title: The protective role of L-carnitine against neurotoxicity evoked by drug of abuse, methamphetamine, could be related to mitochondrial dysfunction.
abstract: There is growing evidence that suggests that brain injury after amphetamine and methamphetamine (METH) administration is due to an increase in free radical formation and mitochondrial damage, which leads to a failure of cellular energy metabolism followed by a secondary excitotoxicity. Neuronal degeneration caused by drugs of abuse is also associated with decreased ATP synthesis. Defective mitochondrial oxidative phosphorylation and metabolic compromise also play an important role in atherogenesis, in the pathogenesis of Alzheimer's disease, Parkinson's disease, diabetes, and aging. The energy deficits in the central nervous system can lead to the generation of reactive oxygen and nitrogen species as indicated by increased activity of the free radical scavenging enzymes like catalase and superoxide dismutase. The METH-induced dopaminergic neurotoxicity may be mediated by the generation of peroxynitrite and can be protected by antioxidants selenium, melatonin, and selective nNOS inhibitor, 7-nitroindazole. L-Carnitine (LC) is well known to carry long-chain fatty acyl groups into mitochondria for beta-oxidation. It also plays a protective role in 3-nitropropioinc acid (3-NPA)-induced neurotoxicity as demonstrated in vitro and in vivo. LC has also been utilized in detoxification efforts in fatty acid-related metabolic disorders. In this study we have tested the hypothesis that enhancement of mitochondrial energy metabolism by LC could prevent the generation of peroxynitrite and free radicals produced by METH. Adult male C57BL/6N mice were divided into four groups. Group I served as control. Groups III and IV received LC (100 mg/kg, orally) for one week. Groups II and IV received 4 x 10 mg/kg METH i.p. at 2-h intervals after one week of LC administration. LC treatment continued for one more week to groups III and IV. One week after METH administration, mice were sacrificed by decapitation, and striatum was dissected to measure the formation of 3-nitrotyrosine (3-NT) by HPLC/Coularry system. METH treatment produced significant formation of 3-NT, a marker of peroxynitrite generation, in mice striatum. The pre- and post-treatment of mice with LC significantly attenuated the production of 3-NT in the striatum resulting from METH treatment. The protective effects by the compound LC in this study could be related to the prevention of the possible metabolic compromise by METH and the resulting energy deficits that lead to the generation of reactive oxygen and nitrogen species. These data further confirm our hypothesis that METH-induced neurotoxicity is mediated by the production of peroxynitrite, and LC may reduce the peroxynitrite levels and protect against the underlying mechanism of METH toxicity, which are models for several neurodegenerative disorders like Parkinson's disease.
authors.affiliation: Research and Development, Sigma tau-HealthScience, Pomezia 00040, Italy.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Virmani
authors.forename: Franco
authors.initials: F
authors.lastname: Gaetani
authors.forename: Syed
authors.initials: S
authors.lastname: Imam
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Binienda
authors.forename: Syed
authors.initials: S
authors.lastname: Ali
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002331:Carnitine / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity*; D016716:PC12 Cells; D010673:Pheochromocytoma; D051381:Rats; D019966:Substance-Related Disorders / Q000503:physiopathology*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D009498:Neurotoxins; C002744:3-nitrotyrosine; D014443:Tyrosine; D008694:Methamphetamine; D002331:Carnitine