title: Assessment of therapeutic potential of amantadine in methamphetamine induced neurotoxicity.
abstract: Methamphetamine epidemic has a broad impact on world's health care system. Its abusive potential and neurotoxic effects remain a challenge for the anti-addiction therapies. In addition to oxidative stress, mitochondrial dysfunction and apoptosis, excitotoxicity is also involved in methamphetamine induced neurotoxicity. The N-methyl-D-aspartate (NMDA) type of glutamate receptor is thought to be one of the predominant mediators of excitotoxicity. There is growing evidence that NMDA receptor antagonists could be one of the therapeutic options to manage excitotoxicity. Amantadine, a well-tolerated and modestly effective antiparkinsonian agent, was found to possess NMDA antagonistic properties and has shown to release dopamine from the nerve terminals. The current study aimed to evaluate the effect of amantadine pre-treatment against methamphetamine induced neurotoxicity. Results showed that methamphetamine treatment had depleted striatal dopamine, generated of reactive oxygen species and decreased activity of complex I in the mitochondria. Interestingly, amantadine, at high dose (10 mg/kg), did not prevent dopamine depletion moreover it exacerbated the behavioral manifestations of methamphetamine toxicity such as akinesia and catalepsy. Only lower dose of amantadine (1 mg/kg) produced significant scavenging of the reactive oxygen species induced by methamphetamine. Overall results from the present study suggest that amantadine should not be used concomitantly with methamphetamine as it may results in excessive neurotoxicity.
authors.affiliation: Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, 4306 Walker Building, Auburn, AL, 36849, USA.
authors.forename: Bessy
authors.initials: B
authors.lastname: Thrash-Williams
authors.forename: Manuj
authors.initials: M
authors.lastname: Ahuja
authors.forename: Senthilkumar S
authors.initials: SS
authors.lastname: Karuppagounder
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Uthayathas
authors.forename: Vishnu
authors.initials: V
authors.lastname: Suppiramaniam
authors.forename: Muralikrishnan
authors.initials: M
authors.lastname: Dhanasekaran
mesh_terms: D000547:Amantadine / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced; D004298:Dopamine / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000506:poisoning*; D051379:Mice; D008810:Mice, Inbred C57BL; D028361:Mitochondrial Diseases / Q000139:chemically induced; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000188:drug therapy*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D012701:Serotonin; D008694:Methamphetamine; D000547:Amantadine; D013482:Superoxide Dismutase; D004298:Dopamine
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