Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, 4306 Walker Building, Auburn, AL, 36849, USA.
Neurochem Res. 2013 Oct;38(10):2084-94. doi: 10.1007/s11064-013-1117-x. Epub 2013 Aug 6.
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.
甲基苯丙胺泛滥对世界医疗保健系统产生了广泛影响。其滥用潜力和神经毒性作用仍然是戒毒治疗的挑战。除了氧化应激、线粒体功能障碍和细胞凋亡外，兴奋性毒性也与甲基苯丙胺引起的神经毒性有关。N-甲基-D-天冬氨酸（NMDA）型谷氨酸受体被认为是兴奋性毒性的主要介质之一。越来越多的证据表明，NMDA 受体拮抗剂可能是治疗兴奋性毒性的方法之一。金刚烷胺是一种耐受性好、疗效适度的抗帕金森病药物，被发现具有 NMDA 拮抗作用，并能从神经末梢释放多巴胺。本研究旨在评估金刚烷胺预处理对甲基苯丙胺诱导的神经毒性的影响。结果表明，甲基苯丙胺处理导致纹状体多巴胺耗竭、活性氧生成增加和线粒体复合体 I 活性降低。有趣的是，高剂量（10mg/kg）的金刚烷胺不能预防多巴胺耗竭，反而加剧了甲基苯丙胺毒性的行为表现，如运动不能和僵住。只有较低剂量（1mg/kg）的金刚烷胺才能显著清除甲基苯丙胺诱导的活性氧。本研究的总体结果表明，金刚烷胺不应与甲基苯丙胺同时使用，因为它可能会导致过度的神经毒性。
