Tung Che-Se, Chang Shang-Tang, Huang Chuen-Lin, Huang Nai-Kuei
Division of Medical Research and Education, Cheng Hsin General Hospital, Taipei, Taiwan, ROC.
Department of Psychiatry, Cardinal Tien Hospital, New Taipei City, Taiwan, ROC.
Neurosci Lett. 2017 Feb 3;639:185-191. doi: 10.1016/j.neulet.2017.01.002. Epub 2017 Jan 6.
Amphetamine (AMPH) is a commonly abused psychostimulant that induces neuronal cell death/degeneration in humans and experimental animals. Although multiple neurotoxic mechanisms of AMPH have been intensively investigated, the interplay between these mechanisms has remained elusive. In this study, we used a rat model of AMPH-induced long-lasting striatal dopamine (DA) depletion and identified mechanisms of neurotoxicity, energy failure, excitotoxicity, and oxidative stress. Pretreatment with nicotinamide (NAM, a co-factor for the electron transport chain) blocked AMPH-induced free radical formation, energy failure, and striatal DA decrease. Also, MK-801 (a NMDA receptor antagonist) blocked AMPH-induced free radical formation and striatal DA but not energy failure decrease, indicating excitotoxicity may occur before free radical formation and after energy failure. Thus, these results show that during AMPH intoxication, energy failure, excitotoxicity, and free radical formation are orchestrated consecutively to mediate the depletion of striatal DA.
苯丙胺（AMPH）是一种常见的滥用精神兴奋剂，可导致人类和实验动物的神经元细胞死亡/退化。尽管对AMPH的多种神经毒性机制进行了深入研究，但这些机制之间的相互作用仍不清楚。在本研究中，我们使用了AMPH诱导的长期纹状体多巴胺（DA）耗竭的大鼠模型，并确定了神经毒性、能量衰竭、兴奋性毒性和氧化应激的机制。用烟酰胺（NAM，电子传递链的一种辅助因子）预处理可阻断AMPH诱导的自由基形成、能量衰竭和纹状体DA减少。此外，MK-801（一种NMDA受体拮抗剂）可阻断AMPH诱导的自由基形成和纹状体DA减少，但不能阻断能量衰竭，这表明兴奋性毒性可能在自由基形成之前和能量衰竭之后发生。因此，这些结果表明，在AMPH中毒期间，能量衰竭、兴奋性毒性和自由基形成是依次协调发生的，以介导纹状体DA的耗竭。
