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  1. M D Sanchez-Nino and A Ortiz.
    Differential effects of oral and intravenous L-carnitine on serum lipids: is the microbiota the answer?. Clinical Kidney Journal 7(5):437–441, September 2014.
    URL, DOI BibTeX

    @article{Sanchez-Nino2014,
    	author = "Sanchez-Nino, M. D. and Ortiz, A.",
    	doi = "10.1093/ckj/sfu099",
    	issn = "2048-8505",
    	journal = "Clinical Kidney Journal",
    	month = "sep",
    	number = 5,
    	pages = "437--441",
    	title = "{Differential effects of oral and intravenous L-carnitine on serum lipids: is the microbiota the answer?}",
    	url = "http://ckj.oxfordjournals.org/content/7/5/437.full",
    	volume = 7,
    	year = 2014
    }
    
  2. Marco Onofrj, Fausta Ciccocioppo, Sara Varanese, Antonio Muzio, Menotti Calvani, Santina Chiechio, Maurizio Osio and Astrid Thomas.
    Acetyl-L-carnitine: from a biological curiosity to a drug for the peripheral nervous system and beyond.. Expert review of neurotherapeutics 13(8):925–36, August 2013.
    Abstract Acetyl-L-carnitine (ALC) is a molecule derived from acetylation of carnitine in the mitochondria. Carnitine acetylation enables the function of CoA and facilitates elimination of oxidative products. Beyond this metabolic activity, ALC provides acetyl groups for acetylcholine synthesis, exerts a cholinergic effect and optimizes the balance of energy processes. Acetylcarnitine supplementation induces neuroprotective, neurotrophic and analgesic effects in the peripheral nervous system. In the recent studies, ALC, by acting as a donor of acetyl groups to NF-kb p65/RelA, enhanced the transcription of the GRM2 gene encoding the mGLU2 receptors, inducing long-term upregulation of the mGluR2, evidencing therefore that its long-term analgesic effects are dependent on epigenetic modifications. Several studies, including double-blind, placebo-controlled, parallel group studies and few open studies showed the effect of ALC in diseases characterized by neuropathies and neuropathic pain: the studies included diabetic neuropathy, HIV and antiretroviral therapy-induced neuropathies, neuropathies due to compression and chemotherapeutic agents. Double-blinded studies involved 1773 patients. Statistical evaluations evidenced reduction of pain, improvements of nerve function and trophism. In conclusion, ALC represents a consistent therapeutic option for peripheral neuropathies, and its complex effects, neurotrophic and analgesic, based on epigenetic mechanism, open new pathways in the study of peripheral nerve disease management.
    URL, DOI BibTeX

    @article{Onofrj2013,
    	abstract = "Acetyl-L-carnitine (ALC) is a molecule derived from acetylation of carnitine in the mitochondria. Carnitine acetylation enables the function of CoA and facilitates elimination of oxidative products. Beyond this metabolic activity, ALC provides acetyl groups for acetylcholine synthesis, exerts a cholinergic effect and optimizes the balance of energy processes. Acetylcarnitine supplementation induces neuroprotective, neurotrophic and analgesic effects in the peripheral nervous system. In the recent studies, ALC, by acting as a donor of acetyl groups to NF-kb p65/RelA, enhanced the transcription of the GRM2 gene encoding the mGLU2 receptors, inducing long-term upregulation of the mGluR2, evidencing therefore that its long-term analgesic effects are dependent on epigenetic modifications. Several studies, including double-blind, placebo-controlled, parallel group studies and few open studies showed the effect of ALC in diseases characterized by neuropathies and neuropathic pain: the studies included diabetic neuropathy, HIV and antiretroviral therapy-induced neuropathies, neuropathies due to compression and chemotherapeutic agents. Double-blinded studies involved 1773 patients. Statistical evaluations evidenced reduction of pain, improvements of nerve function and trophism. In conclusion, ALC represents a consistent therapeutic option for peripheral neuropathies, and its complex effects, neurotrophic and analgesic, based on epigenetic mechanism, open new pathways in the study of peripheral nerve disease management.",
    	author = "Onofrj, Marco and Ciccocioppo, Fausta and Varanese, Sara and di Muzio, Antonio and Calvani, Menotti and Chiechio, Santina and Osio, Maurizio and Thomas, Astrid",
    	doi = "10.1586/14737175.2013.814930",
    	issn = "1744-8360",
    	journal = "Expert review of neurotherapeutics",
    	keywords = "Acetylcarnitine,Acetylcarnitine: pharmacology,Animals,Humans,Neuralgia,Neuralgia: drug therapy,Neuralgia: physiopathology,Nootropic Agents,Nootropic Agents: pharmacology,Peripheral Nervous System Diseases,Peripheral Nervous System Diseases: drug therapy,Peripheral Nervous System Diseases: physiopatholog",
    	month = "aug",
    	number = 8,
    	pages = "925--36",
    	pmid = 23965166,
    	title = "{Acetyl-L-carnitine: from a biological curiosity to a drug for the peripheral nervous system and beyond.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23965166",
    	volume = 13,
    	year = 2013
    }
    
  3. Ettore Beghi, Elisabetta Pupillo, Virginio Bonito, Paolo Buzzi, Claudia Caponnetto, Adriano Chiò, Massimo Corbo, Fabio Giannini, Maurizio Inghilleri, Vincenzo La Bella, Giancarlo Logroscino, Lorenzo Lorusso, Christian Lunetta, Letizia Mazzini, Paolo Messina, Gabriele Mora, Michele Perini, Maria Lidia Quadrelli, Vincenzo Silani, Isabella L Simone and Lucio Tremolizzo.
    Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for ALS.. Amyotrophic lateral sclerosis & frontotemporal degeneration 14(5-6):397–405, 2013.
    Abstract Our objective was to assess the effects of acetyl-L-carnitine (ALC) with riluzole on disability and mortality of amyotrophic lateral sclerosis (ALS). Definite/probable ALS patients, 40-70 years of age, duration 6-24 months, self-sufficient (i.e. able to swallow, cut food/handle utensils, and walk), and with forced vital capacity (FVC) > 80% entered a pilot double-blind, placebo-controlled, parallel group trial and were followed for 48 weeks. ALC or placebo 3 g/day was added to riluzole 100 mg/day. Primary endpoint: number of patients no longer self-sufficient. Secondary endpoints: changes in ALSFRS-R, MRC, FVC and McGill Quality of Life (QoL) scores. Analysis was made in the intention-to-treat (ITT) and per-protocol (PP) population, completers and completers/compliers (i.e. taking > 75% of study drug). Forty-two patients received ALC and 40 placebo. In the ITT population, 34 (80.9%) patients receiving ALC and 39 (97.5%) receiving placebo became non-self-sufficient (p = 0.0296). In the PP analysis, percentages were 84.4 and 100.0% (p = 0.0538), respectively. Mean ALSFRS-R scores at 48 weeks were 33.6 (SD 10.4) and 27.6 (9.9) (p = 0.0388), respectively, and mean FVC scores 90.3 (32.6) and 58.6 (31.2) (p = 0.0158), respectively. Median survival was 45 months (ALC) and 22 months (placebo) (p = 0.0176). MRC, QoL and adverse events were similar. In conclusion, ALC may be effective, well-tolerated and safe in ALS. A pivotal phase III trial is needed.
    URL, DOI BibTeX

    @article{Beghi2013,
    	abstract = "Our objective was to assess the effects of acetyl-L-carnitine (ALC) with riluzole on disability and mortality of amyotrophic lateral sclerosis (ALS). Definite/probable ALS patients, 40-70 years of age, duration 6-24 months, self-sufficient (i.e. able to swallow, cut food/handle utensils, and walk), and with forced vital capacity (FVC) > 80\% entered a pilot double-blind, placebo-controlled, parallel group trial and were followed for 48 weeks. ALC or placebo 3 g/day was added to riluzole 100 mg/day. Primary endpoint: number of patients no longer self-sufficient. Secondary endpoints: changes in ALSFRS-R, MRC, FVC and McGill Quality of Life (QoL) scores. Analysis was made in the intention-to-treat (ITT) and per-protocol (PP) population, completers and completers/compliers (i.e. taking > 75\% of study drug). Forty-two patients received ALC and 40 placebo. In the ITT population, 34 (80.9\%) patients receiving ALC and 39 (97.5\%) receiving placebo became non-self-sufficient (p = 0.0296). In the PP analysis, percentages were 84.4 and 100.0\% (p = 0.0538), respectively. Mean ALSFRS-R scores at 48 weeks were 33.6 (SD 10.4) and 27.6 (9.9) (p = 0.0388), respectively, and mean FVC scores 90.3 (32.6) and 58.6 (31.2) (p = 0.0158), respectively. Median survival was 45 months (ALC) and 22 months (placebo) (p = 0.0176). MRC, QoL and adverse events were similar. In conclusion, ALC may be effective, well-tolerated and safe in ALS. A pivotal phase III trial is needed.",
    	author = "Beghi, Ettore and Pupillo, Elisabetta and Bonito, Virginio and Buzzi, Paolo and Caponnetto, Claudia and Chi\`{o}, Adriano and Corbo, Massimo and Giannini, Fabio and Inghilleri, Maurizio and Bella, Vincenzo La and Logroscino, Giancarlo and Lorusso, Lorenzo and Lunetta, Christian and Mazzini, Letizia and Messina, Paolo and Mora, Gabriele and Perini, Michele and Quadrelli, Maria Lidia and Silani, Vincenzo and Simone, Isabella L and Tremolizzo, Lucio",
    	doi = "10.3109/21678421.2013.764568",
    	issn = "2167-9223",
    	journal = "Amyotrophic lateral sclerosis \& frontotemporal degeneration",
    	keywords = "Acetylcarnitine,Acetylcarnitine: therapeutic use,Adult,Aged,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: drug therapy,Disease Progression,Double-Blind Method,Drug Therapy, Combination,Excitatory Amino Acid Antagonists,Excitatory Amino Acid Antagonists: therapeutic use,Female,Humans,Male,Middle Aged,Nootropic Agents,Nootropic Agents: therapeutic use,Pilot Projects,Quality of Life,Riluzole,Riluzole: therapeutic use,Treatment Outcome,Vital Capacity",
    	month = "",
    	number = "5-6",
    	pages = "397--405",
    	pmid = 23421600,
    	title = "{Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for ALS.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23421600",
    	volume = 14,
    	year = 2013
    }
    
  4. M Sun, F Qian, W Shen, C Tian, J Hao, L Sun and J Liu.
    Mitochondrial nutrients stimulate performance and mitochondrial biogenesis in exhaustively exercised rats.. Scandinavian journal of medicine & science in sports 22(6):764–75, December 2012.
    Abstract The aim of this study was to investigate the effects of a combination of nutrients on physical performance, oxidative stress and mitochondrial biogenesis in rats subjected to exhaustive exercise. Rats were divided into sedentary control (SC), exhaustive exercise (EC) and exhaustive exercise with nutrient supplementation (EN). The nutrients include (mg/kg/day): R-$\alpha$-lipoic acid 50, acetyl-L-carnitine 100, biotin 0.1, nicotinamide 15, riboflavin 6, pyridoxine 6, creatine 50, CoQ10 5, resveratrol 5 and taurine 100. Examination of running distances over the 4-week period revealed that EN rats ran significantly longer throughout the entire duration of the exhaustive exercise period compared with the EC rats. Nutrient supplementation significantly inhibited the increase in activities of alanine transaminase, lactate dehydrogenase and creatine kinase, reversed increases in malondialdehyde, inhibited decreases in glutathione S-transferase and total antioxidant capacity in plasma, and suppressed the elevation of reactive oxygen species and apoptosis in splenic lymphocytes. Nutrient supplementation increased the protein expression of mitochondrial complexes I, II and III, mtDNA number and transcription factors involved in mitochondrial biogenesis and fusion in skeletal muscle. These findings suggest that mitochondrial nutrient supplementation can reduce exhaustive exercise-induced oxidative damage and mitochondrial dysfunction, thus leading to enhancement of physical performance and of fatigue recovery.
    URL, DOI BibTeX

    @article{Sun2012,
    	abstract = "The aim of this study was to investigate the effects of a combination of nutrients on physical performance, oxidative stress and mitochondrial biogenesis in rats subjected to exhaustive exercise. Rats were divided into sedentary control (SC), exhaustive exercise (EC) and exhaustive exercise with nutrient supplementation (EN). The nutrients include (mg/kg/day): R-$\alpha$-lipoic acid 50, acetyl-L-carnitine 100, biotin 0.1, nicotinamide 15, riboflavin 6, pyridoxine 6, creatine 50, CoQ10 5, resveratrol 5 and taurine 100. Examination of running distances over the 4-week period revealed that EN rats ran significantly longer throughout the entire duration of the exhaustive exercise period compared with the EC rats. Nutrient supplementation significantly inhibited the increase in activities of alanine transaminase, lactate dehydrogenase and creatine kinase, reversed increases in malondialdehyde, inhibited decreases in glutathione S-transferase and total antioxidant capacity in plasma, and suppressed the elevation of reactive oxygen species and apoptosis in splenic lymphocytes. Nutrient supplementation increased the protein expression of mitochondrial complexes I, II and III, mtDNA number and transcription factors involved in mitochondrial biogenesis and fusion in skeletal muscle. These findings suggest that mitochondrial nutrient supplementation can reduce exhaustive exercise-induced oxidative damage and mitochondrial dysfunction, thus leading to enhancement of physical performance and of fatigue recovery.",
    	author = "Sun, M and Qian, F and Shen, W and Tian, C and Hao, J and Sun, L and Liu, J",
    	doi = "10.1111/j.1600-0838.2011.01314.x",
    	issn = "1600-0838",
    	journal = "Scandinavian journal of medicine \& science in sports",
    	keywords = "Animals,Apoptosis,Apoptosis: drug effects,DNA, Mitochondrial,DNA, Mitochondrial: metabolism,Dietary Supplements,Enzymes,Enzymes: blood,Male,Malondialdehyde,Malondialdehyde: blood,Mitochondria,Mitochondria: drug effects,Mitochondria: metabolism,Mitochondria: ultrastructure,Mitochondrial Turnover,Mitochondrial Turnover: drug effects,Muscle Fatigue,Muscle Fatigue: drug effects,Muscle, Skeletal,Muscle, Skeletal: drug effects,Muscle, Skeletal: metabolism,Muscle, Skeletal: ultrastructure,Oxidative Stress,Oxidative Stress: drug effects,Physical Endurance,Physical Endurance: drug effects,Protein Carbonylation,Protein Carbonylation: drug effects,Rats,Rats, Sprague-Dawley,Reactive Oxygen Species,Reactive Oxygen Species: blood,Transcription Factors,Transcription Factors: metabolism",
    	month = "dec",
    	number = 6,
    	pages = "764--75",
    	pmid = 21507065,
    	title = "{Mitochondrial nutrients stimulate performance and mitochondrial biogenesis in exhaustively exercised rats.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/21507065",
    	volume = 22,
    	year = 2012
    }
    
  5. Hector H Palacios, Bharat B Yendluri, Kalpana Parvathaneni, Vagif B Shadlinski, Mark E Obrenovich, Jerzy Leszek, Dmitry Gokhman, Kazimierz Gąsiorowski, Valentin Bragin and Gjumrakch Aliev.
    Mitochondrion-specific antioxidants as drug treatments for Alzheimer disease.. CNS & neurological disorders drug targets 10(2):149–62, 2011.
    Abstract Age-related dementias such as Alzheimer disease (AD) have been linked to vascular disorders like hypertension, diabetes and atherosclerosis. These risk factors cause ischemia, inflammation, oxidative damage and consequently reperfusion, which is largely due to reactive oxygen species (ROS) that are believed to induce mitochondrial damage. At higher concentrations, ROS can cause cell injury and death which occurs during the aging process, where oxidative stress is incremented due to an accelerated generation of ROS and a gradual decline in cellular antioxidant defense mechanisms. Neuronal mitochondria are especially vulnerable to oxidative stress due to their role in energy supply and use, causing a cascade of debilitating factors such as the production of giant and/or vulnerable young mitochondrion who's DNA has been compromised. Therefore, mitochondria specific antioxidants such as acetyl-L-carnitine and R-alphalipoic acid seem to be potential treatments for AD. They target the factors that damage mitochondria and reverse its effect, thus eliminating the imbalance seen in energy production and amyloid beta oxidation and making these antioxidants very powerful alternate strategies for the treatment of AD.
    URL BibTeX

    @article{Palacios2011,
    	abstract = "Age-related dementias such as Alzheimer disease (AD) have been linked to vascular disorders like hypertension, diabetes and atherosclerosis. These risk factors cause ischemia, inflammation, oxidative damage and consequently reperfusion, which is largely due to reactive oxygen species (ROS) that are believed to induce mitochondrial damage. At higher concentrations, ROS can cause cell injury and death which occurs during the aging process, where oxidative stress is incremented due to an accelerated generation of ROS and a gradual decline in cellular antioxidant defense mechanisms. Neuronal mitochondria are especially vulnerable to oxidative stress due to their role in energy supply and use, causing a cascade of debilitating factors such as the production of giant and/or vulnerable young mitochondrion who's DNA has been compromised. Therefore, mitochondria specific antioxidants such as acetyl-L-carnitine and R-alphalipoic acid seem to be potential treatments for AD. They target the factors that damage mitochondria and reverse its effect, thus eliminating the imbalance seen in energy production and amyloid beta oxidation and making these antioxidants very powerful alternate strategies for the treatment of AD.",
    	author = "Palacios, Hector H and Yendluri, Bharat B and Parvathaneni, Kalpana and Shadlinski, Vagif B and Obrenovich, Mark E and Leszek, Jerzy and Gokhman, Dmitry and Gąsiorowski, Kazimierz and Bragin, Valentin and Aliev, Gjumrakch",
    	issn = "1996-3181",
    	journal = "CNS \& neurological disorders drug targets",
    	keywords = "Aging,Alzheimer Disease,Alzheimer Disease: drug therapy,Alzheimer Disease: metabolism,Alzheimer Disease: pathology,Amyloid beta-Peptides,Amyloid beta-Peptides: metabolism,Animals,Antioxidants,Antioxidants: therapeutic use,Blood-Brain Barrier,Brain,Brain: blood supply,Brain: pathology,Cerebrovascular Disorders,Cerebrovascular Disorders: physiopathology,Humans,Mice,Mitochondria,Mitochondria: metabolism,Mitochondria: pathology",
    	month = "",
    	number = 2,
    	pages = "149--62",
    	pmid = 21222631,
    	title = "{Mitochondrion-specific antioxidants as drug treatments for Alzheimer disease.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/21222631",
    	volume = 10,
    	year = 2011
    }
    
  6. G Nagesh Babu, Alok Kumar and Ram Lakhan Singh.
    Chronic pretreatment with acetyl-L-carnitine and ±DL-$\alpha$-lipoic acid protects against acute glutamate-induced neurotoxicity in rat brain by altering mitochondrial function.. Neurotoxicity research 19(2):319–29, 2011.
    Abstract Cellular oxidative stress and energy failure were shown to be involved in Glutamate (L-Glu) neurotoxicity, whereas, acetyl-L-carnitine (ALCAR) and ±DL-$\alpha$-lipoic acid (LA) are known to be key players in the mitochondrial energy production. To evaluate the effects of the above antioxidants, adult rats were pretreated with ALCAR (100 mg/kg i.p for 21 days) and both ALCAR and LA (100 mg/kg i.p + 50 mg/kg i.p for 21 days), before stereotactically administering L-Glu bolus (1 $\mu$mole/1 $\mu$l) in the cerebral cortex. Results showed that acute L-Glu increased ROS (P < 0.001), LPO (P < 0.001), Ca(2+) (P < 0.001), TNF-$\alpha$ (P < 0.001), IFN-$\gamma$ (P < 0.001), NO (P < 0.001) levels and mRNA expression of Caspase-3, Casapase-9, iNOS, and nNOS genes with respect to saline-injected control group. Key antioxidant parameters such as SOD, CAT, GSH, GR along with mitochondrial transmembrane potential ($¶si$∆m) were decreased (P < 0.05), while ALCAR pretreatment prevented these effects by significantly inhibiting ROS (P < 0.001), LPO (P < 0.001), Ca(2+) (P < 0.05), TNF-$\alpha$ (P < 0.05), IFN-$\gamma$ (P < 0.001), NO (P < 0.01) levels and expression of the above genes. This chronic pretreatment of ALCAR also increased SOD, CAT, GSH, GR, and $¶si$∆m (P < 0.0.01, P < 0.0.01, P < 0.05, P < 0.05, and P < 0.001, respectively) with respect to L: -Glu group. The addition of LA to ALCAR resulted in further increases in CAT (P < 0.05), GSH (P < 0.01), GR (P < 0.05), $¶si$∆m (P < 0.05) and additional decreases in ROS (P < 0.001), LPO (P < 0.05), Ca(2+) (P < 0.05), TNF-$\alpha$ (P < 0.05) and mRNA expression of iNOS and nNOS genes with respect to ALCAR group. Hence, this "one-two punch" of ALCAR + LA may help in ameliorating the deleterious cellular events that occur after L-Glu.
    URL, DOI BibTeX

    @article{NageshBabu2011,
    	abstract = {Cellular oxidative stress and energy failure were shown to be involved in Glutamate (L-Glu) neurotoxicity, whereas, acetyl-L-carnitine (ALCAR) and ±DL-$\alpha$-lipoic acid (LA) are known to be key players in the mitochondrial energy production. To evaluate the effects of the above antioxidants, adult rats were pretreated with ALCAR (100 mg/kg i.p for 21 days) and both ALCAR and LA (100 mg/kg i.p + 50 mg/kg i.p for 21 days), before stereotactically administering L-Glu bolus (1 $\mu$mole/1 $\mu$l) in the cerebral cortex. Results showed that acute L-Glu increased ROS (P < 0.001), LPO (P < 0.001), Ca(2+) (P < 0.001), TNF-$\alpha$ (P < 0.001), IFN-$\gamma$ (P < 0.001), NO (P < 0.001) levels and mRNA expression of Caspase-3, Casapase-9, iNOS, and nNOS genes with respect to saline-injected control group. Key antioxidant parameters such as SOD, CAT, GSH, GR along with mitochondrial transmembrane potential ($\Psi$∆m) were decreased (P < 0.05), while ALCAR pretreatment prevented these effects by significantly inhibiting ROS (P < 0.001), LPO (P < 0.001), Ca(2+) (P < 0.05), TNF-$\alpha$ (P < 0.05), IFN-$\gamma$ (P < 0.001), NO (P < 0.01) levels and expression of the above genes. This chronic pretreatment of ALCAR also increased SOD, CAT, GSH, GR, and $\Psi$∆m (P < 0.0.01, P < 0.0.01, P < 0.05, P < 0.05, and P < 0.001, respectively) with respect to L: -Glu group. The addition of LA to ALCAR resulted in further increases in CAT (P < 0.05), GSH (P < 0.01), GR (P < 0.05), $\Psi$∆m (P < 0.05) and additional decreases in ROS (P < 0.001), LPO (P < 0.05), Ca(2+) (P < 0.05), TNF-$\alpha$ (P < 0.05) and mRNA expression of iNOS and nNOS genes with respect to ALCAR group. Hence, this "one-two punch" of ALCAR + LA may help in ameliorating the deleterious cellular events that occur after L-Glu.},
    	author = "{Nagesh Babu}, G and Kumar, Alok and Singh, Ram Lakhan",
    	doi = "10.1007/s12640-010-9165-3",
    	issn = "1476-3524",
    	journal = "Neurotoxicity research",
    	keywords = "Acetylcarnitine,Acetylcarnitine: administration \& dosage,Animals,Brain,Brain: drug effects,Brain: metabolism,Brain: pathology,Drug Therapy, Combination,Glutamic Acid,Glutamic Acid: toxicity,Male,Mitochondria,Mitochondria: drug effects,Mitochondria: physiology,Neuroprotective Agents,Neuroprotective Agents: administration \& dosage,Neurotoxicity Syndromes,Neurotoxicity Syndromes: metabolism,Neurotoxicity Syndromes: pathology,Neurotoxicity Syndromes: prevention \& control,Rats,Rats, Sprague-Dawley,Reactive Oxygen Species,Reactive Oxygen Species: metabolism,Thioctic Acid,Thioctic Acid: administration \& dosage,Treatment Outcome",
    	month = "",
    	number = 2,
    	pages = "319--29",
    	pmid = 20217290,
    	title = "{Chronic pretreatment with acetyl-L-carnitine and ±DL-$\alpha$-lipoic acid protects against acute glutamate-induced neurotoxicity in rat brain by altering mitochondrial function.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/20217290",
    	volume = 19,
    	year = 2011
    }
    
  7. P M Abdul Muneer, Saleena Alikunju, Adam M Szlachetka, Aaron J Mercer and James Haorah.
    Ethanol impairs glucose uptake by human astrocytes and neurons: protective effects of acetyl-L-carnitine.. International journal of physiology, pathophysiology and pharmacology 3(1):48–56, 2011.
    Abstract Alcohol consumption causes neurocognitive deficits, neuronal injury, and neurodegeneration. At the cellular level, alcohol abuse causes oxidative damage to mitochondria and cellular proteins and interlink with the progression of neuroinflammation and neurological disorders. We previously reported that alcohol inhibits glucose transport across the blood-brain barrier (BBB), leading to BBB dysfunction and neurodegeneration. In this study, we hypothesized that ethanol (EtOH)-mediated disruption in glucose uptake would deprive energy for human astrocytes and neurons inducing neurotoxicity and neuronal degeneration. EtOH may also have a direct effect on glucose uptake in neurons and astrocytes, which has not been previously described. Our results indicate that ethanol exposure decreases the uptake of D-(2-(3)H)-glucose by human astrocytes and neurons. Inhibition of glucose uptake correlates with a reduction in glucose transporter protein expression (GLUT1 in astrocytes and GLUT3 in neurons). Acetyl-L-carnitine (ALC), a neuroprotective agent, suppresses the effects of alcohol on glucose uptake and GLUT levels, thus reducing neurotoxicity and neuronal degeneration. These findings suggest that deprivation of glucose in brain cells contributes to neurotoxicity in alcohol abusers, and highlights ALC as a potential therapeutic agent to prevent the deleterious health conditions caused by alcohol abuse.
    URL BibTeX

    @article{AbdulMuneer2011,
    	abstract = "Alcohol consumption causes neurocognitive deficits, neuronal injury, and neurodegeneration. At the cellular level, alcohol abuse causes oxidative damage to mitochondria and cellular proteins and interlink with the progression of neuroinflammation and neurological disorders. We previously reported that alcohol inhibits glucose transport across the blood-brain barrier (BBB), leading to BBB dysfunction and neurodegeneration. In this study, we hypothesized that ethanol (EtOH)-mediated disruption in glucose uptake would deprive energy for human astrocytes and neurons inducing neurotoxicity and neuronal degeneration. EtOH may also have a direct effect on glucose uptake in neurons and astrocytes, which has not been previously described. Our results indicate that ethanol exposure decreases the uptake of D-(2-(3)H)-glucose by human astrocytes and neurons. Inhibition of glucose uptake correlates with a reduction in glucose transporter protein expression (GLUT1 in astrocytes and GLUT3 in neurons). Acetyl-L-carnitine (ALC), a neuroprotective agent, suppresses the effects of alcohol on glucose uptake and GLUT levels, thus reducing neurotoxicity and neuronal degeneration. These findings suggest that deprivation of glucose in brain cells contributes to neurotoxicity in alcohol abusers, and highlights ALC as a potential therapeutic agent to prevent the deleterious health conditions caused by alcohol abuse.",
    	author = "{Abdul Muneer}, P M and Alikunju, Saleena and Szlachetka, Adam M and Mercer, Aaron J and Haorah, James",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Abdul Muneer et al. - 2011 - Ethanol impairs glucose uptake by human astrocytes and neurons protective effects of acetyl-L-carnitine.pdf:pdf",
    	issn = "1944-8171",
    	journal = "International journal of physiology, pathophysiology and pharmacology",
    	month = "",
    	number = 1,
    	pages = "48--56",
    	pmid = 21258656,
    	title = "{Ethanol impairs glucose uptake by human astrocytes and neurons: protective effects of acetyl-L-carnitine.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3023411\&tool=pmcentrez\&rendertype=abstract",
    	volume = 3,
    	year = 2011
    }
    
  8. Hongyu Zhang, Haiqun Jia, Jianghai Liu, Ni Ao, Bing Yan, Weili Shen, Xuemin Wang, Xin Li, Cheng Luo and Jiankang Liu.
    Combined R-alpha-lipoic acid and acetyl-L-carnitine exerts efficient preventative effects in a cellular model of Parkinson's disease.. Journal of cellular and molecular medicine 14(1-2):215–25, January 2010.
    Abstract Mitochondrial dysfunction and oxidative damage are highly involved in the pathogenesis of Parkinson's disease (PD). Some mitochondrial antioxidants/nutrients that can improve mitochondrial function and/or attenuate oxidative damage have been implicated in PD therapy. However, few studies have evaluated the preventative effects of a combination of mitochondrial antioxidants/nutrients against PD, and even fewer have sought to optimize the doses of the combined agents. The present study examined the preventative effects of two mitochondrial antioxidant/nutrients, R-alpha-lipoic acid (LA) and acetyl-L-carnitine (ALC), in a chronic rotenone-induced cellular model of PD. We demonstrated that 4-week pretreatment with LA and/or ALC effectively protected SK-N-MC human neuroblastoma cells against rotenone-induced mitochondrial dysfunction, oxidative damage and accumulation of alpha-synuclein and ubiquitin. Most notably, we found that when combined, LA and ALC worked at 100-1000-fold lower concentrations than they did individually. We also found that pretreatment with combined LA and ALC increased mitochondrial biogenesis and decreased production of reactive oxygen species through the up-regulation of the peroxisome proliferator-activated receptor-gamma coactivator 1alpha as a possible underlying mechanism. This study provides important evidence that combining mitochondrial antioxidant/nutrients at optimal doses might be an effective and safe prevention strategy for PD.
    URL, DOI BibTeX

    @article{Zhang2010,
    	abstract = "Mitochondrial dysfunction and oxidative damage are highly involved in the pathogenesis of Parkinson's disease (PD). Some mitochondrial antioxidants/nutrients that can improve mitochondrial function and/or attenuate oxidative damage have been implicated in PD therapy. However, few studies have evaluated the preventative effects of a combination of mitochondrial antioxidants/nutrients against PD, and even fewer have sought to optimize the doses of the combined agents. The present study examined the preventative effects of two mitochondrial antioxidant/nutrients, R-alpha-lipoic acid (LA) and acetyl-L-carnitine (ALC), in a chronic rotenone-induced cellular model of PD. We demonstrated that 4-week pretreatment with LA and/or ALC effectively protected SK-N-MC human neuroblastoma cells against rotenone-induced mitochondrial dysfunction, oxidative damage and accumulation of alpha-synuclein and ubiquitin. Most notably, we found that when combined, LA and ALC worked at 100-1000-fold lower concentrations than they did individually. We also found that pretreatment with combined LA and ALC increased mitochondrial biogenesis and decreased production of reactive oxygen species through the up-regulation of the peroxisome proliferator-activated receptor-gamma coactivator 1alpha as a possible underlying mechanism. This study provides important evidence that combining mitochondrial antioxidant/nutrients at optimal doses might be an effective and safe prevention strategy for PD.",
    	author = "Zhang, Hongyu and Jia, Haiqun and Liu, Jianghai and Ao, Ni and Yan, Bing and Shen, Weili and Wang, Xuemin and Li, Xin and Luo, Cheng and Liu, Jiankang",
    	doi = "10.1111/j.1582-4934.2008.00390.x",
    	issn = "1582-4934",
    	journal = "Journal of cellular and molecular medicine",
    	keywords = "Acetylcarnitine,Acetylcarnitine: pharmacology,Acetylcarnitine: therapeutic use,Antioxidants,Antioxidants: pharmacology,Antioxidants: therapeutic use,Drug Synergism,Humans,Mitochondria,Mitochondria: drug effects,Mitochondria: metabolism,Oxidation-Reduction,Oxidative Stress,Parkinson Disease,Parkinson Disease: metabolism,Parkinson Disease: prevention \& control,Rotenone,Rotenone: pharmacology,Thioctic Acid,Thioctic Acid: pharmacology,Thioctic Acid: therapeutic use,Ubiquitin,Ubiquitin: metabolism,Uncoupling Agents,Uncoupling Agents: pharmacology,alpha-Synuclein,alpha-Synuclein: metabolism",
    	month = "jan",
    	number = "1-2",
    	pages = "215--25",
    	pmid = 20414966,
    	title = "{Combined R-alpha-lipoic acid and acetyl-L-carnitine exerts efficient preventative effects in a cellular model of Parkinson's disease.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/20414966",
    	volume = 14,
    	year = 2010
    }
    
  9. Giovanna Traina, Rodolfo Bernardi, Milena Rizzo, Menotti Calvani, Mauro Durante and Marcello Brunelli.
    Acetyl-L-carnitine up-regulates expression of voltage-dependent anion channel in the rat brain.. Neurochemistry international 48(8):673–8, June 2006.
    Abstract Acetyl-L-carnitine (ALC) exerts unique neuroprotective, neuromodulatory, and neurotrophic properties, which play an important role in counteracting various pathological processes, and have antioxidative properties, protecting cells against lipid peroxidation. In this study, suppression subtractive hybridization (SSH) method was applied for the generation of subtracted cDNA libraries and the subsequent identification of differentially expressed transcripts after treatment of rats with ALC. The technique generates an equalized representation of differentially expressed genes irrespective of their relative abundance and it is based on the construction of forward and reverse cDNA libraries that allow the identification of the genes that are regulated after ALC treatment. In the present paper, we report the identification of the gene of mitochondrial voltage-dependent anion channel (VDAC) protein which is positively modulated by the ALC treatment. VDAC is a small pore-forming protein of the mitochondrial outer membrane. It represents an interesting tool for Ca(2+) homeostasis, and it plays a central role in apoptosis. In addition, VDAC seems to have a relevant role in the synaptic plasticity.
    URL, DOI BibTeX

    @article{Traina2006,
    	abstract = "Acetyl-L-carnitine (ALC) exerts unique neuroprotective, neuromodulatory, and neurotrophic properties, which play an important role in counteracting various pathological processes, and have antioxidative properties, protecting cells against lipid peroxidation. In this study, suppression subtractive hybridization (SSH) method was applied for the generation of subtracted cDNA libraries and the subsequent identification of differentially expressed transcripts after treatment of rats with ALC. The technique generates an equalized representation of differentially expressed genes irrespective of their relative abundance and it is based on the construction of forward and reverse cDNA libraries that allow the identification of the genes that are regulated after ALC treatment. In the present paper, we report the identification of the gene of mitochondrial voltage-dependent anion channel (VDAC) protein which is positively modulated by the ALC treatment. VDAC is a small pore-forming protein of the mitochondrial outer membrane. It represents an interesting tool for Ca(2+) homeostasis, and it plays a central role in apoptosis. In addition, VDAC seems to have a relevant role in the synaptic plasticity.",
    	author = "Traina, Giovanna and Bernardi, Rodolfo and Rizzo, Milena and Calvani, Menotti and Durante, Mauro and Brunelli, Marcello",
    	doi = "10.1016/j.neuint.2005.11.005",
    	issn = "0197-0186",
    	journal = "Neurochemistry international",
    	keywords = "Acetylcarnitine,Acetylcarnitine: metabolism,Acetylcarnitine: pharmacology,Animals,Apoptosis,Apoptosis: drug effects,Apoptosis: physiology,Brain,Brain: drug effects,Brain: metabolism,Calcium Signaling,Calcium Signaling: drug effects,Calcium Signaling: physiology,DNA Fingerprinting,Gene Expression Regulation,Gene Expression Regulation: drug effects,Gene Expression Regulation: physiology,Gene Library,Male,Mitochondria,Mitochondria: drug effects,Mitochondria: metabolism,Mitochondrial Membranes,Mitochondrial Membranes: drug effects,Mitochondrial Membranes: metabolism,Neuronal Plasticity,Neuronal Plasticity: drug effects,Neuronal Plasticity: physiology,Nootropic Agents,Nootropic Agents: metabolism,Nootropic Agents: pharmacology,RNA, Messenger,RNA, Messenger: drug effects,RNA, Messenger: metabolism,Rats,Rats, Wistar,Up-Regulation,Up-Regulation: drug effects,Up-Regulation: physiology,Voltage-Dependent Anion Channel 1,Voltage-Dependent Anion Channel 1: genetics",
    	month = "jun",
    	number = 8,
    	pages = "673--8",
    	pmid = 16527372,
    	title = "{Acetyl-L-carnitine up-regulates expression of voltage-dependent anion channel in the rat brain.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/16527372",
    	volume = 48,
    	year = 2006
    }
    
  10. Francis B Stephens, Dumitru Constantin-Teodosiu, David Laithwaite, Elizabeth J Simpson and Paul L Greenhaff.
    Insulin stimulates L-carnitine accumulation in human skeletal muscle.. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20(2):377–9, March 2006.
    Abstract Increasing skeletal muscle carnitine content may alleviate the decline in muscle fat oxidation seen during intense exercise. Studies to date, however, have failed to increase muscle carnitine content, in healthy humans, by dietary or intravenous L-carnitine administration. We hypothesized that insulin could augment Na+-dependent skeletal muscle carnitine transport. On two randomized visits, eight healthy men underwent 5 h of intravenous L-carnitine infusion with serum insulin maintained at fasting (7.4+/-0.4 mIU*l(-1)) or physiologically high (149.2+/-6.9 mIU*l(-1)) concentrations. The combination of hypercarnitinemia (approximately 500 micromol*l(-1)) and hyperinsulinemia increased muscle total carnitine (TC) content from 22.0 +/- 0.9 to 24.7 +/- 1.4 mmol*(kg dm)(-1) (P<0.05) and was associated with a 2.3 +/- 0.3-fold increase in carnitine transporter protein (OCTN2) mRNA expression (P<0.05). Hypercarnitinemia in the presence of a fasting insulin concentration had no effect on either of these parameters. This study demonstrates that insulin can acutely increase muscle TC content in humans during hypercarnitinemia, which is associated with an increase in OCTN2 transcription. These novel findings may be of importance to the regulation of muscle fat oxidation during exercise, particularly in obesity and type 2 diabetes where it is known to be impaired.
    URL, DOI BibTeX

    @article{Stephens2006,
    	abstract = "Increasing skeletal muscle carnitine content may alleviate the decline in muscle fat oxidation seen during intense exercise. Studies to date, however, have failed to increase muscle carnitine content, in healthy humans, by dietary or intravenous L-carnitine administration. We hypothesized that insulin could augment Na+-dependent skeletal muscle carnitine transport. On two randomized visits, eight healthy men underwent 5 h of intravenous L-carnitine infusion with serum insulin maintained at fasting (7.4+/-0.4 mIU*l(-1)) or physiologically high (149.2+/-6.9 mIU*l(-1)) concentrations. The combination of hypercarnitinemia (approximately 500 micromol*l(-1)) and hyperinsulinemia increased muscle total carnitine (TC) content from 22.0 +/- 0.9 to 24.7 +/- 1.4 mmol*(kg dm)(-1) (P<0.05) and was associated with a 2.3 +/- 0.3-fold increase in carnitine transporter protein (OCTN2) mRNA expression (P<0.05). Hypercarnitinemia in the presence of a fasting insulin concentration had no effect on either of these parameters. This study demonstrates that insulin can acutely increase muscle TC content in humans during hypercarnitinemia, which is associated with an increase in OCTN2 transcription. These novel findings may be of importance to the regulation of muscle fat oxidation during exercise, particularly in obesity and type 2 diabetes where it is known to be impaired.",
    	author = "Stephens, Francis B and Constantin-Teodosiu, Dumitru and Laithwaite, David and Simpson, Elizabeth J and Greenhaff, Paul L",
    	doi = "10.1096/fj.05-4985fje",
    	issn = "1530-6860",
    	journal = "FASEB journal : official publication of the Federation of American Societies for Experimental Biology",
    	keywords = "Adult,Carnitine,Carnitine: blood,Carnitine: metabolism,Carnitine: urine,Humans,Insulin,Insulin: blood,Insulin: pharmacology,Male,Muscle, Skeletal,Muscle, Skeletal: drug effects,Muscle, Skeletal: metabolism,Organic Cation Transport Proteins,Organic Cation Transport Proteins: metabolism,RNA, Messenger,RNA, Messenger: metabolism,Sodium,Sodium: metabolism,Transcription, Genetic",
    	month = "mar",
    	number = 2,
    	pages = "377--9",
    	pmid = 16368715,
    	title = "{Insulin stimulates L-carnitine accumulation in human skeletal muscle.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/16368715",
    	volume = 20,
    	year = 2006
    }
    
  11. Hafiz Mohmmad Abdul, Vittorio Calabrese, Menotti Calvani and Allan D Butterfield.
    Acetyl-L-carnitine-induced up-regulation of heat shock proteins protects cortical neurons against amyloid-beta peptide 1-42-mediated oxidative stress and neurotoxicity: implications for Alzheimer's disease.. Journal of neuroscience research 84(2):398–408, 2006.
    Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by loss of memory and cognition and by senile plaques and neurofibrillary tangles in brain. Amyloid-beta peptide, particularly the 42-amino-acid peptide (Abeta(1-42)), is a principal component of senile plaques and is thought to be central to the pathogenesis of the disease. The AD brain is under significant oxidative stress, and Abeta(1-42) peptide is known to cause oxidative stress in vitro and in vivo. Acetyl-L-carnitine (ALCAR) is an endogenous mitochondrial membrane compound that helps to maintain mitochondrial bioenergetics and lowers the increased oxidative stress associated with aging. Glutathione (GSH) is an important endogenous antioxidant, and its levels have been shown to decrease with aging. Administration of ALCAR increases cellular levels of GSH in rat astrocytes. In the current study, we investigated whether ALCAR plays a protective role in cortical neuronal cells against Abeta(1-42)-mediated oxidative stress and neurotoxicity. Decreased cell survival in neuronal cultures treated with Abeta(1-42) correlated with an increase in protein oxidation (protein carbonyl, 3-nitrotyrosine) and lipid peroxidation (4-hydroxy-2-nonenal) formation. Pretreatment of primary cortical neuronal cultures with ALCAR significantly attenuated Abeta(1-42)-induced cytotoxicity, protein oxidation, lipid peroxidation, and apoptosis in a dose-dependent manner. Addition of ALCAR to neurons also led to an elevated cellular GSH and heat shock proteins (HSPs) levels compared with untreated control cells. Our results suggest that ALCAR exerts protective effects against Abeta(1-42) toxicity and oxidative stress in part by up-regulating the levels of GSH and HSPs. This evidence supports the pharmacological potential of acetyl carnitine in the management of Abeta(1-42)-induced oxidative stress and neurotoxicity. Therefore, ALCAR may be useful as a possible therapeutic strategy for patients with AD.
    URL, DOI BibTeX

    @article{Abdul2006,
    	abstract = "Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by loss of memory and cognition and by senile plaques and neurofibrillary tangles in brain. Amyloid-beta peptide, particularly the 42-amino-acid peptide (Abeta(1-42)), is a principal component of senile plaques and is thought to be central to the pathogenesis of the disease. The AD brain is under significant oxidative stress, and Abeta(1-42) peptide is known to cause oxidative stress in vitro and in vivo. Acetyl-L-carnitine (ALCAR) is an endogenous mitochondrial membrane compound that helps to maintain mitochondrial bioenergetics and lowers the increased oxidative stress associated with aging. Glutathione (GSH) is an important endogenous antioxidant, and its levels have been shown to decrease with aging. Administration of ALCAR increases cellular levels of GSH in rat astrocytes. In the current study, we investigated whether ALCAR plays a protective role in cortical neuronal cells against Abeta(1-42)-mediated oxidative stress and neurotoxicity. Decreased cell survival in neuronal cultures treated with Abeta(1-42) correlated with an increase in protein oxidation (protein carbonyl, 3-nitrotyrosine) and lipid peroxidation (4-hydroxy-2-nonenal) formation. Pretreatment of primary cortical neuronal cultures with ALCAR significantly attenuated Abeta(1-42)-induced cytotoxicity, protein oxidation, lipid peroxidation, and apoptosis in a dose-dependent manner. Addition of ALCAR to neurons also led to an elevated cellular GSH and heat shock proteins (HSPs) levels compared with untreated control cells. Our results suggest that ALCAR exerts protective effects against Abeta(1-42) toxicity and oxidative stress in part by up-regulating the levels of GSH and HSPs. This evidence supports the pharmacological potential of acetyl carnitine in the management of Abeta(1-42)-induced oxidative stress and neurotoxicity. Therefore, ALCAR may be useful as a possible therapeutic strategy for patients with AD.",
    	author = "Abdul, Hafiz Mohmmad and Calabrese, Vittorio and Calvani, Menotti and Butterfield, D Allan",
    	doi = "10.1002/jnr.20877",
    	issn = "0360-4012",
    	journal = "Journal of neuroscience research",
    	keywords = "Acetylcarnitine,Acetylcarnitine: pharmacology,Alzheimer Disease,Alzheimer Disease: metabolism,Amyloid beta-Peptides,Amyloid beta-Peptides: toxicity,Animals,Blotting, Western,Cells, Cultured,Cerebral Cortex,Cerebral Cortex: drug effects,Cerebral Cortex: pathology,DNA Fragmentation,Glutathione,Glutathione: drug effects,Glutathione: metabolism,Heat-Shock Proteins,Heat-Shock Proteins: drug effects,Heat-Shock Proteins: metabolism,Lipid Peroxidation,Lipid Peroxidation: drug effects,Neurons,Neurons: drug effects,Neurons: metabolism,Neuroprotective Agents,Neuroprotective Agents: pharmacology,Oxidation-Reduction,Oxidation-Reduction: drug effects,Oxidative Stress,Oxidative Stress: drug effects,Oxidative Stress: physiology,Proteins,Proteins: drug effects,Rats,Rats, Sprague-Dawley,Up-Regulation",
    	month = "",
    	number = 2,
    	pages = "398--408",
    	pmid = 16634066,
    	title = "{Acetyl-L-carnitine-induced up-regulation of heat shock proteins protects cortical neurons against amyloid-beta peptide 1-42-mediated oxidative stress and neurotoxicity: implications for Alzheimer's disease.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/16634066",
    	volume = 84,
    	year = 2006
    }
    
  12. P Bigini, S Larini, C Pasquali, V Muzio and T Mennini.
    Acetyl-L-carnitine shows neuroprotective and neurotrophic activity in primary culture of rat embryo motoneurons.. Neuroscience letters 329(3):334–8, September 2002.
    Abstract We evaluated the role of acetyl-L-carnitine (ALCAR) in protecting primary motoneuron cultures exposed to excitotoxic agents or serum-brain derived neurotrophic factor (BDNF) deprived. To exclude that ALCAR works as a metabolic source, we compared its effects with those of L-carnitine (L-CAR), that seems to have no neurotrophic effect. A concentration of 10 mM ALCAR, but not L-CAR, significantly reduced the toxic effect of 50 microM N-methyl-D-aspartate (NMDA, % viability: NMDA 45.4+/-2.80, NMDA+ALCAR 90.8+/-11.8; P<0.01) and of 5 microM kainate in cultured motoneurons (% viability: kainate 40.66+/-10.73; kainate+ALCAR 63.80+/-13.88; P<0.05). The effect was due to a shift to the right of the dose-response curve for kainate (EC50 for kainate 5.99+/-1.012 microM; kainate+ALCAR 8.62+/-1.13 microM; P<0.05). ALCAR, but not L-CAR, significantly protected against BDNF and serum-deprivation reducing the apoptotic cell death (% viability respect to control: without BDNF/serum 61.8+/-13.3: without BDNF/serum+ALCAR 111.8+/-13.9; P<0.01). Immunocytochemistry showed an increase in choline acethyltransferase and tyrosine kinaseB receptors in motoneurons treated with ALCAR but not with L-CAR. These results suggest that ALCAR treatment improves the motoneurons activity, acting as a neurotrophic factor.
    URL BibTeX

    @article{Bigini2002,
    	abstract = "We evaluated the role of acetyl-L-carnitine (ALCAR) in protecting primary motoneuron cultures exposed to excitotoxic agents or serum-brain derived neurotrophic factor (BDNF) deprived. To exclude that ALCAR works as a metabolic source, we compared its effects with those of L-carnitine (L-CAR), that seems to have no neurotrophic effect. A concentration of 10 mM ALCAR, but not L-CAR, significantly reduced the toxic effect of 50 microM N-methyl-D-aspartate (NMDA, \% viability: NMDA 45.4+/-2.80, NMDA+ALCAR 90.8+/-11.8; P<0.01) and of 5 microM kainate in cultured motoneurons (\% viability: kainate 40.66+/-10.73; kainate+ALCAR 63.80+/-13.88; P<0.05). The effect was due to a shift to the right of the dose-response curve for kainate (EC50 for kainate 5.99+/-1.012 microM; kainate+ALCAR 8.62+/-1.13 microM; P<0.05). ALCAR, but not L-CAR, significantly protected against BDNF and serum-deprivation reducing the apoptotic cell death (\% viability respect to control: without BDNF/serum 61.8+/-13.3: without BDNF/serum+ALCAR 111.8+/-13.9; P<0.01). Immunocytochemistry showed an increase in choline acethyltransferase and tyrosine kinaseB receptors in motoneurons treated with ALCAR but not with L-CAR. These results suggest that ALCAR treatment improves the motoneurons activity, acting as a neurotrophic factor.",
    	author = "Bigini, P and Larini, S and Pasquali, C and Muzio, V and Mennini, T",
    	issn = "0304-3940",
    	journal = "Neuroscience letters",
    	keywords = "Acetylcarnitine,Acetylcarnitine: pharmacology,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: drug therapy,Animals,Cells, Cultured,Choline O-Acetyltransferase,Choline O-Acetyltransferase: metabolism,Fetus,Fetus: cytology,Motor Neurons,Motor Neurons: cytology,Motor Neurons: drug effects,Neuroprotective Agents,Neuroprotective Agents: pharmacology,Neurotoxins,Neurotoxins: pharmacology,Nootropic Agents,Nootropic Agents: pharmacology,Rats,Rats, Sprague-Dawley,Receptor Protein-Tyrosine Kinases,Receptor Protein-Tyrosine Kinases: metabolism",
    	month = "sep",
    	number = 3,
    	pages = "334--8",
    	pmid = 12183043,
    	title = "{Acetyl-L-carnitine shows neuroprotective and neurotrophic activity in primary culture of rat embryo motoneurons.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/12183043",
    	volume = 329,
    	year = 2002
    }
    
  13. K V Rao and I A Qureshi.
    Reduction in the MK-801 binding sites of the NMDA sub-type of glutamate receptor in a mouse model of congenital hyperammonemia: prevention by acetyl-L-carnitine.. Neuropharmacology 38(3):383–94, March 1999.
    Abstract Our earlier studies on the pharmacotherapeutic effects of acetyl-L-carnitine (ALCAR), in sparse-fur (spf) mutant mice with X linked ornithine transcarbamylase deficiency, have shown a restoration of cerebral ATP, depleted by congenital hyperammonemia and hyperglutaminemia. The reduced cortical glutamate and increased quinolinate may cause a down-regulation of the N-methyl-D-aspartate (NMDA) receptors, observed by us in adult spf mice. We have now studied the kinetics of [3H]-MK-801 binding to NMDA receptors in spf mice of different ages to see the effect of chronic hyperammonemia on the glutamate neurotransmission. We have also studied the Ca2+-dependent and independent (4-aminopyridine (AP) and veratridine-mediated) release of glutamate and the uptake of [3H]-glutamate in synaptosomes isolated from mutant spf mice and normal CD-1 controls. All these studies were done with and without ALCAR treatment (4 mmol/kg wt i.p. daily for 2 weeks), to see if its effect on ATP repletion could correct the glutamate neurotransmitter abnormalities. Our results indicate a normal MK-801 binding in 12-day-old spf mice but a significant reduction immediately after weaning (21 day), continuing into the adult stage. The Ca2+-independent release of endogenous glutamate from synaptosomes was significantly elevated at 35 days, while the uptake of glutamate into synaptosomes was significantly reduced in spf mice. ALCAR treatment significantly enhanced the MK-801 binding, neutralized the increased glutamate release and restored the glutamate uptake into synaptosomes of spf mice. These studies point out that: (a) the developmental abnormalities of the NMDA sub-type of glutamate receptor in spf mice could be due to the effect of sustained hyperammonemia, causing a persistent release of excess glutamate and inhibition of the ATP-dependent glutamate transport, (b) the modulatory effects of ALCAR on the NMDA binding sites could be through a repletion of ATP, required by the transporters to efficiently remove extracellular glutamate.
    URL BibTeX

    @article{Rao1999,
    	abstract = "Our earlier studies on the pharmacotherapeutic effects of acetyl-L-carnitine (ALCAR), in sparse-fur (spf) mutant mice with X linked ornithine transcarbamylase deficiency, have shown a restoration of cerebral ATP, depleted by congenital hyperammonemia and hyperglutaminemia. The reduced cortical glutamate and increased quinolinate may cause a down-regulation of the N-methyl-D-aspartate (NMDA) receptors, observed by us in adult spf mice. We have now studied the kinetics of [3H]-MK-801 binding to NMDA receptors in spf mice of different ages to see the effect of chronic hyperammonemia on the glutamate neurotransmission. We have also studied the Ca2+-dependent and independent (4-aminopyridine (AP) and veratridine-mediated) release of glutamate and the uptake of [3H]-glutamate in synaptosomes isolated from mutant spf mice and normal CD-1 controls. All these studies were done with and without ALCAR treatment (4 mmol/kg wt i.p. daily for 2 weeks), to see if its effect on ATP repletion could correct the glutamate neurotransmitter abnormalities. Our results indicate a normal MK-801 binding in 12-day-old spf mice but a significant reduction immediately after weaning (21 day), continuing into the adult stage. The Ca2+-independent release of endogenous glutamate from synaptosomes was significantly elevated at 35 days, while the uptake of glutamate into synaptosomes was significantly reduced in spf mice. ALCAR treatment significantly enhanced the MK-801 binding, neutralized the increased glutamate release and restored the glutamate uptake into synaptosomes of spf mice. These studies point out that: (a) the developmental abnormalities of the NMDA sub-type of glutamate receptor in spf mice could be due to the effect of sustained hyperammonemia, causing a persistent release of excess glutamate and inhibition of the ATP-dependent glutamate transport, (b) the modulatory effects of ALCAR on the NMDA binding sites could be through a repletion of ATP, required by the transporters to efficiently remove extracellular glutamate.",
    	author = "Rao, K V and Qureshi, I A",
    	issn = "0028-3908",
    	journal = "Neuropharmacology",
    	keywords = "Acetylcarnitine,Acetylcarnitine: pharmacology,Adenosine Triphosphate,Adenosine Triphosphate: metabolism,Aging,Aging: metabolism,Amino Acid Metabolism, Inborn Errors,Amino Acid Metabolism, Inborn Errors: metabolism,Ammonia,Ammonia: blood,Animals,Cerebral Cortex,Cerebral Cortex: growth \& development,Cerebral Cortex: metabolism,Dizocilpine Maleate,Dizocilpine Maleate: metabolism,Excitatory Amino Acid Antagonists,Excitatory Amino Acid Antagonists: metabolism,Gene Expression Regulation, Developmental,Kinetics,Mice,Mice, Mutant Strains,Nootropic Agents,Nootropic Agents: pharmacology,Ornithine Carbamoyltransferase Deficiency Disease,Receptors, N-Methyl-D-Aspartate,Receptors, N-Methyl-D-Aspartate: genetics,Receptors, N-Methyl-D-Aspartate: metabolism,Reference Values,Synaptic Membranes,Synaptic Membranes: metabolism",
    	month = "mar",
    	number = 3,
    	pages = "383--94",
    	pmid = 10219976,
    	title = "{Reduction in the MK-801 binding sites of the NMDA sub-type of glutamate receptor in a mouse model of congenital hyperammonemia: prevention by acetyl-L-carnitine.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/10219976",
    	volume = 38,
    	year = 1999
    }
    
  14. M Calvani and E Arrigoni-Martelli.
    Attenuation by acetyl-L-carnitine of neurological damage and biochemical derangement following brain ischemia and reperfusion.. International journal of tissue reactions 21(1):1–6, January 1999.
    Abstract Alterations in brain metabolism after ischemia and reperfusion are described herein. Several roles played by carnitine and acetylcarnitine can be of particular relevance in counteracting these brain metabolism alterations. The effects of acetylcarnitine in several experimental models of brain ischemia in rats are described. The data obtained show that acetylcarnitine can have significant clinical neuroprotective effects when administered shortly after the onset of focal or global cerebral ischemia. In the canine cardiac arrest model, acetylcarnitine improved the postischemic neurological outcome and tissue levels of lactate and pyruvate were normalized. A trend toward reversal of pyruvate dehydrogenase inhibition in acetylcarnitine-treated dogs was also observed. The immediate postischemic administration of acetylcarnitine prevents free radical-mediated protein oxidation in the frontal cortex of dogs submitted to cardiac arrest and resuscitation. The transfer of the acetyl group to coenzyme A (CoA) to form acetyl-CoA as the primary source of energy is a plausible mechanism of action of acetylcarnitine.
    URL BibTeX

    @article{Calvani1999,
    	abstract = "Alterations in brain metabolism after ischemia and reperfusion are described herein. Several roles played by carnitine and acetylcarnitine can be of particular relevance in counteracting these brain metabolism alterations. The effects of acetylcarnitine in several experimental models of brain ischemia in rats are described. The data obtained show that acetylcarnitine can have significant clinical neuroprotective effects when administered shortly after the onset of focal or global cerebral ischemia. In the canine cardiac arrest model, acetylcarnitine improved the postischemic neurological outcome and tissue levels of lactate and pyruvate were normalized. A trend toward reversal of pyruvate dehydrogenase inhibition in acetylcarnitine-treated dogs was also observed. The immediate postischemic administration of acetylcarnitine prevents free radical-mediated protein oxidation in the frontal cortex of dogs submitted to cardiac arrest and resuscitation. The transfer of the acetyl group to coenzyme A (CoA) to form acetyl-CoA as the primary source of energy is a plausible mechanism of action of acetylcarnitine.",
    	author = "Calvani, M and Arrigoni-Martelli, E",
    	issn = "0250-0868",
    	journal = "International journal of tissue reactions",
    	keywords = "Acetylcarnitine,Acetylcarnitine: therapeutic use,Animals,Brain,Brain Ischemia,Brain Ischemia: metabolism,Brain Ischemia: pathology,Brain: drug effects,Brain: metabolism,Brain: pathology,Carnitine,Carnitine: physiology,Dogs,Oxidation-Reduction,Rats,Reperfusion Injury,Reperfusion Injury: prevention \& control",
    	month = "jan",
    	number = 1,
    	pages = "1--6",
    	pmid = 10463134,
    	title = "{Attenuation by acetyl-L-carnitine of neurological damage and biochemical derangement following brain ischemia and reperfusion.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/10463134",
    	volume = 21,
    	year = 1999
    }
    
  15. J Nakamura, N Koh, F Sakakibara, Y Hamada, T Hara, H Sasaki, S Chaya, T Komori, E Nakashima, K Naruse, K Kato, N Takeuchi, Y Kasuya and N Hotta.
    Polyol pathway hyperactivity is closely related to carnitine deficiency in the pathogenesis of diabetic neuropathy of streptozotocin-diabetic rats.. The Journal of pharmacology and experimental therapeutics 287(3):897–902, 1998.
    Abstract To investigate the relationship between polyol pathway hyperactivity and altered carnitine metabolism in the pathogenesis of diabetic neuropathy, the effects of an aldose reductase inhibitor, [5-(3-thienyl) tetrazol-1-yl]acetic acid (TAT), and a carnitine analog, acetyl-L-carnitine (ALC), on neural functions and biochemistry and hemodynamic factors were compared in streptozotocin-diabetic rats. Significantly delayed motor nerve conduction velocity, decreased R-R interval variation, reduced sciatic nerve blood flow and decreased erythrocyte 2, 3-diphosphoglycerate concentrations in diabetic rats were all ameliorated by treatment with TAT (administered with rat chow containing 0.05% TAT, approximately 50 mg/kg/day) or ALC (by gavage, 300 mg/kg/day) for 4 weeks. Platelet hyperaggregation activity in diabetic rats was diminished by TAT but not by ALC. TAT decreased sorbitol accumulation and prevented not only myo-inositol depletion but also free-carnitine deficiency in diabetic nerves. On the other hand, ALC also increased the myo-inositol as well as the free-carnitine content without affecting the sorbitol content. These observations suggest that there is a close relationship between increased polyol pathway activity and carnitine deficiency in the development of diabetic neuropathy and that an aldose reductase inhibitor, TAT, and a carnitine analog, ALC, have therapeutic potential for the treatment of diabetic neuropathy.
    URL BibTeX

    @article{Nakamura1998,
    	abstract = "To investigate the relationship between polyol pathway hyperactivity and altered carnitine metabolism in the pathogenesis of diabetic neuropathy, the effects of an aldose reductase inhibitor, [5-(3-thienyl) tetrazol-1-yl]acetic acid (TAT), and a carnitine analog, acetyl-L-carnitine (ALC), on neural functions and biochemistry and hemodynamic factors were compared in streptozotocin-diabetic rats. Significantly delayed motor nerve conduction velocity, decreased R-R interval variation, reduced sciatic nerve blood flow and decreased erythrocyte 2, 3-diphosphoglycerate concentrations in diabetic rats were all ameliorated by treatment with TAT (administered with rat chow containing 0.05\% TAT, approximately 50 mg/kg/day) or ALC (by gavage, 300 mg/kg/day) for 4 weeks. Platelet hyperaggregation activity in diabetic rats was diminished by TAT but not by ALC. TAT decreased sorbitol accumulation and prevented not only myo-inositol depletion but also free-carnitine deficiency in diabetic nerves. On the other hand, ALC also increased the myo-inositol as well as the free-carnitine content without affecting the sorbitol content. These observations suggest that there is a close relationship between increased polyol pathway activity and carnitine deficiency in the development of diabetic neuropathy and that an aldose reductase inhibitor, TAT, and a carnitine analog, ALC, have therapeutic potential for the treatment of diabetic neuropathy.",
    	author = "Nakamura, J and Koh, N and Sakakibara, F and Hamada, Y and Hara, T and Sasaki, H and Chaya, S and Komori, T and Nakashima, E and Naruse, K and Kato, K and Takeuchi, N and Kasuya, Y and Hotta, N",
    	issn = "0022-3565",
    	journal = "The Journal of pharmacology and experimental therapeutics",
    	keywords = "Acetylcarnitine,Acetylcarnitine: therapeutic use,Aldehyde Reductase,Aldehyde Reductase: antagonists \& inhibitors,Aldehyde Reductase: metabolism,Animals,Body Weight,Carnitine,Carnitine: analysis,Carnitine: deficiency,Diabetes Mellitus, Experimental,Diabetes Mellitus, Experimental: blood,Diabetes Mellitus, Experimental: complications,Diabetic Neuropathies,Diabetic Neuropathies: blood,Diabetic Neuropathies: drug therapy,Diabetic Neuropathies: etiology,Enzyme Inhibitors,Enzyme Inhibitors: therapeutic use,Hemodynamics,Hemodynamics: drug effects,Male,Neural Conduction,Neural Conduction: drug effects,Polymers,Polymers: analysis,Rats,Rats, Sprague-Dawley,Sciatic Nerve,Sciatic Nerve: blood supply,Tetrazoles,Tetrazoles: therapeutic use,Thiophenes,Thiophenes: therapeutic use",
    	month = "",
    	number = 3,
    	pages = "897--902",
    	pmid = 9864270,
    	title = "{Polyol pathway hyperactivity is closely related to carnitine deficiency in the pathogenesis of diabetic neuropathy of streptozotocin-diabetic rats.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/9864270",
    	volume = 287,
    	year = 1998
    }
    
  16. E Fernandez, R Pallini, L Lauretti, F La Marca, A Scogna and G F Rossi.
    Motonuclear changes after cranial nerve injury and regeneration.. Archives italiennes de biologie 135(4):343–51, September 1997.
    Abstract Little is known about the mechanisms at play in nerve regeneration after nerve injury. Personal studies are reported regarding motonuclear changes after regeneration of injured cranial nerves, in particular of the facial and oculomotor nerves, as well as the influence that the natural molecule acetyl-L-carnitine (ALC) has on post-axotomy cranial nerve motoneuron degeneration after facial and vagus nerve lesions. Adult and newborn animal models were used. Massive motoneuron response after nerve section and reconstruction was observed in the motonuclei of all nerves studied. ALC showed to have significant neuroprotective effects on the degeneration of axotomized motoneurons. Complex quantitative, morphological and somatotopic nuclear changes occurred that sustain new hypotheses regarding the capacities of motoneurons to regenerate and the possibilities of new neuron proliferation. The particularities of such observations are described and discussed.
    URL BibTeX

    @article{Fernandez1997,
    	abstract = "Little is known about the mechanisms at play in nerve regeneration after nerve injury. Personal studies are reported regarding motonuclear changes after regeneration of injured cranial nerves, in particular of the facial and oculomotor nerves, as well as the influence that the natural molecule acetyl-L-carnitine (ALC) has on post-axotomy cranial nerve motoneuron degeneration after facial and vagus nerve lesions. Adult and newborn animal models were used. Massive motoneuron response after nerve section and reconstruction was observed in the motonuclei of all nerves studied. ALC showed to have significant neuroprotective effects on the degeneration of axotomized motoneurons. Complex quantitative, morphological and somatotopic nuclear changes occurred that sustain new hypotheses regarding the capacities of motoneurons to regenerate and the possibilities of new neuron proliferation. The particularities of such observations are described and discussed.",
    	author = "Fernandez, E and Pallini, R and Lauretti, L and {La Marca}, F and Scogna, A and Rossi, G F",
    	issn = "0003-9829",
    	journal = "Archives italiennes de biologie",
    	keywords = "Acetylcarnitine,Acetylcarnitine: pharmacology,Animals,Axons,Axons: physiology,Cell Nucleus,Cell Nucleus: physiology,Facial Nerve,Facial Nerve Injuries,Facial Nerve: ultrastructure,Guinea Pigs,Motor Neurons,Motor Neurons: physiology,Nerve Degeneration,Nerve Degeneration: physiology,Nerve Regeneration,Nerve Regeneration: physiology,Nootropic Agents,Nootropic Agents: pharmacology,Oculomotor Nerve,Oculomotor Nerve Injuries,Oculomotor Nerve: ultrastructure,Rats,Vagus Nerve,Vagus Nerve: physiology",
    	month = "sep",
    	number = 4,
    	pages = "343--51",
    	pmid = 9270896,
    	title = "{Motonuclear changes after cranial nerve injury and regeneration.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/9270896",
    	volume = 135,
    	year = 1997
    }
    
  17. K Schönheit, L Gille and H Nohl.
    Effect of alpha-lipoic acid and dihydrolipoic acid on ischemia/reperfusion injury of the heart and heart mitochondria.. Biochimica et biophysica acta 1271(2-3):335–42, 1995.
    Abstract The aim of the present study was to evaluate a possible interference of alpha-lipoic acid (LA) or its reduced form (dithiol dihydrolipoic acid = DHLA) in the cardiac ischemia/reperfusion injury both at the level of the intact organ and at the subcellular level of mitochondria. In order to follow the effect of LA on the ischemia/reperfusion injury of the heart the isolated perfused organ was subjected to total global ischemia and reperfusion in the presence and absence of different concentrations of LA. Treatment with 0.5 microM LA improved the recovery of hemodynamic parameters; electrophysiological parameters were not influenced. However, application of 10 microM LA to rat hearts further impaired the recovery of hemodynamic functions and prolonged the duration of severe rhythm disturbances in comparison to reperfusion of control hearts. Treatment of isolated mitochondria with any concentration of DHLA could not prevent the impairment of respiratory-linked energy conservation caused by the exposure of mitochondria to 'reperfusion' conditions. However, DHLA was effective in decreasing the formation and the existence of mitochondrial superoxide radicals (O2.-). Apart from its direct O(2.-)-scavenging activities DHLA was also found to control mitochondrial O2.- formation indirectly by regulating redox-cycling ubiquinone. It is suggested that impairment of this mitochondrial O2.- generator mitigates postischemic oxidative stress which in turn reduces damage to hemodynamic heart function.
    URL BibTeX

    @article{Schonheit1995,
    	abstract = "The aim of the present study was to evaluate a possible interference of alpha-lipoic acid (LA) or its reduced form (dithiol dihydrolipoic acid = DHLA) in the cardiac ischemia/reperfusion injury both at the level of the intact organ and at the subcellular level of mitochondria. In order to follow the effect of LA on the ischemia/reperfusion injury of the heart the isolated perfused organ was subjected to total global ischemia and reperfusion in the presence and absence of different concentrations of LA. Treatment with 0.5 microM LA improved the recovery of hemodynamic parameters; electrophysiological parameters were not influenced. However, application of 10 microM LA to rat hearts further impaired the recovery of hemodynamic functions and prolonged the duration of severe rhythm disturbances in comparison to reperfusion of control hearts. Treatment of isolated mitochondria with any concentration of DHLA could not prevent the impairment of respiratory-linked energy conservation caused by the exposure of mitochondria to 'reperfusion' conditions. However, DHLA was effective in decreasing the formation and the existence of mitochondrial superoxide radicals (O2.-). Apart from its direct O(2.-)-scavenging activities DHLA was also found to control mitochondrial O2.- formation indirectly by regulating redox-cycling ubiquinone. It is suggested that impairment of this mitochondrial O2.- generator mitigates postischemic oxidative stress which in turn reduces damage to hemodynamic heart function.",
    	author = {Sch\"{o}nheit, K and Gille, L and Nohl, H},
    	issn = "0006-3002",
    	journal = "Biochimica et biophysica acta",
    	keywords = "Animals,Hemodynamics,Male,Mitochondria, Heart,Mitochondria, Heart: drug effects,Myocardial Ischemia,Myocardial Ischemia: prevention \& control,Myocardial Reperfusion Injury,Myocardial Reperfusion Injury: prevention \& contro,Oxidative Stress,Perfusion,Rats,Rats, Sprague-Dawley,Thioctic Acid,Thioctic Acid: analogs \& derivatives,Thioctic Acid: metabolism,Thioctic Acid: pharmacology",
    	month = "",
    	number = "2-3",
    	pages = "335--42",
    	pmid = 7605800,
    	title = "{Effect of alpha-lipoic acid and dihydrolipoic acid on ischemia/reperfusion injury of the heart and heart mitochondria.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/7605800",
    	volume = 1271,
    	year = 1995
    }
    
  18. T Kato.
    Choline acetyltransferase activities in single spinal motor neurons from patients with amyotrophic lateral sclerosis.. Journal of neurochemistry 52(2):636–40, March 1989.
    Abstract Activities of choline acetyltransferase (ChAT) were microassayed in individual cell bodies of motor neurons, isolated from freeze-dried sections after autopsy of lumbar spinal cords from four patients with sporadic amyotrophic lateral sclerosis (ALS) and four control patients with nonneurological diseases. Numerous large neurons were found in the anterior horn at the early degeneration stage of ALS, but the cell bodies atrophied and decreased in number at the late advanced stage. The small, atrophied neurons were very fragile and were easily destroyed during the isolation procedure with a microknife. The average activity, expressed on a dry weight basis, of 58 ALS neurons was lower than that of 67 control neurons. The large, well-preserved neurons at the early nonadvanced stage had markedly lower ChAT activities than control neurons. The specific activity gradually increased with the progress of atrophy but did not return to the control level.
    URL BibTeX

    @article{Kato1989,
    	abstract = "Activities of choline acetyltransferase (ChAT) were microassayed in individual cell bodies of motor neurons, isolated from freeze-dried sections after autopsy of lumbar spinal cords from four patients with sporadic amyotrophic lateral sclerosis (ALS) and four control patients with nonneurological diseases. Numerous large neurons were found in the anterior horn at the early degeneration stage of ALS, but the cell bodies atrophied and decreased in number at the late advanced stage. The small, atrophied neurons were very fragile and were easily destroyed during the isolation procedure with a microknife. The average activity, expressed on a dry weight basis, of 58 ALS neurons was lower than that of 67 control neurons. The large, well-preserved neurons at the early nonadvanced stage had markedly lower ChAT activities than control neurons. The specific activity gradually increased with the progress of atrophy but did not return to the control level.",
    	author = "Kato, T",
    	issn = "0022-3042",
    	journal = "Journal of neurochemistry",
    	keywords = "Adult,Aged,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: enzymology,Amyotrophic Lateral Sclerosis: pathology,Animals,Cats,Choline O-Acetyltransferase,Choline O-Acetyltransferase: metabolism,Cytoplasmic Granules,Female,Humans,Lipofuscin,Lipofuscin: metabolism,Male,Middle Aged,Motor Neurons,Motor Neurons: enzymology,Motor Neurons: pathology,Spinal Cord,Spinal Cord: enzymology,Spinal Cord: pathology",
    	month = "mar",
    	number = 2,
    	pages = "636--40",
    	pmid = 2911033,
    	title = "{Choline acetyltransferase activities in single spinal motor neurons from patients with amyotrophic lateral sclerosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/2911033",
    	volume = 52,
    	year = 1989
    }
    
  19. P Harper, C E Elwin and G Cederblad.
    Pharmacokinetics of intravenous and oral bolus doses of L-carnitine in healthy subjects.. European journal of clinical pharmacology 35(5):555–62, January 1988.
    Abstract The pharmacokinetics of single intravenous and oral doses of L-carnitine 2 g and 6 g has been investigated in 6 healthy subjects on a low carnitine diet. Carnitine was more rapidly eliminated from plasma after the higher dose. Comparing the 2-g and 6-g doses, the t1/2 beta of the elimination phase (beta) was 6.5 h vs 3.9 h, the elimination constant was 0.40 vs 0.50 h-1 and the plasma carnitine clearance was 5.4 vs 6.1 1 x h-1 (p less than 0.025), thus showing dose-related elimination. Saturable kinetics was not found in the range of doses given. The apparent volumes of distribution after the two doses were not significantly different and they were of the same order as the total body water. Urinary recoveries after the 2-g and 6-g doses were 70% and 82% during the first 24 h, respectively. Following the two oral dosing, there was no significant difference in AUCs of plasma carnitine. Urinary recoveries were 8% and 4% for the 2-g and 6-g doses during the first 24 h. The oral bioavailability of the 2-g dose was 16% and of the 6 h dose 5%. The results suggest that the mucosal absorption of carnitine is already saturated at the 2-g dose.
    URL BibTeX

    @article{Harper1988,
    	abstract = "The pharmacokinetics of single intravenous and oral doses of L-carnitine 2 g and 6 g has been investigated in 6 healthy subjects on a low carnitine diet. Carnitine was more rapidly eliminated from plasma after the higher dose. Comparing the 2-g and 6-g doses, the t1/2 beta of the elimination phase (beta) was 6.5 h vs 3.9 h, the elimination constant was 0.40 vs 0.50 h-1 and the plasma carnitine clearance was 5.4 vs 6.1 1 x h-1 (p less than 0.025), thus showing dose-related elimination. Saturable kinetics was not found in the range of doses given. The apparent volumes of distribution after the two doses were not significantly different and they were of the same order as the total body water. Urinary recoveries after the 2-g and 6-g doses were 70\% and 82\% during the first 24 h, respectively. Following the two oral dosing, there was no significant difference in AUCs of plasma carnitine. Urinary recoveries were 8\% and 4\% for the 2-g and 6-g doses during the first 24 h. The oral bioavailability of the 2-g dose was 16\% and of the 6 h dose 5\%. The results suggest that the mucosal absorption of carnitine is already saturated at the 2-g dose.",
    	author = "Harper, P and Elwin, C E and Cederblad, G",
    	issn = "0031-6970",
    	journal = "European journal of clinical pharmacology",
    	keywords = "Administration, Oral,Adult,Biological Availability,Carnitine,Carnitine: administration \& dosage,Carnitine: blood,Carnitine: pharmacokinetics,Diet,Female,Half-Life,Humans,Injections, Intravenous,Metabolic Clearance Rate,Middle Aged",
    	month = "jan",
    	number = 5,
    	pages = "555--62",
    	pmid = 3234464,
    	title = "{Pharmacokinetics of intravenous and oral bolus doses of L-carnitine in healthy subjects.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/3234464",
    	volume = 35,
    	year = 1988
    }
    
  20. S Di Donato, F E Frerman, M Rimoldi, P Rinaldo, F Taroni and U N Wiesmann.
    Systemic carnitine deficiency due to lack of electron transfer flavoprotein:ubiquinone oxidoreductase.. Neurology 36(7):957–63, 1986.
    Abstract A child with myopathy and systemic carnitine deficiency died at age 8 years in an acute metabolic attack. He had glutaric aciduria type II, and his cultured fibroblasts contained normal activity of four different acyl CoA dehydrogenases, but there was deficiency of electron transfer flavoprotein:ubiquinone oxidoreductase (ETF-QO). This enzyme is thought to reduce coenzyme Q in the respiratory chain, funneling reducing equivalents from seven flavoproteins in the beta-oxidation of acyl CoAs. There was massive urinary excretion of the short-chain acylcarnitines that accumulated in mitochondria as a result of the ETF-QO defect. Carnitine therefore acts as a buffer for excessive accumulation of intramitochondrial acyl CoAs, and defective beta-oxidation can cause carnitine insufficiency.
    URL BibTeX

    @article{DiDonato1986,
    	abstract = "A child with myopathy and systemic carnitine deficiency died at age 8 years in an acute metabolic attack. He had glutaric aciduria type II, and his cultured fibroblasts contained normal activity of four different acyl CoA dehydrogenases, but there was deficiency of electron transfer flavoprotein:ubiquinone oxidoreductase (ETF-QO). This enzyme is thought to reduce coenzyme Q in the respiratory chain, funneling reducing equivalents from seven flavoproteins in the beta-oxidation of acyl CoAs. There was massive urinary excretion of the short-chain acylcarnitines that accumulated in mitochondria as a result of the ETF-QO defect. Carnitine therefore acts as a buffer for excessive accumulation of intramitochondrial acyl CoAs, and defective beta-oxidation can cause carnitine insufficiency.",
    	author = "{Di Donato}, S and Frerman, F E and Rimoldi, M and Rinaldo, P and Taroni, F and Wiesmann, U N",
    	issn = "0028-3878",
    	journal = "Neurology",
    	keywords = "Acetylcarnitine,Acetylcarnitine: analysis,Adult,Animals,Carnitine,Carnitine: deficiency,Cattle,Child,Electron-Transferring Flavoproteins,Fatty Acid Desaturases,Fatty Acid Desaturases: deficiency,Fatty Acid Desaturases: metabolism,Fatty Acid Desaturases: urine,Fibroblasts,Fibroblasts: metabolism,Glutarates,Glutarates: urine,Humans,Iron-Sulfur Proteins,Male,Mitochondria,Mitochondria: metabolism,Multienzyme Complexes,Multienzyme Complexes: deficiency,Multienzyme Complexes: metabolism,Oxidoreductases Acting on CH-NH Group Donors,Swine",
    	month = "",
    	number = 7,
    	pages = "957--63",
    	pmid = 3714057,
    	title = "{Systemic carnitine deficiency due to lack of electron transfer flavoprotein:ubiquinone oxidoreductase.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/3714057",
    	volume = 36,
    	year = 1986
    }
    
  21. G Taglialatela, D Navarra, R Cruciani, M T Ramacci, G S Alemà and L Angelucci.
    Acetyl-L-carnitine treatment increases nerve growth factor levels and choline acetyltransferase activity in the central nervous system of aged rats.. Experimental gerontology 29(1):55–66.
    Abstract The hypothesis that some neurodegenerative events associated with ageing of the central nervous system (CNS) may be due to a lack of neurotrophic support to neurons is suggestive of a possible reparative pharmacological strategy intended to enhance the activity of endogenous neurotrophic agents. Here we report that treatment with acetyl-l-carnitine (ALCAR), a substance which has been shown to prevent some impairments of the aged CNS in experimental animals as well as in patients, is able to increase the levels and utilization of nerve growth factor (NGF) in the CNS of old rats. The stimulation of NGF levels in the CNS can be attained when ALCAR is given either for long or short periods to senescent animals of various ages, thus indicating a direct effect of the substance on the NGF system which is independent of the actual degenerative stage of the neurons. Furthermore, long-term treatment with ALCAR completely prevents the loss of choline acetyltransferase (ChAT) activity in the CNS of aged rats, suggesting that ALCAR may rescue cholinergic pathways from age-associated degeneration due to lack of retrogradely transported NGF.
    URL BibTeX

    @article{Taglialatela,
    	abstract = "The hypothesis that some neurodegenerative events associated with ageing of the central nervous system (CNS) may be due to a lack of neurotrophic support to neurons is suggestive of a possible reparative pharmacological strategy intended to enhance the activity of endogenous neurotrophic agents. Here we report that treatment with acetyl-l-carnitine (ALCAR), a substance which has been shown to prevent some impairments of the aged CNS in experimental animals as well as in patients, is able to increase the levels and utilization of nerve growth factor (NGF) in the CNS of old rats. The stimulation of NGF levels in the CNS can be attained when ALCAR is given either for long or short periods to senescent animals of various ages, thus indicating a direct effect of the substance on the NGF system which is independent of the actual degenerative stage of the neurons. Furthermore, long-term treatment with ALCAR completely prevents the loss of choline acetyltransferase (ChAT) activity in the CNS of aged rats, suggesting that ALCAR may rescue cholinergic pathways from age-associated degeneration due to lack of retrogradely transported NGF.",
    	author = "Taglialatela, G and Navarra, D and Cruciani, R and Ramacci, M T and Alem\`{a}, G S and Angelucci, L",
    	issn = "0531-5565",
    	journal = "Experimental gerontology",
    	keywords = "Acetylcarnitine,Acetylcarnitine: pharmacology,Aging,Aging: metabolism,Animals,Choline O-Acetyltransferase,Choline O-Acetyltransferase: biosynthesis,Choline O-Acetyltransferase: genetics,Corticosterone,Corticosterone: blood,Enzyme Induction,Enzyme Induction: drug effects,Frontal Lobe,Frontal Lobe: cytology,Frontal Lobe: drug effects,Gene Expression Regulation,Gene Expression Regulation: drug effects,Male,Nerve Degeneration,Nerve Degeneration: drug effects,Nerve Growth Factors,Nerve Growth Factors: biosynthesis,Nerve Growth Factors: genetics,Nerve Tissue Proteins,Nerve Tissue Proteins: biosynthesis,Nerve Tissue Proteins: genetics,Neurons,Neurons: drug effects,Neurons: enzymology,Neurons: metabolism,Prosencephalon,Prosencephalon: cytology,Prosencephalon: drug effects,Rats,Rats, Sprague-Dawley,Stimulation, Chemical",
    	number = 1,
    	pages = "55--66",
    	pmid = 8187841,
    	title = "{Acetyl-L-carnitine treatment increases nerve growth factor levels and choline acetyltransferase activity in the central nervous system of aged rats.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/8187841",
    	volume = 29
    }