl, and Taf15 for FUS. We showed that TDP-43 has a destabilizing activity on Vegfa and Grn mRNAs and may ultimately affect progranulin protein content, whereas FUS does not affect mRNA stability/translation of its targets. We also demonstrated that three different point mutations in TDP-43 did not change the binding affinity for Vegfa and Grn mRNAs or their protein level. Our data indicate that TDP-43 and FUS recognize distinct sets of mRNAs and differently regulate their fate in the cytoplasm of motoneuron-like cells, therefore suggesting complementary roles in neuronal RNA metabolism and neurodegeneration.",
    	author = "Colombrita, Claudia and Onesto, Elisa and Megiorni, Francesca and Pizzuti, Antonio and Baralle, Francisco E and Buratti, Emanuele and Silani, Vincenzo and Ratti, Antonia",
    	doi = "10.1074/jbc.M111.333450",
    	issn = "1083-351X",
    	journal = "The Journal of biological chemistry",
    	keywords = "3' Untranslated Regions,3' Untranslated Regions: genetics,Animals,Blotting, Western,Cell Line,Cytoplasm,Cytoplasm: genetics,Cytoplasm: metabolism,DNA-Binding Proteins,DNA-Binding Proteins: genetics,DNA-Binding Proteins: metabolism,Humans,Immunoprecipitation,Intercellular Signaling Peptides and Proteins,Intercellular Signaling Peptides and Proteins: gen,Intercellular Signaling Peptides and Proteins: met,Mice,Motor Neurons,Motor Neurons: cytology,Motor Neurons: metabolism,Mutation,Nucleotide Motifs,Nucleotide Motifs: genetics,Oligonucleotide Array Sequence Analysis,Protein Binding,Protein Biosynthesis,RNA Interference,RNA Stability,RNA, Messenger,RNA, Messenger: genetics,RNA, Messenger: metabolism,RNA-Binding Protein FUS,RNA-Binding Protein FUS: genetics,RNA-Binding Protein FUS: metabolism,Reverse Transcriptase Polymerase Chain Reaction,TATA-Binding Protein Associated Factors,TATA-Binding Protein Associated Factors: genetics,TATA-Binding Protein Associated Factors: metabolis,Vascular Endothelial Growth Factor A,Vascular Endothelial Growth Factor A: genetics,Vascular Endothelial Growth Factor A: metabolism,Vesicular Transport Proteins,Vesicular Transport Proteins: genetics,Vesicular Transport Proteins: metabolism",
    	month = "may",
    	number = 19,
    	pages = "15635--47",
    	pmid = 22427648,
    	title = "{TDP-43 and FUS RNA-binding proteins bind distinct sets of cytoplasmic messenger RNAs and differently regulate their post-transcriptional fate in motoneuron-like cells.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3346140\&tool=pmcentrez\&rendertype=abstract",
    	volume = 287,
    	year = 2012
    }
    
  25. Luis B Tovar-y-Romo and Ricardo Tapia.
    Delayed administration of VEGF rescues spinal motor neurons from death with a short effective time frame in excitotoxic experimental models in vivo.. ASN neuro 4(2), January 2012.
    Abstract VEGF (vascular endothelial growth factor) prevents neuronal death in different models of ALS (amyotrophic lateral sclerosis), but few studies have addressed the efficacy of VEGF to protect motor neurons after the onset of symptoms, a critical point when considering VEGF as a potential therapeutic target for ALS. We studied the capability of VEGF to protect motor neurons after an excitotoxic challenge in two models of spinal neurodegeneration in rats induced by AMPA ($\alpha$-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) administered either chronically with osmotic minipumps or acutely by microdialysis. VEGF was administered through osmotic minipumps in the chronic model or injected intracerebroventricularly in the acute model, and its effects were assessed by immunohistochemical and histological analyses and motor performance tests. In the chronic model, VEGF stopped the progression of the paralysis and protected motor neurons when administered after AMPA before the onset of the motor symptoms, whereas no protection was observed when administered after the onset. VEGF was also protective in the acute model, but with a short time window, since the protection was effective when administered 1 h but not 2 h after AMPA. Our results indicate that while VEGF has an indubitable neuroprotective effect, its therapeutic potential for halting or delaying the progression of motor neuron loss in ALS would likely have a short effective time frame.
    URL, DOI BibTeX

    @article{Tovar-y-Romo2012,
    	abstract = "VEGF (vascular endothelial growth factor) prevents neuronal death in different models of ALS (amyotrophic lateral sclerosis), but few studies have addressed the efficacy of VEGF to protect motor neurons after the onset of symptoms, a critical point when considering VEGF as a potential therapeutic target for ALS. We studied the capability of VEGF to protect motor neurons after an excitotoxic challenge in two models of spinal neurodegeneration in rats induced by AMPA ($\alpha$-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) administered either chronically with osmotic minipumps or acutely by microdialysis. VEGF was administered through osmotic minipumps in the chronic model or injected intracerebroventricularly in the acute model, and its effects were assessed by immunohistochemical and histological analyses and motor performance tests. In the chronic model, VEGF stopped the progression of the paralysis and protected motor neurons when administered after AMPA before the onset of the motor symptoms, whereas no protection was observed when administered after the onset. VEGF was also protective in the acute model, but with a short time window, since the protection was effective when administered 1 h but not 2 h after AMPA. Our results indicate that while VEGF has an indubitable neuroprotective effect, its therapeutic potential for halting or delaying the progression of motor neuron loss in ALS would likely have a short effective time frame.",
    	author = "Tovar-y-Romo, Luis B and Tapia, Ricardo",
    	doi = "10.1042/AN20110057",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Tovar-y-Romo, Tapia - 2012 - Delayed administration of VEGF rescues spinal motor neurons from death with a short effective time frame in.pdf:pdf",
    	issn = "1759-0914",
    	journal = "ASN neuro",
    	keywords = "Analysis of Variance,Animals,Brain-Derived Neurotrophic Factor,Brain-Derived Neurotrophic Factor: administration ,Cell Death,Cell Death: drug effects,Choline O-Acetyltransferase,Choline O-Acetyltransferase: metabolism,Disease Models, Animal,Drug Administration Routes,Drug Administration Schedule,Drug Delivery Systems,Excitatory Amino Acid Agonists,Excitatory Amino Acid Agonists: toxicity,Glial Fibrillary Acidic Protein,Glial Fibrillary Acidic Protein: metabolism,Male,Microdialysis,Motor Activity,Motor Activity: drug effects,Motor Activity: physiology,Motor Neurons,Motor Neurons: drug effects,Motor Neurons: metabolism,Nerve Degeneration,Nerve Degeneration: drug therapy,Nerve Degeneration: etiology,Paralysis,Paralysis: etiology,Paralysis: prevention \& control,Rats,Rats, Wistar,Spinal Cord Diseases,Spinal Cord Diseases: chemically induced,Spinal Cord Diseases: complications,Spinal Cord Diseases: drug therapy,Spinal Cord Diseases: pathology,Time Factors,Vascular Endothelial Growth Factor A,Vascular Endothelial Growth Factor A: administrati,alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropioni",
    	month = "jan",
    	number = 2,
    	pmid = 22369757,
    	title = "{Delayed administration of VEGF rescues spinal motor neurons from death with a short effective time frame in excitotoxic experimental models in vivo.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3314302\&tool=pmcentrez\&rendertype=abstract",
    	volume = 4,
    	year = 2012
    }
    
  26. E V Lysogorskaia, Iu N Abramycheva, M N Zakharova and S N Illarioshkin.
    [Association between the VEGF -2578С/A polymorphism and amyotrophic lateral sclerosis in a Russian population].. Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova / Ministerstvo zdravookhraneniia i meditsinskoĭ promyshlennosti Rossiĭskoĭ Federatsii, Vserossiĭskoe obshchestvo nevrologov [i] Vserossiĭskoe obshchestvo psikhiatrov 112(11):42–5, January 2012.
    Abstract {Genetic predisposition plays an important role in the development of amyotrophic lateral sclerosis (ALS). One of the most promising candidate genes in ALS is the vascular endothelial growth factor (VEGF) gene. In a Russian population, 192 ALS patients (103 males and 89 females), aged from 20 to 83 years (52.0±13.4), were examined. A control group comprised 128 age- and sex-matched people. All individuals studied were Slavs. Polymorphism -2578С/А (rs699947) in the VEGF gene was studied by real-time PCR. It was shown that the genotype distribution was significantly different between the ALS and control groups ($\chi$2=11.1; р=0.004); in the ALS cohort, the 2578A/A genotype was significantly more frequent (29.7% vs. 20.3%
    URL BibTeX

    @article{Lysogorskaia2012,
    	abstract = "{Genetic predisposition plays an important role in the development of amyotrophic lateral sclerosis (ALS). One of the most promising candidate genes in ALS is the vascular endothelial growth factor (VEGF) gene. In a Russian population, 192 ALS patients (103 males and 89 females), aged from 20 to 83 years (52.0±13.4), were examined. A control group comprised 128 age- and sex-matched people. All individuals studied were Slavs. Polymorphism -2578С/А (rs699947) in the VEGF gene was studied by real-time PCR. It was shown that the genotype distribution was significantly different between the ALS and control groups ($\chi$2=11.1; р=0.004); in the ALS cohort, the 2578A/A genotype was significantly more frequent (29.7\% vs. 20.3\%",
    	p = "",
    	author = "Lysogorskaia, E V and Abramycheva, N Iu and Zakharova, M N and Illarioshkin, S N",
    	issn = "1997-7298",
    	journal = "Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova / Ministerstvo zdravookhraneniia i meditsinskoĭ promyshlennosti Rossiĭskoĭ Federatsii, Vserossiĭskoe obshchestvo nevrologov [i] Vserossiĭskoe obshchestvo psikhiatrov",
    	keywords = "Adult,Aged,Aged, 80 and over,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: epidemiology,Amyotrophic Lateral Sclerosis: genetics,Female,Gene Frequency,Genetic Predisposition to Disease,Humans,Male,Middle Aged,Polymorphism, Genetic,Population,Russia,Russia: epidemiology,Vascular Endothelial Growth Factor A,Vascular Endothelial Growth Factor A: genetics,Young Adult",
    	month = "jan",
    	number = 11,
    	pages = "42--5",
    	pmid = 23257745,
    	title = "{[Association between the VEGF -2578С/A polymorphism and amyotrophic lateral sclerosis in a Russian population].}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23257745",
    	volume = 112,
    	year = 2012
    }
    
  27. Himshikha Bhutani and Akshay Anand.
    Biomarkers in amyotrophic lateral sclerosis: is there a neurovascular pathway?. Current neurovascular research 9(4):302–9, 2012.
    Abstract The establishment of a link between VEGF, hypoxia and ALS pathogenesis placed angiogenic factors and oxidative stress at the focal point for further studies. Recreation of a phenotype strikingly similar to that of mutant SOD1 mouse and human ALS, like muscle weakness and atrophy owing to lower motor neuron degeneration was observed following the targeted deletion of the hypoxia response element (HRE) from promoter of mouse vascular endothelial growth factor (VEGF). The crucial link between vasculature, angiogenic molecules and motor neuron degeneration has thus been constantly scrutinized. In this review, we have proposed to correlate human, in vitro and cadaveric studies so as to find out whether molecules like VEGF and various others, at the interface of neurovascular network and oxidative stress, have a prognostic, diagnostic and therapeutic potential for treatment of a fatal neurodegenerative disorder namely ALS.
    URL BibTeX

    @article{Bhutani2012,
    	abstract = "The establishment of a link between VEGF, hypoxia and ALS pathogenesis placed angiogenic factors and oxidative stress at the focal point for further studies. Recreation of a phenotype strikingly similar to that of mutant SOD1 mouse and human ALS, like muscle weakness and atrophy owing to lower motor neuron degeneration was observed following the targeted deletion of the hypoxia response element (HRE) from promoter of mouse vascular endothelial growth factor (VEGF). The crucial link between vasculature, angiogenic molecules and motor neuron degeneration has thus been constantly scrutinized. In this review, we have proposed to correlate human, in vitro and cadaveric studies so as to find out whether molecules like VEGF and various others, at the interface of neurovascular network and oxidative stress, have a prognostic, diagnostic and therapeutic potential for treatment of a fatal neurodegenerative disorder namely ALS.",
    	author = "Bhutani, Himshikha and Anand, Akshay",
    	issn = "1875-5739",
    	journal = "Current neurovascular research",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Amyotrophic Lateral Sclerosis: physiopathology,Animals,Biological Markers,Biological Markers: metabolism,Cell Hypoxia,Cell Hypoxia: physiology,Humans,Neurons,Neurons: pathology,Oxidative Stress,Oxidative Stress: physiology,Signal Transduction,Signal Transduction: physiology,Vascular Endothelial Growth Factor A,Vascular Endothelial Growth Factor A: metabolism",
    	month = "",
    	number = 4,
    	pages = "302--9",
    	pmid = 22873722,
    	title = "{Biomarkers in amyotrophic lateral sclerosis: is there a neurovascular pathway?}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/22873722",
    	volume = 9,
    	year = 2012
    }
    
  28. A Anand, P K Gupta, N K Sharma and S Prabhakar.
    Soluble VEGFR1 (sVEGFR1) as a novel marker of amyotrophic lateral sclerosis (ALS) in the North Indian ALS patients.. European journal of neurology : the official journal of the European Federation of Neurological Societies 19(5):788–92, 2012.
    Abstract BACKGROUND AND PURPOSE:   North Indian patients with amyotrophic lateral sclerosis (ALS) exhibit substantially extended survival time after onset of the disease as compared to their Western counterparts. Earlier, we found that vascular endothelial growth factor-A (VEGF-A) may be associated with increased survival of these patients. We now measured soluble vascular endothelial growth factor receptor-1 (sVEGFR1), an inhibitor receptor for VEGF-A, in these patients with ALS. METHODS: Patients with sporadic ALS (n = 36) attending the Neurology Outpatient at Post Graduate Institute of Medical Education and Research (PGIMER) at Chandigarh were included on the basis of El Escorial criteria. The sVEGFR1 levels were analyzed in serum of these patients using enzyme-linked immunosorbent assay (ELISA) and compared with normal controls (n = 36). RESULTS:   Soluble vascular endothelial growth factor receptor-1 was found to be decreased significantly in serum of patients with ALS. Serum obtained from definite ALS revealed significantly lower sVEGFR1 as compared to probable ALS. However, there was no difference in serum sVEGFR1 levels between male and female patients with ALS. CONCLUSIONS: Soluble vascular endothelial growth factor receptor-1 downregulation may result in increased serum VEGF-A reported previously in our patients with ALS and may indicate the activation of compensatory mechanism in response to neurodegeneration. The lower serum sVEGFR1 levels may have a possible clinicopathological association, if not causal, to the extended survival of North Indian patients with ALS; however, the result needs further investigations particularly in comparable Caucasian ALS population.
    URL, DOI BibTeX

    @article{Anand2012,
    	abstract = "BACKGROUND AND PURPOSE:   North Indian patients with amyotrophic lateral sclerosis (ALS) exhibit substantially extended survival time after onset of the disease as compared to their Western counterparts. Earlier, we found that vascular endothelial growth factor-A (VEGF-A) may be associated with increased survival of these patients. We now measured soluble vascular endothelial growth factor receptor-1 (sVEGFR1), an inhibitor receptor for VEGF-A, in these patients with ALS. METHODS: Patients with sporadic ALS (n = 36) attending the Neurology Outpatient at Post Graduate Institute of Medical Education and Research (PGIMER) at Chandigarh were included on the basis of El Escorial criteria. The sVEGFR1 levels were analyzed in serum of these patients using enzyme-linked immunosorbent assay (ELISA) and compared with normal controls (n = 36). RESULTS:   Soluble vascular endothelial growth factor receptor-1 was found to be decreased significantly in serum of patients with ALS. Serum obtained from definite ALS revealed significantly lower sVEGFR1 as compared to probable ALS. However, there was no difference in serum sVEGFR1 levels between male and female patients with ALS. CONCLUSIONS: Soluble vascular endothelial growth factor receptor-1 downregulation may result in increased serum VEGF-A reported previously in our patients with ALS and may indicate the activation of compensatory mechanism in response to neurodegeneration. The lower serum sVEGFR1 levels may have a possible clinicopathological association, if not causal, to the extended survival of North Indian patients with ALS; however, the result needs further investigations particularly in comparable Caucasian ALS population.",
    	author = "Anand, A and Gupta, P K and Sharma, N K and Prabhakar, S",
    	doi = "10.1111/j.1468-1331.2011.03548.x",
    	issn = "1468-1331",
    	journal = "European journal of neurology : the official journal of the European Federation of Neurological Societies",
    	keywords = "Adult,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: blood,Amyotrophic Lateral Sclerosis: ethnology,Enzyme-Linked Immunosorbent Assay,Female,Humans,Indians, North American,Male,Middle Aged,Vascular Endothelial Growth Factor Receptor-1,Vascular Endothelial Growth Factor Receptor-1: blo",
    	month = "",
    	number = 5,
    	pages = "788--92",
    	pmid = 21978169,
    	title = "{Soluble VEGFR1 (sVEGFR1) as a novel marker of amyotrophic lateral sclerosis (ALS) in the North Indian ALS patients.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/21978169",
    	volume = 19,
    	year = 2012
    }
    
  29. Michele A Kliem, Brenten L Heeke, Colin K Franz, Igor Radovitskiy, Bethwel Raore, Emily Barrow, Brooke R Snyder, Thais Federici, S Kaye Spratt and Nicholas M Boulis.
    Intramuscular administration of a VEGF zinc finger transcription factor activator (VEGF-ZFP-TF) improves functional outcomes in SOD1 rats.. Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases 12(5):331–9, September 2011.
    Abstract Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron loss leading to paralysis and death. Vascular endothelial growth factor (VEGF) has angiogenic, neurotrophic, and neuroprotective properties, and has preserved neuromuscular function and protected motor neurons in rats engineered to overexpress the human gene coding the mutated G93A form of the superoxide dismutase-1 (SOD1). We assessed the effects of intramuscular administration of a plasmid that encodes a zinc finger protein transcription factor (ZFP-TF) engineered to induce VEGF expression in the SOD1 rat model of ALS. Weekly injections of the plasmid preserved ipsilateral hindlimb grip strength and markedly improved rotarod performance in SOD1 rats compared to the vehicle-treated group. The number of motor neurons and the proportion of innervated neuromuscular junctions were similar in both groups. In conclusion, our data suggest that administration of the VEGF-ZFP-TF may be neuroprotective and has potential as a safe and practical approach for the management of motor disability in ALS.
    URL, DOI BibTeX

    @article{Kliem2011,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron loss leading to paralysis and death. Vascular endothelial growth factor (VEGF) has angiogenic, neurotrophic, and neuroprotective properties, and has preserved neuromuscular function and protected motor neurons in rats engineered to overexpress the human gene coding the mutated G93A form of the superoxide dismutase-1 (SOD1). We assessed the effects of intramuscular administration of a plasmid that encodes a zinc finger protein transcription factor (ZFP-TF) engineered to induce VEGF expression in the SOD1 rat model of ALS. Weekly injections of the plasmid preserved ipsilateral hindlimb grip strength and markedly improved rotarod performance in SOD1 rats compared to the vehicle-treated group. The number of motor neurons and the proportion of innervated neuromuscular junctions were similar in both groups. In conclusion, our data suggest that administration of the VEGF-ZFP-TF may be neuroprotective and has potential as a safe and practical approach for the management of motor disability in ALS.",
    	author = "Kliem, Michele A and Heeke, Brenten L and Franz, Colin K and Radovitskiy, Igor and Raore, Bethwel and Barrow, Emily and Snyder, Brooke R and Federici, Thais and {Kaye Spratt}, S and Boulis, Nicholas M",
    	doi = "10.3109/17482968.2011.574142",
    	issn = "1471-180X",
    	journal = "Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: therapy,Animals,Disease Models, Animal,Female,Genetic Therapy,Genetic Therapy: methods,Humans,Injections, Intramuscular,Male,Muscle, Skeletal,Muscle, Skeletal: physiology,Rats,Rats, Transgenic,Superoxide Dismutase,Superoxide Dismutase: biosynthesis,Superoxide Dismutase: genetics,Superoxide Dismutase: physiology,Transcription Factors,Transcription Factors: administration \& dosage,Transcription Factors: genetics,Transcription Factors: physiology,Vascular Endothelial Growth Factor A,Vascular Endothelial Growth Factor A: administrati,Vascular Endothelial Growth Factor A: genetics,Vascular Endothelial Growth Factor A: physiology,Zinc Fingers,Zinc Fingers: genetics",
    	month = "sep",
    	number = 5,
    	pages = "331--9",
    	pmid = 21864053,
    	title = "{Intramuscular administration of a VEGF zinc finger transcription factor activator (VEGF-ZFP-TF) improves functional outcomes in SOD1 rats.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/21864053",
    	volume = 12,
    	year = 2011
    }
    
  30. Keqiang Zhang, Jianming Lu, Taisuke Mori, Leslie Smith-Powell, Timothy W Synold, Shiuan Chen and Wei Wen.
    {Baicalin increases VEGF expression and angiogenesis by activating the ERRalpha/PGC-1alpha pathway.}. Cardiovascular research 89(2):426–35, February 2011.
    Abstract AIMS: Baicalin is the major component found in Scutellaria baicalensis root, a widely used herb in traditional Chinese medicine. Although it has been used for thousands of years to treat stroke, the mechanisms of action of S. baicalensis have not been clearly elucidated. In this report, we studied the modulation of angiogenesis as one possible mechanism by investigating the effects of these agents on expression of vascular endothelial growth factor (VEGF), a critical factor for angiogenesis. METHODS AND RESULTS: The effects of baicalin and an extract of S. baicalensis on VEGF expression were tested in several cell lines. Both agents induced VEGF expression in all cells without increasing expression of hypoxia-inducible factor-1$\alpha$ (HIF-1$\alpha$). The expression of reporter genes was also activated under the control of the VEGF promoter containing either a functional or a defective HIF response element (HRE). Only minimal effects were observed on reporter activation under the HRE promoter. Instead, both agents significantly induced oestrogen-related receptor (ERR$\alpha$) expression as well as the activity of reporter genes under the control of ERR$\alpha$-binding element. Their ability to induce VEGF expression was suppressed once ERR$\alpha$ expression was knocked down by siRNA or ERR$\alpha$-binding sites were deleted in the VEGF promoter. We also found that both agents stimulated cell migration and vessel sprout formation from the aorta. CONCLUSION: Our results implicate baicalin and S. baicalensis in angiogenesis by inducing VEGF expression through the activation of the ERR$\alpha$ pathway. These data may facilitate a better understanding of the potential health benefits of these agents in the treatment of cardiovascular diseases.
    URL, DOI BibTeX

    @article{Zhang2011,
    	abstract = "AIMS: Baicalin is the major component found in Scutellaria baicalensis root, a widely used herb in traditional Chinese medicine. Although it has been used for thousands of years to treat stroke, the mechanisms of action of S. baicalensis have not been clearly elucidated. In this report, we studied the modulation of angiogenesis as one possible mechanism by investigating the effects of these agents on expression of vascular endothelial growth factor (VEGF), a critical factor for angiogenesis. METHODS AND RESULTS: The effects of baicalin and an extract of S. baicalensis on VEGF expression were tested in several cell lines. Both agents induced VEGF expression in all cells without increasing expression of hypoxia-inducible factor-1$\alpha$ (HIF-1$\alpha$). The expression of reporter genes was also activated under the control of the VEGF promoter containing either a functional or a defective HIF response element (HRE). Only minimal effects were observed on reporter activation under the HRE promoter. Instead, both agents significantly induced oestrogen-related receptor (ERR$\alpha$) expression as well as the activity of reporter genes under the control of ERR$\alpha$-binding element. Their ability to induce VEGF expression was suppressed once ERR$\alpha$ expression was knocked down by siRNA or ERR$\alpha$-binding sites were deleted in the VEGF promoter. We also found that both agents stimulated cell migration and vessel sprout formation from the aorta. CONCLUSION: Our results implicate baicalin and S. baicalensis in angiogenesis by inducing VEGF expression through the activation of the ERR$\alpha$ pathway. These data may facilitate a better understanding of the potential health benefits of these agents in the treatment of cardiovascular diseases.",
    	author = "Zhang, Keqiang and Lu, Jianming and Mori, Taisuke and Smith-Powell, Leslie and Synold, Timothy W and Chen, Shiuan and Wen, Wei",
    	doi = "10.1093/cvr/cvq296",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Zhang et al. - 2011 - Baicalin increases VEGF expression and angiogenesis by activating the ERR\{alpha\}PGC-1\{alpha\} pathway.pdf:pdf",
    	issn = "1755-3245",
    	journal = "Cardiovascular research",
    	keywords = "Angiogenesis Inducing Agents,Angiogenesis Inducing Agents: pharmacology,Animals,Aorta, Thoracic,Aorta, Thoracic: drug effects,Aorta, Thoracic: embryology,Binding Sites,Cell Line, Tumor,Cell Movement,Cell Movement: drug effects,Cells, Cultured,Chick Embryo,Dose-Response Relationship, Drug,Endothelial Cells,Endothelial Cells: drug effects,Endothelial Cells: metabolism,Flavonoids,Flavonoids: pharmacology,Genes, Reporter,Heat-Shock Proteins,Heat-Shock Proteins: drug effects,Heat-Shock Proteins: metabolism,Humans,Hypoxia-Inducible Factor 1, alpha Subunit,Hypoxia-Inducible Factor 1, alpha Subunit: metabol,Neovascularization, Physiologic,Neovascularization, Physiologic: drug effects,Plant Extracts,Plant Extracts: pharmacology,Plant Roots,Promoter Regions, Genetic,Promoter Regions, Genetic: drug effects,RNA Interference,Receptors, Estrogen,Receptors, Estrogen: drug effects,Receptors, Estrogen: genetics,Receptors, Estrogen: metabolism,Scutellaria baicalensis,Signal Transduction,Signal Transduction: drug effects,Tissue Culture Techniques,Transcription Factors,Transcription Factors: drug effects,Transcription Factors: metabolism,Transcription, Genetic,Transcription, Genetic: drug effects,Transfection,Up-Regulation,Vascular Endothelial Growth Factor A,Vascular Endothelial Growth Factor A: genetics,Vascular Endothelial Growth Factor A: metabolism",
    	month = "feb",
    	number = 2,
    	pages = "426--35",
    	pmid = 20851810,
    	title = "{Baicalin increases VEGF expression and angiogenesis by activating the ERR\{alpha\}/PGC-1\{alpha\} pathway.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3020130\&tool=pmcentrez\&rendertype=abstract",
    	volume = 89,
    	year = 2011
    }
    
  31. Atsushi Kasai, Toshihiko Kinjo, Rie Ishihara, Ikumi Sakai, Yuki Ishimaru, Yasuhiro Yoshioka, Akiko Yamamuro, Kumiko Ishige, Yoshihisa Ito and Sadaaki Maeda.
    Apelin deficiency accelerates the progression of amyotrophic lateral sclerosis.. PloS one 6(8):e23968, January 2011.
    Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Recent studies have implicated that chronic hypoxia and insufficient vascular endothelial growth factor (VEGF)-dependent neuroprotection may lead to the degeneration of motor neurons in ALS. Expression of apelin, an endogenous ligand for the G protein-coupled receptor APJ, is regulated by hypoxia. In addition, recent reports suggest that apelin protects neurons against glutamate-induced excitotoxicity. Here, we examined whether apelin is an endogenous neuroprotective factor using SOD1(G93A) mouse model of ALS. In mouse CNS tissues, the highest expressions of both apelin and APJ mRNAs were detected in spinal cord. APJ immunoreactivity was observed in neuronal cell bodies located in gray matter of spinal cord. Although apelin mRNA expression in the spinal cord of wild-type mice was not changed from 4 to 18 weeks age, that of SOD1(G93A) mice was reduced along with the paralytic phenotype. In addition, double mutant apelin-deficient and SOD1(G93A) displayed the disease phenotypes earlier than SOD1(G93A) littermates. Immunohistochemical observation revealed that the number of motor neurons was decreased and microglia were activated in the spinal cord of the double mutant mice, indicating that apelin deficiency pathologically accelerated the progression of ALS. Furthermore, we showed that apelin enhanced the protective effect of VEGF on H(2)O(2)-induced neuronal death in primary neurons. These results suggest that apelin/APJ system in the spinal cord has a neuroprotective effect against the pathogenesis of ALS.
    URL, DOI BibTeX

    @article{Kasai2011,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Recent studies have implicated that chronic hypoxia and insufficient vascular endothelial growth factor (VEGF)-dependent neuroprotection may lead to the degeneration of motor neurons in ALS. Expression of apelin, an endogenous ligand for the G protein-coupled receptor APJ, is regulated by hypoxia. In addition, recent reports suggest that apelin protects neurons against glutamate-induced excitotoxicity. Here, we examined whether apelin is an endogenous neuroprotective factor using SOD1(G93A) mouse model of ALS. In mouse CNS tissues, the highest expressions of both apelin and APJ mRNAs were detected in spinal cord. APJ immunoreactivity was observed in neuronal cell bodies located in gray matter of spinal cord. Although apelin mRNA expression in the spinal cord of wild-type mice was not changed from 4 to 18 weeks age, that of SOD1(G93A) mice was reduced along with the paralytic phenotype. In addition, double mutant apelin-deficient and SOD1(G93A) displayed the disease phenotypes earlier than SOD1(G93A) littermates. Immunohistochemical observation revealed that the number of motor neurons was decreased and microglia were activated in the spinal cord of the double mutant mice, indicating that apelin deficiency pathologically accelerated the progression of ALS. Furthermore, we showed that apelin enhanced the protective effect of VEGF on H(2)O(2)-induced neuronal death in primary neurons. These results suggest that apelin/APJ system in the spinal cord has a neuroprotective effect against the pathogenesis of ALS.",
    	author = "Kasai, Atsushi and Kinjo, Toshihiko and Ishihara, Rie and Sakai, Ikumi and Ishimaru, Yuki and Yoshioka, Yasuhiro and Yamamuro, Akiko and Ishige, Kumiko and Ito, Yoshihisa and Maeda, Sadaaki",
    	doi = "10.1371/journal.pone.0023968",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Kasai et al. - 2011 - Apelin deficiency accelerates the progression of amyotrophic lateral sclerosis.pdf:pdf",
    	issn = "1932-6203",
    	journal = "PloS one",
    	keywords = "Age Factors,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: pathology,Animals,Disease Progression,Intercellular Signaling Peptides and Proteins,Intercellular Signaling Peptides and Proteins: ana,Intercellular Signaling Peptides and Proteins: def,Intercellular Signaling Peptides and Proteins: gen,Mice,Motor Neurons,Motor Neurons: pathology,Neuroprotective Agents,RNA, Messenger,RNA, Messenger: analysis,Spinal Cord,Spinal Cord: chemistry,Tissue Distribution",
    	month = "jan",
    	number = 8,
    	pages = "e23968",
    	pmid = 21887354,
    	title = "{Apelin deficiency accelerates the progression of amyotrophic lateral sclerosis.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3161091\&tool=pmcentrez\&rendertype=abstract",
    	volume = 6,
    	year = 2011
    }
    
  32. Pawan K Gupta, Sudesh Prabhakar, Suresh Sharma and Akshay Anand.
    Vascular endothelial growth factor-A (VEGF-A) and chemokine ligand-2 (CCL2) in amyotrophic lateral sclerosis (ALS) patients.. Journal of neuroinflammation 8:47, January 2011.
    Abstract BACKGROUND: Vascular endothelial growth factor-A (VEGF-A) and chemokne ligand-2 (CCL2) levels have been examined in Amyotrophic Lateral Sclerosis (ALS) patients in Western countries. We measured these values in North Indian ALS patients, since these patients display considerably enhanced survival duration. METHODS: Sporadic ALS patients were included on the basis of El Escorial criteria. VEGF-A and CCL2 levels were analyzed in serum and cerebrospinal fluid (CSF) of 50 ALS patients using enzyme linked immunosorbent assay (ELISA) and compared with normal controls. Their levels were adjusted for possible confounders like cigarette smoking, alcohol and meat consumption. RESULTS: Contrary to previous studies, VEGF-A was found to be elevated significantly in serum and CSF in ALS patient population studied. We also found an increase in CCL2 levels in CSF of these ALS patients. Serum and CSF from definite ALS revealed higher VEGF-A as compared to probable and possible ALS. CCL2 was unaltered between definite, probable and possible ALS. Univariate and multivariate analysis revealed a lack of association of smoking, alcohol and meat consumption with VEGF-A and CCL2 levels. CONCLUSIONS: VEGF-A upregulation may indicate an activation of compensatory responses in ALS which may reflect or in fact account for increased survival of North Indian ALS patients after disease onset. The intrathecal synthesis of CCL2 suggests the involvement of adult neural stem cells and microglial activation in ALS pathogenesis which needs further investigation.
    URL, DOI BibTeX

    @article{Gupta2011,
    	abstract = "BACKGROUND: Vascular endothelial growth factor-A (VEGF-A) and chemokne ligand-2 (CCL2) levels have been examined in Amyotrophic Lateral Sclerosis (ALS) patients in Western countries. We measured these values in North Indian ALS patients, since these patients display considerably enhanced survival duration. METHODS: Sporadic ALS patients were included on the basis of El Escorial criteria. VEGF-A and CCL2 levels were analyzed in serum and cerebrospinal fluid (CSF) of 50 ALS patients using enzyme linked immunosorbent assay (ELISA) and compared with normal controls. Their levels were adjusted for possible confounders like cigarette smoking, alcohol and meat consumption. RESULTS: Contrary to previous studies, VEGF-A was found to be elevated significantly in serum and CSF in ALS patient population studied. We also found an increase in CCL2 levels in CSF of these ALS patients. Serum and CSF from definite ALS revealed higher VEGF-A as compared to probable and possible ALS. CCL2 was unaltered between definite, probable and possible ALS. Univariate and multivariate analysis revealed a lack of association of smoking, alcohol and meat consumption with VEGF-A and CCL2 levels. CONCLUSIONS: VEGF-A upregulation may indicate an activation of compensatory responses in ALS which may reflect or in fact account for increased survival of North Indian ALS patients after disease onset. The intrathecal synthesis of CCL2 suggests the involvement of adult neural stem cells and microglial activation in ALS pathogenesis which needs further investigation.",
    	author = "Gupta, Pawan K and Prabhakar, Sudesh and Sharma, Suresh and Anand, Akshay",
    	doi = "10.1186/1742-2094-8-47",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Gupta et al. - 2011 - Vascular endothelial growth factor-A (VEGF-A) and chemokine ligand-2 (CCL2) in amyotrophic lateral sclerosis (ALS).pdf:pdf",
    	issn = "1742-2094",
    	journal = "Journal of neuroinflammation",
    	keywords = "Adult,Aged,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: blood,Amyotrophic Lateral Sclerosis: cerebrospinal fluid,Chemokine CCL2,Chemokine CCL2: blood,Chemokine CCL2: cerebrospinal fluid,Enzyme-Linked Immunosorbent Assay,Female,Humans,India,Male,Middle Aged,Survival Rate,Vascular Endothelial Growth Factor A,Vascular Endothelial Growth Factor A: blood,Vascular Endothelial Growth Factor A: cerebrospina",
    	month = "jan",
    	pages = 47,
    	pmid = 21569455,
    	title = "{Vascular endothelial growth factor-A (VEGF-A) and chemokine ligand-2 (CCL2) in amyotrophic lateral sclerosis (ALS) patients.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3117705\&tool=pmcentrez\&rendertype=abstract",
    	volume = 8,
    	year = 2011
    }
    
  33. Grazia Devigili, Nurcan Uçeyler, Marcus Beck, Karlheinz Reiners, Guido Stoll, Klaus V Toyka and Claudia Sommer.
    Vasculitis-like neuropathy in amyotrophic lateral sclerosis unresponsive to treatment.. Acta neuropathologica 122(3):343–52, 2011.
    Abstract Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with variable involvement of other systems. A pathogenetic role of immune-mediated mechanisms has been suggested. We retrospectively analyzed sural nerve pathology and the clinical course in 18 patients with ALS. These patients had undergone sural nerve biopsy because of clinical or neurophysiological signs indicating sensory involvement (ALS+). Eleven of the 18 ALS+ patients had inflammatory cell infiltrates (ALS(vasc)) resembling infiltrates seen in patients with vasculitic neuropathy. Data were compared with the 7 patients without vasculitic infiltrates (ALS(nonvasc)) and with those of 16 patients with isolated peripheral nerve vasculitis (NP(vasc)). Biopsy specimens were processed with standard histological stains and with immunohistochemistry for a panel of inflammatory markers, with the hypothesis that the composition of infiltrates should differ between ALS(vasc) and NP(vasc). Immunoreactive cells were quantified in a blinded manner. Unlike patients with NP(vasc), those with ALS(vasc) had only minor neurophysiological abnormalities in the sural nerve and, except for the infiltrates, almost normal nerve morphology on semithin sections. The difference in epineurial T cell count was significant between ALS(vasc) and ALS(nonvasc) (p = 0.031). Surprisingly, the cellular composition of epineurial infiltrates in sural nerve biopsies was indistinguishable between ALS(vasc) and NP(vasc) despite a significant difference in fiber pathology (p < 0.0001). Standard immunosuppressive treatment did not prevent clinical progression of the motor neuron disease in any of the patients with ALS(vasc). ALS(vasc) appears as a neuropathological subtype in ALS+ suggesting immune-mediated disease components but without response to standard immunosuppressive treatment.
    URL, DOI BibTeX

    @article{Devigili2011,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with variable involvement of other systems. A pathogenetic role of immune-mediated mechanisms has been suggested. We retrospectively analyzed sural nerve pathology and the clinical course in 18 patients with ALS. These patients had undergone sural nerve biopsy because of clinical or neurophysiological signs indicating sensory involvement (ALS+). Eleven of the 18 ALS+ patients had inflammatory cell infiltrates (ALS(vasc)) resembling infiltrates seen in patients with vasculitic neuropathy. Data were compared with the 7 patients without vasculitic infiltrates (ALS(nonvasc)) and with those of 16 patients with isolated peripheral nerve vasculitis (NP(vasc)). Biopsy specimens were processed with standard histological stains and with immunohistochemistry for a panel of inflammatory markers, with the hypothesis that the composition of infiltrates should differ between ALS(vasc) and NP(vasc). Immunoreactive cells were quantified in a blinded manner. Unlike patients with NP(vasc), those with ALS(vasc) had only minor neurophysiological abnormalities in the sural nerve and, except for the infiltrates, almost normal nerve morphology on semithin sections. The difference in epineurial T cell count was significant between ALS(vasc) and ALS(nonvasc) (p = 0.031). Surprisingly, the cellular composition of epineurial infiltrates in sural nerve biopsies was indistinguishable between ALS(vasc) and NP(vasc) despite a significant difference in fiber pathology (p < 0.0001). Standard immunosuppressive treatment did not prevent clinical progression of the motor neuron disease in any of the patients with ALS(vasc). ALS(vasc) appears as a neuropathological subtype in ALS+ suggesting immune-mediated disease components but without response to standard immunosuppressive treatment.",
    	author = "Devigili, Grazia and U\c{c}eyler, Nurcan and Beck, Marcus and Reiners, Karlheinz and Stoll, Guido and Toyka, Klaus V and Sommer, Claudia",
    	doi = "10.1007/s00401-011-0837-8",
    	issn = "1432-0533",
    	journal = "Acta neuropathologica",
    	keywords = "Adult,Aged,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: pathology,Amyotrophic Lateral Sclerosis: therapy,Antigens, CD,Antigens, CD: metabolism,Biopsy,Complement Membrane Attack Complex,Complement Membrane Attack Complex: metabolism,Cytokines,Cytokines: metabolism,Electrophysiology,Female,Humans,Immunotherapy,Immunotherapy: adverse effects,Leukemic Infiltration,Leukemic Infiltration: pathology,Leukemic Infiltration: physiopathology,Male,Middle Aged,Neural Conduction,Neural Conduction: physiology,Reaction Time,Reaction Time: physiology,Retrospective Studies,Statistics, Nonparametric,Sural Nerve,Sural Nerve: pathology,Sural Nerve: physiopathology,T-Lymphocytes,T-Lymphocytes: pathology,Vascular Endothelial Growth Factor A,Vascular Endothelial Growth Factor A: metabolism,Vasculitis,Vasculitis: pathology,Vasculitis: physiopathology",
    	month = "",
    	number = 3,
    	pages = "343--52",
    	pmid = 21626035,
    	title = "{Vasculitis-like neuropathy in amyotrophic lateral sclerosis unresponsive to treatment.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/21626035",
    	volume = 122,
    	year = 2011
    }
    
  34. Torsten Falk, Shiling Zhang and Scott J Sherman.
    Vascular endothelial growth factor B (VEGF-B) is up-regulated and exogenous VEGF-B is neuroprotective in a culture model of Parkinson's disease.. Molecular neurodegeneration 4:49, January 2009.
    Abstract Parkinson's disease (PD) results from the degeneration of dopaminergic neurons in the substantia nigra and the consequent deficit of dopamine released in the striatum. Current oral dopamine replacement or surgical therapies do not address the underlying issue of neurodegeneration, they neither slow nor halt disease. Neurotrophic factors have shown preclinical promise, but the choice of an appropriate growth factor as well as the delivery has proven difficult. In this study, we used a rotenone rat midbrain culture model to identify genes that are changed after addition of the neurotoxin. (1) We challenged rat midbrain cultures with rotenone (20 nM), a pesticide that has been shown to be toxic for dopaminergic neurons and that has been a well-characterized model of PD. A gene chip array analysis demonstrated that several genes were up-regulated after the rotenone treatment. Interestingly transcriptional activation of vascular endothelial growth factor B (VEGF-B) was evident, while vascular endothelial growth factor A (VEGF-A) levels remained unaltered. The results from the gene chip array experiment were verified with real time PCR and semi-quantitative western analysis using beta-actin as the internal standard. (2) We have also found evidence that exogenously applied VEGF-B performed as a neuroprotective agent facilitating neuron survival in an even more severe rotenone culture model of PD (40 nM rotenone). VEGF-B has very recently been added to the list of trophic factors that reduce effects of neurodegeneration, as was shown in an in vivo model of motor neuron degeneration, while lacking potential adverse angiogenic activity. The data of an in vivo protective effect on motor neurons taken together with the presented results demonstrate that VEGF-B is a new candidate trophic factor distinct from the GDNF family of trophic factors. VEGF-B is activated by neurodegenerative challenges to the midbrain, and exogenous application of VEGF-B has a neuroprotective effect in a culture model of PD. Strengthening this natural protective response by either adding exogenous VEGF-B or up-regulating the endogenous VEGF-B levels may have the potential to be a disease modifying therapy for PD. We conclude that the growth factor VEGF-B can improve neuronal survival in a culture model of PD.
    URL, DOI BibTeX

    @article{Falk2009,
    	abstract = "Parkinson's disease (PD) results from the degeneration of dopaminergic neurons in the substantia nigra and the consequent deficit of dopamine released in the striatum. Current oral dopamine replacement or surgical therapies do not address the underlying issue of neurodegeneration, they neither slow nor halt disease. Neurotrophic factors have shown preclinical promise, but the choice of an appropriate growth factor as well as the delivery has proven difficult. In this study, we used a rotenone rat midbrain culture model to identify genes that are changed after addition of the neurotoxin. (1) We challenged rat midbrain cultures with rotenone (20 nM), a pesticide that has been shown to be toxic for dopaminergic neurons and that has been a well-characterized model of PD. A gene chip array analysis demonstrated that several genes were up-regulated after the rotenone treatment. Interestingly transcriptional activation of vascular endothelial growth factor B (VEGF-B) was evident, while vascular endothelial growth factor A (VEGF-A) levels remained unaltered. The results from the gene chip array experiment were verified with real time PCR and semi-quantitative western analysis using beta-actin as the internal standard. (2) We have also found evidence that exogenously applied VEGF-B performed as a neuroprotective agent facilitating neuron survival in an even more severe rotenone culture model of PD (40 nM rotenone). VEGF-B has very recently been added to the list of trophic factors that reduce effects of neurodegeneration, as was shown in an in vivo model of motor neuron degeneration, while lacking potential adverse angiogenic activity. The data of an in vivo protective effect on motor neurons taken together with the presented results demonstrate that VEGF-B is a new candidate trophic factor distinct from the GDNF family of trophic factors. VEGF-B is activated by neurodegenerative challenges to the midbrain, and exogenous application of VEGF-B has a neuroprotective effect in a culture model of PD. Strengthening this natural protective response by either adding exogenous VEGF-B or up-regulating the endogenous VEGF-B levels may have the potential to be a disease modifying therapy for PD. We conclude that the growth factor VEGF-B can improve neuronal survival in a culture model of PD.",
    	author = "Falk, Torsten and Zhang, Shiling and Sherman, Scott J",
    	doi = "10.1186/1750-1326-4-49",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Falk, Zhang, Sherman - 2009 - Vascular endothelial growth factor B (VEGF-B) is up-regulated and exogenous VEGF-B is neuroprotective in a.pdf:pdf",
    	issn = "1750-1326",
    	journal = "Molecular neurodegeneration",
    	month = "jan",
    	pages = 49,
    	pmid = 20003314,
    	title = "{Vascular endothelial growth factor B (VEGF-B) is up-regulated and exogenous VEGF-B is neuroprotective in a culture model of Parkinson's disease.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2799405\&tool=pmcentrez\&rendertype=abstract",
    	volume = 4,
    	year = 2009
    }