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  1. Showkat Ahmad Ganie, Tanveer Ali Dar, Aashiq Hussain Bhat, Khalid B Dar, Suhail Anees, Mohammad Afzal Zargar and Akbar Masood.
    Melatonin: A Potential Anti-Oxidant Therapeutic Agent for Mitochondrial Dysfunctions and Related Disorders.. Rejuvenation research 19(1):21–40, 2016.
    Abstract Mitochondria play a central role in cellular physiology. Besides their classic function of energy metabolism, mitochondria are involved in multiple cell functions, including energy distribution through the cell, energy/heat modulation, regulation of reactive oxygen species (ROS), calcium homeostasis, and control of apoptosis. Simultaneously, mitochondria are the main producer and target of ROS with the result that multiple mitochondrial diseases are related to ROS-induced mitochondrial injuries. Increased free radical generation, enhanced mitochondrial inducible nitric oxide synthase (iNOS) activity, enhanced nitric oxide (NO) production, decreased respiratory complex activity, impaired electron transport system, and opening of mitochondrial permeability transition pores have all been suggested as factors responsible for impaired mitochondrial function. Because of these, neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and aging, are caused by ROS-induced mitochondrial dysfunctions. Melatonin, the major hormone of the pineal gland, also acts as an anti-oxidant and as a regulator of mitochondrial bioenergetic function. Melatonin is selectively taken up by mitochondrial membranes, a function not shared by other anti-oxidants, and thus has emerged as a major potential therapeutic tool for treating neurodegenerative disorders. Multiple in vitro and in vivo experiments have shown the protective role of melatonin for preventing oxidative stress-induced mitochondrial dysfunction seen in experimental models of PD, AD, and HD. With these functions in mind, this article reviews the protective role of melatonin with mechanistic insights against mitochondrial diseases and suggests new avenues for safe and effective treatment modalities against these devastating neurodegenerative diseases. Future insights are also discussed.
    URL, DOI BibTeX

    @article{Ganie2016,
    	abstract = "Mitochondria play a central role in cellular physiology. Besides their classic function of energy metabolism, mitochondria are involved in multiple cell functions, including energy distribution through the cell, energy/heat modulation, regulation of reactive oxygen species (ROS), calcium homeostasis, and control of apoptosis. Simultaneously, mitochondria are the main producer and target of ROS with the result that multiple mitochondrial diseases are related to ROS-induced mitochondrial injuries. Increased free radical generation, enhanced mitochondrial inducible nitric oxide synthase (iNOS) activity, enhanced nitric oxide (NO) production, decreased respiratory complex activity, impaired electron transport system, and opening of mitochondrial permeability transition pores have all been suggested as factors responsible for impaired mitochondrial function. Because of these, neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and aging, are caused by ROS-induced mitochondrial dysfunctions. Melatonin, the major hormone of the pineal gland, also acts as an anti-oxidant and as a regulator of mitochondrial bioenergetic function. Melatonin is selectively taken up by mitochondrial membranes, a function not shared by other anti-oxidants, and thus has emerged as a major potential therapeutic tool for treating neurodegenerative disorders. Multiple in vitro and in vivo experiments have shown the protective role of melatonin for preventing oxidative stress-induced mitochondrial dysfunction seen in experimental models of PD, AD, and HD. With these functions in mind, this article reviews the protective role of melatonin with mechanistic insights against mitochondrial diseases and suggests new avenues for safe and effective treatment modalities against these devastating neurodegenerative diseases. Future insights are also discussed.",
    	author = "Ganie, Showkat Ahmad and Dar, Tanveer Ali and Bhat, Aashiq Hussain and Dar, Khalid B and Anees, Suhail and Zargar, Mohammad Afzal and Masood, Akbar",
    	doi = "10.1089/rej.2015.1704",
    	issn = "1557-8577",
    	journal = "Rejuvenation research",
    	month = "",
    	number = 1,
    	pages = "21--40",
    	pmid = 26087000,
    	title = "{Melatonin: A Potential Anti-Oxidant Therapeutic Agent for Mitochondrial Dysfunctions and Related Disorders.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/26087000",
    	volume = 19,
    	year = 2016
    }
    
  2. Giovanni Polimeni, Emanuela Esposito, Valentina Bevelacqua, Claudio Guarneri and Salvatore Cuzzocrea.
    Role of melatonin supplementation in neurodegenerative disorders.. Frontiers in bioscience (Landmark edition) 19:429–46, January 2014.
    Abstract Neurodegenerative diseases are chronic and progressive disorders characterized by selective destruction of neurons in motor, sensory and cognitive systems. Despite their different origin, free radicals accumulation and consequent tissue damage are importantly concerned for the majority of them. In recent years, research on melatonin revealed a potent activity of this hormone against oxidative and nitrosative stress-induced damage within the nervous system. Indeed, melatonin turned out to be more effective than other naturally occurring antioxidants, suggesting its beneficial effects in a number of diseases where oxygen radical-mediated tissue damage is involved. With specific reference to the brain, the considerable amount of evidence accumulated from studies on various neurodegeneration models and recent clinical reports support the use of melatonin for the preventive treatment of major neurodegenerative disorders. This review summarizes the literature on the protective effects of melatonin on Alzheimer disease, Parkinson disease, Huntington's disease and Amyotrophic Lateral Sclerosis. Additional studies are required to test the clinical efficacy of melatonin supplementation in such disorders, and to identify the specific therapeutic concentrations needed.
    URL BibTeX

    @article{Polimeni2014,
    	abstract = "Neurodegenerative diseases are chronic and progressive disorders characterized by selective destruction of neurons in motor, sensory and cognitive systems. Despite their different origin, free radicals accumulation and consequent tissue damage are importantly concerned for the majority of them. In recent years, research on melatonin revealed a potent activity of this hormone against oxidative and nitrosative stress-induced damage within the nervous system. Indeed, melatonin turned out to be more effective than other naturally occurring antioxidants, suggesting its beneficial effects in a number of diseases where oxygen radical-mediated tissue damage is involved. With specific reference to the brain, the considerable amount of evidence accumulated from studies on various neurodegeneration models and recent clinical reports support the use of melatonin for the preventive treatment of major neurodegenerative disorders. This review summarizes the literature on the protective effects of melatonin on Alzheimer disease, Parkinson disease, Huntington's disease and Amyotrophic Lateral Sclerosis. Additional studies are required to test the clinical efficacy of melatonin supplementation in such disorders, and to identify the specific therapeutic concentrations needed.",
    	author = "Polimeni, Giovanni and Esposito, Emanuela and Bevelacqua, Valentina and Guarneri, Claudio and Cuzzocrea, Salvatore",
    	issn = "1093-4715",
    	journal = "Frontiers in bioscience (Landmark edition)",
    	keywords = "Dietary Supplements,Humans,Melatonin,Melatonin: administration \& dosage,Melatonin: therapeutic use,Neurodegenerative Diseases,Neurodegenerative Diseases: drug therapy",
    	month = "jan",
    	pages = "429--46",
    	pmid = 24389194,
    	title = "{Role of melatonin supplementation in neurodegenerative disorders.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24389194",
    	volume = 19,
    	year = 2014
    }
    
  3. Yi Zhang, Anna Cook, Jinho Kim, Sergei V Baranov, Jiying Jiang, Karen Smith, Kerry Cormier, Erik Bennett, Robert P Browser, Arthur L Day, Diane L Carlisle, Robert J Ferrante, Xin Wang and Robert M Friedlander.
    Melatonin inhibits the caspase-1/cytochrome c/caspase-3 cell death pathway, inhibits MT1 receptor loss and delays disease progression in a mouse model of amyotrophic lateral sclerosis.. Neurobiology of disease 55:26–35, July 2013.
    Abstract Caspase-mediated cell death contributes to the pathogenesis of motor neuron degeneration in the mutant SOD1(G93A) transgenic mouse model of amyotrophic lateral sclerosis (ALS), along with other factors such as inflammation and oxidative damage. By screening a drug library, we found that melatonin, a pineal hormone, inhibited cytochrome c release in purified mitochondria and prevented cell death in cultured neurons. In this study, we evaluated whether melatonin would slow disease progression in SOD1(G93A) mice. We demonstrate that melatonin significantly delayed disease onset, neurological deterioration and mortality in ALS mice. ALS-associated ventral horn atrophy and motor neuron death were also inhibited by melatonin treatment. Melatonin inhibited Rip2/caspase-1 pathway activation, blocked the release of mitochondrial cytochrome c, and reduced the overexpression and activation of caspase-3. Moreover, for the first time, we determined that disease progression was associated with the loss of both melatonin and the melatonin receptor 1A (MT1) in the spinal cord of ALS mice. These results demonstrate that melatonin is neuroprotective in transgenic ALS mice, and this protective effect is mediated through its effects on the caspase-mediated cell death pathway. Furthermore, our data suggest that melatonin and MT1 receptor loss may play a role in the pathological phenotype observed in ALS. The above observations indicate that melatonin and modulation of Rip2/caspase-1/cytochrome c or MT1 pathways may be promising therapeutic approaches for ALS.
    URL, DOI BibTeX

    @article{Zhang2013,
    	abstract = "Caspase-mediated cell death contributes to the pathogenesis of motor neuron degeneration in the mutant SOD1(G93A) transgenic mouse model of amyotrophic lateral sclerosis (ALS), along with other factors such as inflammation and oxidative damage. By screening a drug library, we found that melatonin, a pineal hormone, inhibited cytochrome c release in purified mitochondria and prevented cell death in cultured neurons. In this study, we evaluated whether melatonin would slow disease progression in SOD1(G93A) mice. We demonstrate that melatonin significantly delayed disease onset, neurological deterioration and mortality in ALS mice. ALS-associated ventral horn atrophy and motor neuron death were also inhibited by melatonin treatment. Melatonin inhibited Rip2/caspase-1 pathway activation, blocked the release of mitochondrial cytochrome c, and reduced the overexpression and activation of caspase-3. Moreover, for the first time, we determined that disease progression was associated with the loss of both melatonin and the melatonin receptor 1A (MT1) in the spinal cord of ALS mice. These results demonstrate that melatonin is neuroprotective in transgenic ALS mice, and this protective effect is mediated through its effects on the caspase-mediated cell death pathway. Furthermore, our data suggest that melatonin and MT1 receptor loss may play a role in the pathological phenotype observed in ALS. The above observations indicate that melatonin and modulation of Rip2/caspase-1/cytochrome c or MT1 pathways may be promising therapeutic approaches for ALS.",
    	author = "Zhang, Yi and Cook, Anna and Kim, Jinho and Baranov, Sergei V and Jiang, Jiying and Smith, Karen and Cormier, Kerry and Bennett, Erik and Browser, Robert P and Day, Arthur L and Carlisle, Diane L and Ferrante, Robert J and Wang, Xin and Friedlander, Robert M",
    	doi = "10.1016/j.nbd.2013.03.008",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Zhang et al. - 2013 - Melatonin inhibits the caspase-1cytochrome ccaspase-3 cell death pathway, inhibits MT1 receptor loss and delays di.pdf:pdf",
    	issn = "1095-953X",
    	journal = "Neurobiology of disease",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: drug therapy,Amyotrophic Lateral Sclerosis: genetics,Analysis of Variance,Animals,Antioxidants,Antioxidants: therapeutic use,Caspase 3,Caspase 3: metabolism,Cell Death,Cell Death: drug effects,Cell Death: ethics,Cytochromes c,Cytochromes c: metabolism,Disease Models, Animal,Disease Progression,Enzyme-Linked Immunosorbent Assay,Melatonin,Melatonin: therapeutic use,Mice,Mice, Transgenic,Receptor, Melatonin, MT1,Receptor, Melatonin, MT1: metabolism,Signal Transduction,Signal Transduction: drug effects,Superoxide Dismutase,Superoxide Dismutase: genetics",
    	month = "jul",
    	pages = "26--35",
    	pmid = 23537713,
    	title = "{Melatonin inhibits the caspase-1/cytochrome c/caspase-3 cell death pathway, inhibits MT1 receptor loss and delays disease progression in a mouse model of amyotrophic lateral sclerosis.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3652329\&tool=pmcentrez\&rendertype=abstract",
    	volume = 55,
    	year = 2013
    }
    
  4. Seithikurippu R Pandi-Perumal, Ahmed S BaHammam, Gregory M Brown, Warren D Spence, Vijay K Bharti, Charanjit Kaur, Rüdiger Hardeland and Daniel P Cardinali.
    Melatonin antioxidative defense: therapeutical implications for aging and neurodegenerative processes.. Neurotoxicity research 23(3):267–300, 2013.
    Abstract The pineal product melatonin has remarkable antioxidant properties. It is secreted during darkness and plays a key role in various physiological responses including regulation of circadian rhythms, sleep homeostasis, retinal neuromodulation, and vasomotor responses. It scavenges hydroxyl, carbonate, and various organic radicals as well as a number of reactive nitrogen species. Melatonin also enhances the antioxidant potential of the cell by stimulating the synthesis of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, and glutathione reductase, and by augmenting glutathione levels. Melatonin preserves mitochondrial homeostasis, reduces free radical generation and protects mitochondrial ATP synthesis by stimulating Complexes I and IV activities. The decline in melatonin production in aged individuals has been suggested as one of the primary contributing factors for the development of age-associated neurodegenerative diseases. The efficacy of melatonin in preventing oxidative damage in either cultured neuronal cells or in the brains of animals treated with various neurotoxic agents, suggests that melatonin has a potential therapeutic value as a neuroprotective drug in treatment of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), stroke, and brain trauma. Therapeutic trials with melatonin indicate that it has a potential therapeutic value as a neuroprotective drug in treatment of AD, ALS, and HD. In the case of other neurological conditions, like PD, the evidence is less compelling. Melatonin's efficacy in combating free radical damage in the brain suggests that it can be a valuable therapeutic agent in the treatment of cerebral edema following traumatic brain injury or stroke. Clinical trials employing melatonin doses in the range of 50-100 mg/day are warranted before its relative merits as a neuroprotective agent is definitively established.
    URL, DOI BibTeX

    @article{Pandi-Perumal2013,
    	abstract = "The pineal product melatonin has remarkable antioxidant properties. It is secreted during darkness and plays a key role in various physiological responses including regulation of circadian rhythms, sleep homeostasis, retinal neuromodulation, and vasomotor responses. It scavenges hydroxyl, carbonate, and various organic radicals as well as a number of reactive nitrogen species. Melatonin also enhances the antioxidant potential of the cell by stimulating the synthesis of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, and glutathione reductase, and by augmenting glutathione levels. Melatonin preserves mitochondrial homeostasis, reduces free radical generation and protects mitochondrial ATP synthesis by stimulating Complexes I and IV activities. The decline in melatonin production in aged individuals has been suggested as one of the primary contributing factors for the development of age-associated neurodegenerative diseases. The efficacy of melatonin in preventing oxidative damage in either cultured neuronal cells or in the brains of animals treated with various neurotoxic agents, suggests that melatonin has a potential therapeutic value as a neuroprotective drug in treatment of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), stroke, and brain trauma. Therapeutic trials with melatonin indicate that it has a potential therapeutic value as a neuroprotective drug in treatment of AD, ALS, and HD. In the case of other neurological conditions, like PD, the evidence is less compelling. Melatonin's efficacy in combating free radical damage in the brain suggests that it can be a valuable therapeutic agent in the treatment of cerebral edema following traumatic brain injury or stroke. Clinical trials employing melatonin doses in the range of 50-100 mg/day are warranted before its relative merits as a neuroprotective agent is definitively established.",
    	author = {Pandi-Perumal, Seithikurippu R and BaHammam, Ahmed S and Brown, Gregory M and Spence, D Warren and Bharti, Vijay K and Kaur, Charanjit and Hardeland, R\"{u}diger and Cardinali, Daniel P},
    	doi = "10.1007/s12640-012-9337-4",
    	issn = "1476-3524",
    	journal = "Neurotoxicity research",
    	keywords = "Aging,Aging: drug effects,Aging: metabolism,Aging: physiology,Animals,Antioxidants,Antioxidants: therapeutic use,Apoptosis,Apoptosis: drug effects,Brain Injuries,Brain Injuries: drug therapy,Circadian Rhythm,Circadian Rhythm: physiology,Clinical Trials as Topic,Double-Blind Method,Drug Evaluation, Preclinical,Free Radicals,Free Radicals: metabolism,Homeostasis,Homeostasis: physiology,Humans,Light,Melatonin,Melatonin: agonists,Melatonin: pharmacology,Melatonin: physiology,Melatonin: therapeutic use,Mice,Mice, Transgenic,Mitochondria,Mitochondria: metabolism,Multicenter Studies as Topic,Nerve Tissue Proteins,Nerve Tissue Proteins: biosynthesis,Nerve Tissue Proteins: physiology,Neurodegenerative Diseases,Neurodegenerative Diseases: metabolism,Neurodegenerative Diseases: prevention \& control,Neurons,Neurons: metabolism,Neurons: pathology,Neuroprotective Agents,Neuroprotective Agents: pharmacology,Neuroprotective Agents: therapeutic use,Oxidative Stress,Oxidative Stress: drug effects,Pineal Gland,Pineal Gland: metabolism,Pineal Gland: radiation effects,Pineal Gland: secretion,Sleep Initiation and Maintenance Disorders,Sleep Initiation and Maintenance Disorders: drug t,Tryptophan,Tryptophan: metabolism",
    	month = "",
    	number = 3,
    	pages = "267--300",
    	pmid = 22739839,
    	title = "{Melatonin antioxidative defense: therapeutical implications for aging and neurodegenerative processes.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/22739839",
    	volume = 23,
    	year = 2013
    }
    
  5. Arabinda Das, Gerald Wallace, Russel J Reiter, Abhay K Varma, Swapan K Ray and Naren L Banik.
    Overexpression of melatonin membrane receptors increases calcium-binding proteins and protects VSC4.1 motoneurons from glutamate toxicity through multiple mechanisms.. Journal of pineal research 54(1):58–68, 2013.
    Abstract Melatonin has shown particular promise as a neuroprotective agent to prevent motoneuron death in animal models of both amyotrophic lateral sclerosis (ALS) and spinal cord injuries (SCI). However, an understanding of the roles of endogenous melatonin receptors including MT1, MT2, and orphan G-protein receptor 50 (GPR50) in neuroprotection is lacking. To address this deficiency, we utilized plasmids for transfection and overexpression of individual melatonin receptors in the ventral spinal cord 4.1 (VSC4.1) motoneuron cell line. Receptor-mediated cytoprotection following exposure to glutamate at a toxic level (25 $\mu$m) was determined by assessing cell viability, apoptosis, and intracellular free Ca(2+) levels. Our findings indicate a novel role for MT1 and MT2 for increasing expression of the calcium-binding proteins calbindin D28K and parvalbumin. Increased levels of calbindin D28K and parvalbumin in VSC4.1 cells overexpressing MT1 and MT2 were associated with cytoprotective effects including inhibition of proapoptotic signaling, downregulation of inflammatory factors, and expression of prosurvival markers. Interestingly, the neuroprotective effects conferred by overexpression of MT1 and/or MT2 were also associated with increases in the estrogen receptor $\beta$ (ER$\beta$): estrogen receptor $\alpha$ (ER$\alpha$) ratio and upregulation of angiogenic factors. GPR50 did not exhibit cytoprotective effects. To further confirm the involvement of the melatonin receptors, we silenced both MT1 and MT2 in VSC4.1 cells using RNA interference technology. Knockdown of MT1 and MT2 led to an increase in glutamate toxicity, which was only partially reversed by melatonin treatment. Taken together, our findings suggest that the neuroprotection against glutamate toxicity exhibited by melatonin may depend on MT1 and MT2 but not GPR50.
    URL, DOI BibTeX

    @article{Das2013,
    	abstract = "Melatonin has shown particular promise as a neuroprotective agent to prevent motoneuron death in animal models of both amyotrophic lateral sclerosis (ALS) and spinal cord injuries (SCI). However, an understanding of the roles of endogenous melatonin receptors including MT1, MT2, and orphan G-protein receptor 50 (GPR50) in neuroprotection is lacking. To address this deficiency, we utilized plasmids for transfection and overexpression of individual melatonin receptors in the ventral spinal cord 4.1 (VSC4.1) motoneuron cell line. Receptor-mediated cytoprotection following exposure to glutamate at a toxic level (25 $\mu$m) was determined by assessing cell viability, apoptosis, and intracellular free Ca(2+) levels. Our findings indicate a novel role for MT1 and MT2 for increasing expression of the calcium-binding proteins calbindin D28K and parvalbumin. Increased levels of calbindin D28K and parvalbumin in VSC4.1 cells overexpressing MT1 and MT2 were associated with cytoprotective effects including inhibition of proapoptotic signaling, downregulation of inflammatory factors, and expression of prosurvival markers. Interestingly, the neuroprotective effects conferred by overexpression of MT1 and/or MT2 were also associated with increases in the estrogen receptor $\beta$ (ER$\beta$): estrogen receptor $\alpha$ (ER$\alpha$) ratio and upregulation of angiogenic factors. GPR50 did not exhibit cytoprotective effects. To further confirm the involvement of the melatonin receptors, we silenced both MT1 and MT2 in VSC4.1 cells using RNA interference technology. Knockdown of MT1 and MT2 led to an increase in glutamate toxicity, which was only partially reversed by melatonin treatment. Taken together, our findings suggest that the neuroprotection against glutamate toxicity exhibited by melatonin may depend on MT1 and MT2 but not GPR50.",
    	author = "Das, Arabinda and Wallace, Gerald and Reiter, Russel J and Varma, Abhay K and Ray, Swapan K and Banik, Naren L",
    	doi = "10.1111/j.1600-079X.2012.01022.x",
    	issn = "1600-079X",
    	journal = "Journal of pineal research",
    	keywords = "Animals,Apoptosis,Apoptosis: drug effects,Calbindins,Calbindins: biosynthesis,Cell Line,Cell Survival,Cell Survival: drug effects,Gene Knockdown Techniques,Glutamic Acid,Glutamic Acid: toxicity,Mice,Motor Neurons,Motor Neurons: drug effects,Motor Neurons: metabolism,Nerve Tissue Proteins,Nerve Tissue Proteins: drug effects,Neuroprotective Agents,Neuroprotective Agents: pharmacology,Parvalbumins,Parvalbumins: biosynthesis,RNA, Small Interfering,RNA, Small Interfering: pharmacology,Receptor, Melatonin, MT1,Receptor, Melatonin, MT1: genetics,Receptor, Melatonin, MT2,Receptor, Melatonin, MT2: genetics,Receptors, G-Protein-Coupled,Receptors, G-Protein-Coupled: drug effects,Receptors, Melatonin,Receptors, Melatonin: biosynthesis",
    	month = "",
    	number = 1,
    	pages = "58--68",
    	pmid = 22823500,
    	title = "{Overexpression of melatonin membrane receptors increases calcium-binding proteins and protects VSC4.1 motoneurons from glutamate toxicity through multiple mechanisms.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/22823500",
    	volume = 54,
    	year = 2013
    }
    
  6. Efthimios Dardiotis, Elena Panayiotou, Marianne L Feldman, Andreas Hadjisavvas, Stavros Malas, Ilia Vonta, Georgios Hadjigeorgiou, Kyriakos Kyriakou and Theodoros Kyriakides.
    Intraperitoneal melatonin is not neuroprotective in the G93ASOD1 transgenic mouse model of familial ALS and may exacerbate neurodegeneration.. Neuroscience letters 548:170–5, 2013.
    Abstract In amyotrophic lateral sclerosis (ALS) reactive oxygen species and apoptosis are implicated in disease pathogenesis. Melatonin with its anti-oxidant and anti-apoptotic properties is expected to ameliorate disease phenotype. The aim of this study was to assess possible neuroprotection of melatonin in the G93A-copper/zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. Four groups of mice, 14 animals each, were injected intraperitoneally with 0mg/kg, 0.5mg/kg, 2.5mg/kg and 50mg/kg of melatonin from age 40 days. The primary end points were; disease onset, disease duration, survival and rotarod performance. No statistically significant difference in disease onset between the four groups was found. Survival was significantly reduced with the 0.5mg/kg and 50mg/kg doses and tended to be reduced with the 2.5mg/kg dose. Histological analysis of spinal cords revealed increased motoneuron loss in melatonin treated mice. Melatonin treated animals were associated with increased oxidative stress as assessed with 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation. Histochemistry and Western blot data of spinal cord from melatonin treated mice revealed upregulation of human SOD1 compared to untreated mice. In addition, real-time PCR revealed a dose dependent upregulation of human SOD1 in melatonin treated animals. Thus, intraperitoneal melatonin, at the doses used, does not ameliorate and perhaps exacerbates phenotype in the G93ASOD1 mouse ALS model. This is probably due to melatonin's effect on upregulating gene expression of human toxic SOD1. This action presumably overrides any of its direct anti-oxidant and anti-apoptotic properties.
    URL, DOI BibTeX

    @article{Dardiotis2013,
    	abstract = "In amyotrophic lateral sclerosis (ALS) reactive oxygen species and apoptosis are implicated in disease pathogenesis. Melatonin with its anti-oxidant and anti-apoptotic properties is expected to ameliorate disease phenotype. The aim of this study was to assess possible neuroprotection of melatonin in the G93A-copper/zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. Four groups of mice, 14 animals each, were injected intraperitoneally with 0mg/kg, 0.5mg/kg, 2.5mg/kg and 50mg/kg of melatonin from age 40 days. The primary end points were; disease onset, disease duration, survival and rotarod performance. No statistically significant difference in disease onset between the four groups was found. Survival was significantly reduced with the 0.5mg/kg and 50mg/kg doses and tended to be reduced with the 2.5mg/kg dose. Histological analysis of spinal cords revealed increased motoneuron loss in melatonin treated mice. Melatonin treated animals were associated with increased oxidative stress as assessed with 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation. Histochemistry and Western blot data of spinal cord from melatonin treated mice revealed upregulation of human SOD1 compared to untreated mice. In addition, real-time PCR revealed a dose dependent upregulation of human SOD1 in melatonin treated animals. Thus, intraperitoneal melatonin, at the doses used, does not ameliorate and perhaps exacerbates phenotype in the G93ASOD1 mouse ALS model. This is probably due to melatonin's effect on upregulating gene expression of human toxic SOD1. This action presumably overrides any of its direct anti-oxidant and anti-apoptotic properties.",
    	author = "Dardiotis, Efthimios and Panayiotou, Elena and Feldman, Marianne L and Hadjisavvas, Andreas and Malas, Stavros and Vonta, Ilia and Hadjigeorgiou, Georgios and Kyriakou, Kyriakos and Kyriakides, Theodoros",
    	doi = "10.1016/j.neulet.2013.05.058",
    	issn = "1872-7972",
    	journal = "Neuroscience letters",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: chemically induced,Amyotrophic Lateral Sclerosis: drug therapy,Amyotrophic Lateral Sclerosis: metabolism,Animals,Antioxidants,Antioxidants: administration \& dosage,Antioxidants: adverse effects,Central Nervous System Depressants,Central Nervous System Depressants: administration,Central Nervous System Depressants: adverse effect,Dose-Response Relationship, Drug,Infusions, Parenteral,Melatonin,Melatonin: administration \& dosage,Melatonin: adverse effects,Mice,Mice, Transgenic,Neuroprotective Agents,Neuroprotective Agents: administration \& dosage,Oxidative Stress,Oxidative Stress: drug effects,Superoxide Dismutase,Superoxide Dismutase: genetics,Superoxide Dismutase: metabolism,Treatment Outcome",
    	month = "",
    	pages = "170--5",
    	pmid = 23748038,
    	title = "{Intraperitoneal melatonin is not neuroprotective in the G93ASOD1 transgenic mouse model of familial ALS and may exacerbate neurodegeneration.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23748038",
    	volume = 548,
    	year = 2013
    }
    
  7. M E Camacho, M D Carrion, L C Lopez-Cara, A Entrena, M A Gallo, A Espinosa, G Escames and D Acuna-Castroviejo.
    Melatonin synthetic analogs as nitric oxide synthase inhibitors.. Mini reviews in medicinal chemistry 12(7):600–17, 2012.
    Abstract Nitric oxide (NO), which is produced by oxidation of L-arginine to L-citrulline in a process catalyzed by different isoforms of nitric oxide synthase (NOS), exhibits diverse roles in several physiological processes, including neurotransmission, blood pressure regulation and immunological defense mechanisms. On the other hand, an overproduction of NO is related with several disorders as Alzheimer's disease, Huntington's disease and the amyotrophic lateral sclerosis. Taking melatonin as a model, our research group has designed and synthesized several families of compounds that act as NOS inhibitors, and their effects on the excitability of N-methyl-D-aspartate (NMDA)-dependent neurons in rat striatum, and on the activity on both nNOS and iNOS were evaluated. Structural comparison between the three most representative families of compounds (kynurenines, kynurenamines and 4,5-dihydro-1H-pyrazole derivatives) allows the establishment of structure-activity relationships for the inhibition of nNOS, and a pharmacophore model that fulfills all of the observed SARs were developed. This model could serve as a template for the design of other potential nNOS inhibitors. The last family of compounds, pyrrole derivatives, shows moderate in vitro NOS inhibition, but some of these compounds show good iNOS/nNOS selectivity. Two of these compounds, 5-(2-aminophenyl)-1H-pyrrole-2-carboxylic acid methylamide and cyclopentylamide, have been tested as regulators of the in vivo nNOS and iNOS activity. Both compounds prevented the increment of the inducible NOS activity in both cytosol (iNOS) and mitochondria (i-mtNOS) observed in a MPTP model of Parkinson's disease.
    URL BibTeX

    @article{Camacho2012,
    	abstract = "Nitric oxide (NO), which is produced by oxidation of L-arginine to L-citrulline in a process catalyzed by different isoforms of nitric oxide synthase (NOS), exhibits diverse roles in several physiological processes, including neurotransmission, blood pressure regulation and immunological defense mechanisms. On the other hand, an overproduction of NO is related with several disorders as Alzheimer's disease, Huntington's disease and the amyotrophic lateral sclerosis. Taking melatonin as a model, our research group has designed and synthesized several families of compounds that act as NOS inhibitors, and their effects on the excitability of N-methyl-D-aspartate (NMDA)-dependent neurons in rat striatum, and on the activity on both nNOS and iNOS were evaluated. Structural comparison between the three most representative families of compounds (kynurenines, kynurenamines and 4,5-dihydro-1H-pyrazole derivatives) allows the establishment of structure-activity relationships for the inhibition of nNOS, and a pharmacophore model that fulfills all of the observed SARs were developed. This model could serve as a template for the design of other potential nNOS inhibitors. The last family of compounds, pyrrole derivatives, shows moderate in vitro NOS inhibition, but some of these compounds show good iNOS/nNOS selectivity. Two of these compounds, 5-(2-aminophenyl)-1H-pyrrole-2-carboxylic acid methylamide and cyclopentylamide, have been tested as regulators of the in vivo nNOS and iNOS activity. Both compounds prevented the increment of the inducible NOS activity in both cytosol (iNOS) and mitochondria (i-mtNOS) observed in a MPTP model of Parkinson's disease.",
    	author = "Camacho, M E and Carrion, M D and Lopez-Cara, L C and Entrena, A and Gallo, M A and Espinosa, A and Escames, G and Acuna-Castroviejo, D",
    	issn = "1875-5607",
    	journal = "Mini reviews in medicinal chemistry",
    	keywords = "Animals,Enzyme Inhibitors,Enzyme Inhibitors: chemical synthesis,Enzyme Inhibitors: chemistry,Enzyme Inhibitors: pharmacology,Humans,Melatonin,Melatonin: analogs \& derivatives,Melatonin: chemical synthesis,Melatonin: chemistry,Melatonin: pharmacology,Nitric Oxide Synthase,Nitric Oxide Synthase: antagonists \& inhibitors",
    	month = "",
    	number = 7,
    	pages = "600--17",
    	pmid = 22512552,
    	title = "{Melatonin synthetic analogs as nitric oxide synthase inhibitors.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/22512552",
    	volume = 12,
    	year = 2012
    }
    
  8. Jorge H Limón-Pacheco and Mar\'ıa E Gonsebatt.
    The glutathione system and its regulation by neurohormone melatonin in the central nervous system.. Central nervous system agents in medicinal chemistry 10(4):287–97, 2010.
    Abstract The glutathione system includes reduced (GSH) and oxidized (GSSG) forms of glutathione; the enzymes required for its synthesis and recycling, such as gamma-glutamate cysteine ligase ($\gamma$-GCL), glutathione synthetase (GS), glutathione reductase (GSR) and gamma glutamyl transpeptidase ($\gamma$-GGT); and the enzymes required for its use in metabolism and in mechanisms of defense against free radical-induced oxidative damage, such as glutathione s-transferases (GSTs) and glutathione peroxidases (GPxs). Glutathione functions in the central nervous system (CNS) include maintenance of neurotransmitters, membrane protection, detoxification, metabolic regulation, and modulation of signal transduction. A common pathological hallmark in various neurodegenerative disorders, such as amyotrophic lateral sclerosis and Alzheimer's and Parkinson's diseases is the increase in oxidative stress and the failure of antioxidant systems, such as the decrease in the GSH content. The administration of exogenous neurohormone melatonin at pharmacological doses has been shown not only to be an effective scavenger of reactive oxygen and nitrogen species but also to enhance the levels of GSH and the expression and activities of the GSH-related enzymes including $\gamma$-GCL, GPxs, and GSR. The exact mechanisms by which melatonin regulates the glutathione system are not fully understood. The main purpose of this short review is to discuss evidence relating to the potential common modulation signals between the glutathione system and melatonin in the CNS. The potential regulatory mechanisms and interactions between neurons and non-neuronal cells are also discussed.
    URL BibTeX

    @article{Limon-Pacheco2010,
    	abstract = "The glutathione system includes reduced (GSH) and oxidized (GSSG) forms of glutathione; the enzymes required for its synthesis and recycling, such as gamma-glutamate cysteine ligase ($\gamma$-GCL), glutathione synthetase (GS), glutathione reductase (GSR) and gamma glutamyl transpeptidase ($\gamma$-GGT); and the enzymes required for its use in metabolism and in mechanisms of defense against free radical-induced oxidative damage, such as glutathione s-transferases (GSTs) and glutathione peroxidases (GPxs). Glutathione functions in the central nervous system (CNS) include maintenance of neurotransmitters, membrane protection, detoxification, metabolic regulation, and modulation of signal transduction. A common pathological hallmark in various neurodegenerative disorders, such as amyotrophic lateral sclerosis and Alzheimer's and Parkinson's diseases is the increase in oxidative stress and the failure of antioxidant systems, such as the decrease in the GSH content. The administration of exogenous neurohormone melatonin at pharmacological doses has been shown not only to be an effective scavenger of reactive oxygen and nitrogen species but also to enhance the levels of GSH and the expression and activities of the GSH-related enzymes including $\gamma$-GCL, GPxs, and GSR. The exact mechanisms by which melatonin regulates the glutathione system are not fully understood. The main purpose of this short review is to discuss evidence relating to the potential common modulation signals between the glutathione system and melatonin in the CNS. The potential regulatory mechanisms and interactions between neurons and non-neuronal cells are also discussed.",
    	author = "Lim\'{o}n-Pacheco, Jorge H and Gonsebatt, Mar\'{\i}a E",
    	issn = "1875-6166",
    	journal = "Central nervous system agents in medicinal chemistry",
    	keywords = "Animals,Antioxidants,Antioxidants: pharmacology,Astrocytes,Astrocytes: physiology,Central Nervous System,Central Nervous System: physiology,Glutathione,Glutathione Peroxidase,Glutathione Peroxidase: metabolism,Glutathione: physiology,Humans,Melatonin,Melatonin: pharmacology,Melatonin: physiology,Neurons,Neurons: physiology",
    	month = "",
    	number = 4,
    	pages = "287--97",
    	pmid = 20868358,
    	title = "{The glutathione system and its regulation by neurohormone melatonin in the central nervous system.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/20868358",
    	volume = 10,
    	year = 2010
    }
    
  9. Xin Wang.
    The antiapoptotic activity of melatonin in neurodegenerative diseases.. CNS neuroscience & therapeutics 15(4):345–57, January 2009.
    Abstract Melatonin plays a neuroprotective role in models of neurodegenerative diseases. However, the molecular mechanisms underlying neuroprotection by melatonin are not well understood. Apoptotic cell death in the central nervous system is a feature of neurodegenerative diseases. The intrinsic and extrinsic apoptotic pathways and the antiapoptotic survival signal pathways play critical roles in neurodegeneration. This review summarizes the reports to date showing inhibition by melatonin of the intrinsic apoptotic pathways in neurodegenerative diseases including stroke, Alzheimer disease, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis. Furthermore, the activation of survival signal pathways by melatonin in neurodegenerative diseases is discussed.
    URL, DOI BibTeX

    @article{Wang2009,
    	abstract = "Melatonin plays a neuroprotective role in models of neurodegenerative diseases. However, the molecular mechanisms underlying neuroprotection by melatonin are not well understood. Apoptotic cell death in the central nervous system is a feature of neurodegenerative diseases. The intrinsic and extrinsic apoptotic pathways and the antiapoptotic survival signal pathways play critical roles in neurodegeneration. This review summarizes the reports to date showing inhibition by melatonin of the intrinsic apoptotic pathways in neurodegenerative diseases including stroke, Alzheimer disease, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis. Furthermore, the activation of survival signal pathways by melatonin in neurodegenerative diseases is discussed.",
    	author = "Wang, Xin",
    	doi = "10.1111/j.1755-5949.2009.00105.x",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Wang - 2009 - The antiapoptotic activity of melatonin in neurodegenerative diseases.pdf:pdf",
    	issn = "1755-5949",
    	journal = "CNS neuroscience \& therapeutics",
    	keywords = "Animals,Apoptosis,Apoptosis: drug effects,Humans,Melatonin,Melatonin: pharmacology,Melatonin: therapeutic use,Models, Biological,Neurodegenerative Diseases,Neurodegenerative Diseases: drug therapy,Neurodegenerative Diseases: physiopathology,Neuroprotective Agents,Neuroprotective Agents: pharmacology,Neuroprotective Agents: therapeutic use",
    	month = "jan",
    	number = 4,
    	pages = "345--57",
    	pmid = 19818070,
    	title = "{The antiapoptotic activity of melatonin in neurodegenerative diseases.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2846661\&tool=pmcentrez\&rendertype=abstract",
    	volume = 15,
    	year = 2009
    }
    
  10. Charanjit Kaur and Eng-Ang Ling.
    Antioxidants and neuroprotection in the adult and developing central nervous system.. Current medicinal chemistry 15(29):3068–80, January 2008.
    Abstract Oxidative stress is implicated in the pathogenesis of a number of neurological disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis and stroke in the adult as well as in conditions such as periventricular white matter damage in the neonatal brain. It has also been linked to the disruption of blood brain barrier (BBB) in hypoxic-ischemic injury. Both experimental and clinical results have shown that antioxidants such as melatonin, a neurohormone synthesized and secreted by the pineal gland and edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a newly developed drug, are effective in reducing oxidative stress and are promising neuroprotectants in reducing brain damage. Indeed, the neuroprotective effects of melatonin in many central nervous system (CNS) disease conditions such as amyotrophic lateral sclerosis, PD, AD, ischemic injury, neuropsychiatric disorders and head injury are well documented. Melatonin affords protection to the BBB in hypoxic conditions by suppressing the production of vascular endothelial growth factor and nitric oxide which are known to increase vascular permeability. The protective effects of melatonin against hypoxic damage have also been demonstrated in newborn animals whereby it attenuated damage in different areas of the brain. Furthermore, exogenous administration of melatonin in newborn animals effectively enhanced the surface receptors and antigens on the macrophages/microglia in the CNS indicating its immunoregulatory actions. Edaravone has been shown to reduce oxidative stress, edema, infarct volume, inflammation and apoptosis following ischemic injury of the brain in the adult as well as decrease free radical production in the neonatal brain following hypoxic-ischemic insult. It can counteract toxicity from activated microglia. This review summarizes the clinical and experimental data highlighting the therapeutic potential of melatonin and edaravone in neuroprotection in various disorders of the CNS.
    URL BibTeX

    @article{Kaur2008,
    	abstract = "Oxidative stress is implicated in the pathogenesis of a number of neurological disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis and stroke in the adult as well as in conditions such as periventricular white matter damage in the neonatal brain. It has also been linked to the disruption of blood brain barrier (BBB) in hypoxic-ischemic injury. Both experimental and clinical results have shown that antioxidants such as melatonin, a neurohormone synthesized and secreted by the pineal gland and edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a newly developed drug, are effective in reducing oxidative stress and are promising neuroprotectants in reducing brain damage. Indeed, the neuroprotective effects of melatonin in many central nervous system (CNS) disease conditions such as amyotrophic lateral sclerosis, PD, AD, ischemic injury, neuropsychiatric disorders and head injury are well documented. Melatonin affords protection to the BBB in hypoxic conditions by suppressing the production of vascular endothelial growth factor and nitric oxide which are known to increase vascular permeability. The protective effects of melatonin against hypoxic damage have also been demonstrated in newborn animals whereby it attenuated damage in different areas of the brain. Furthermore, exogenous administration of melatonin in newborn animals effectively enhanced the surface receptors and antigens on the macrophages/microglia in the CNS indicating its immunoregulatory actions. Edaravone has been shown to reduce oxidative stress, edema, infarct volume, inflammation and apoptosis following ischemic injury of the brain in the adult as well as decrease free radical production in the neonatal brain following hypoxic-ischemic insult. It can counteract toxicity from activated microglia. This review summarizes the clinical and experimental data highlighting the therapeutic potential of melatonin and edaravone in neuroprotection in various disorders of the CNS.",
    	author = "Kaur, Charanjit and Ling, Eng-Ang",
    	issn = "0929-8673",
    	journal = "Current medicinal chemistry",
    	keywords = "Animals,Antioxidants,Antioxidants: pharmacology,Antipyrine,Antipyrine: analogs \& derivatives,Antipyrine: pharmacology,Apoptosis,Apoptosis: physiology,Central Nervous System,Central Nervous System: growth \& development,Central Nervous System: physiology,Free Radical Scavengers,Free Radical Scavengers: pharmacology,Humans,Melatonin,Melatonin: pharmacology,Melatonin: physiology,Neurodegenerative Diseases,Neurodegenerative Diseases: pathology,Neurodegenerative Diseases: physiopathology,Neurons,Neurons: pathology,Neurons: physiology,Neuroprotective Agents,Neuroprotective Agents: pharmacology,Oxidative Stress,Oxidative Stress: physiology",
    	month = "jan",
    	number = 29,
    	pages = "3068--80",
    	pmid = 19075654,
    	title = "{Antioxidants and neuroprotection in the adult and developing central nervous system.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/19075654",
    	volume = 15,
    	year = 2008
    }
    
  11. Reuven Sandyk.
    Serotonergic mechanisms in amyotrophic lateral sclerosis.. The International journal of neuroscience 116(7):775–826, 2006.
    Abstract Serotonin (5-HT) has been intimately linked with global regulation of motor behavior, local control of motoneuron excitability, functional recovery of spinal motoneurons as well as neuronal maturation and aging. Selective degeneration of motoneurons is the pathological hallmark of amyotrophic lateral sclerosis (ALS). Motoneurons that are preferentially affected in ALS are also densely innervated by 5-HT neurons (e.g., trigeminal, facial, ambiguus, and hypoglossal brainstem nuclei as well as ventral horn and motor cortex). Conversely, motoneuron groups that appear more resistant to the process of neurodegeneration in ALS (e.g., oculomotor, trochlear, and abducens nuclei) as well as the cerebellum receive only sparse 5-HT input. The glutamate excitotoxicity theory maintains that in ALS degeneration of motoneurons is caused by excessive glutamate neurotransmission, which is neurotoxic. Because of its facilitatory effects on glutaminergic motoneuron excitation, 5-HT may be pivotal to the pathogenesis and therapy of ALS. 5-HT levels as well as the concentrations 5-hydroxyindole acetic acid (5-HIAA), the major metabolite of 5-HT, are reduced in postmortem spinal cord tissue of ALS patients indicating decreased 5-HT release. Furthermore, cerebrospinal fluid levels of tryptophan, a precursor of 5-HT, are decreased in patients with ALS and plasma concentrations of tryptophan are also decreased with the lowest levels found in the most severely affected patients. In ALS progressive degeneration of 5-HT neurons would result in a compensatory increase in glutamate excitation of motoneurons. Additionally, because 5-HT, acting through presynaptic 5-HT1B receptors, inhibits glutamatergic synaptic transmission, lowered 5-HT activity would lead to increased synaptic glutamate release. Furthermore, 5-HT is a precursor of melatonin, which inhibits glutamate release and glutamate-induced neurotoxicity. Thus, progressive degeneration of 5-HT neurons affecting motoneuron activity constitutes the prime mover of the disease and its progression and treatment of ALS needs to be focused primarily on boosting 5-HT functions (e.g., pharmacologically via its precursors, reuptake inhibitors, selective 5-HT1A receptor agonists/5-HT2 receptor antagonists, and electrically through transcranial administration of AC pulsed picotesla electromagnetic fields) to prevent excessive glutamate activity in the motoneurons. In fact, 5HT1A and 5HT2 receptor agonists have been shown to prevent glutamate-induced neurotoxicity in primary cortical cell cultures and the 5-HT precursor 5-hydroxytryptophan (5-HTP) improved locomotor function and survival of transgenic SOD1 G93A mice, an animal model of ALS.
    URL, DOI BibTeX

    @article{Sandyk2006,
    	abstract = "Serotonin (5-HT) has been intimately linked with global regulation of motor behavior, local control of motoneuron excitability, functional recovery of spinal motoneurons as well as neuronal maturation and aging. Selective degeneration of motoneurons is the pathological hallmark of amyotrophic lateral sclerosis (ALS). Motoneurons that are preferentially affected in ALS are also densely innervated by 5-HT neurons (e.g., trigeminal, facial, ambiguus, and hypoglossal brainstem nuclei as well as ventral horn and motor cortex). Conversely, motoneuron groups that appear more resistant to the process of neurodegeneration in ALS (e.g., oculomotor, trochlear, and abducens nuclei) as well as the cerebellum receive only sparse 5-HT input. The glutamate excitotoxicity theory maintains that in ALS degeneration of motoneurons is caused by excessive glutamate neurotransmission, which is neurotoxic. Because of its facilitatory effects on glutaminergic motoneuron excitation, 5-HT may be pivotal to the pathogenesis and therapy of ALS. 5-HT levels as well as the concentrations 5-hydroxyindole acetic acid (5-HIAA), the major metabolite of 5-HT, are reduced in postmortem spinal cord tissue of ALS patients indicating decreased 5-HT release. Furthermore, cerebrospinal fluid levels of tryptophan, a precursor of 5-HT, are decreased in patients with ALS and plasma concentrations of tryptophan are also decreased with the lowest levels found in the most severely affected patients. In ALS progressive degeneration of 5-HT neurons would result in a compensatory increase in glutamate excitation of motoneurons. Additionally, because 5-HT, acting through presynaptic 5-HT1B receptors, inhibits glutamatergic synaptic transmission, lowered 5-HT activity would lead to increased synaptic glutamate release. Furthermore, 5-HT is a precursor of melatonin, which inhibits glutamate release and glutamate-induced neurotoxicity. Thus, progressive degeneration of 5-HT neurons affecting motoneuron activity constitutes the prime mover of the disease and its progression and treatment of ALS needs to be focused primarily on boosting 5-HT functions (e.g., pharmacologically via its precursors, reuptake inhibitors, selective 5-HT1A receptor agonists/5-HT2 receptor antagonists, and electrically through transcranial administration of AC pulsed picotesla electromagnetic fields) to prevent excessive glutamate activity in the motoneurons. In fact, 5HT1A and 5HT2 receptor agonists have been shown to prevent glutamate-induced neurotoxicity in primary cortical cell cultures and the 5-HT precursor 5-hydroxytryptophan (5-HTP) improved locomotor function and survival of transgenic SOD1 G93A mice, an animal model of ALS.",
    	author = "Sandyk, Reuven",
    	doi = "10.1080/00207450600754087",
    	issn = "0020-7454",
    	journal = "The International journal of neuroscience",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: drug therapy,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Animals,Glutamic Acid,Glutamic Acid: metabolism,Humans,Motor Activity,Motor Activity: drug effects,Motor Activity: physiology,Neurons,Neurons: metabolism,Serotonin,Serotonin: metabolism,Serotonin: therapeutic use,Sleep, REM,Sleep, REM: drug effects,Sleep, REM: physiology",
    	month = "",
    	number = 7,
    	pages = "775--826",
    	pmid = 16861147,
    	title = "{Serotonergic mechanisms in amyotrophic lateral sclerosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/16861147",
    	volume = 116,
    	year = 2006
    }