Neurotoxicity mechanisms of thioether ecstasy metabolites
Neurotoxicity mechanisms of thioether ecstasy metabolites
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DOI：
10.1016/j.neuroscience.2007.03.028
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发表时间：
2007-06-08
期刊：
影响因子：
3.3
通讯作者：
Carvalho, F.
中科院分区：
文献类型：
--
作者：
Capela, J. P.;Macedo, C.;Carvalho, F.
3，4-亚甲基二氧基甲基苯丙胺(MDMA或“摇头丸”)是一种被广泛滥用的、具有精神活性的娱乐药物，已知会引起神经毒性作用。人和大鼠肝脏中MDMA的代谢涉及N-脱甲基为3，4-亚甲基二氧基苯丙胺(MDA)，这也是一种滥用药物。MDMA和MDA分别被O-去甲基化为N-甲基-甲基多巴胺(N-Me-α-MEDA)和α-甲基多巴胺(α-MEDA)，这两种物质都是儿茶酚，可以氧化成相应的邻苯二酚。邻苯二酚可与谷胱甘肽(GSH)偶联形成谷胱甘肽加合物，谷胱甘肽可转运到脑内并代谢成相应的N-乙酰半胱氨酸加合物(NAC)。在这项研究中，我们评估了通过合成得到的九种MDMA代谢物：N-Me-α-Meda、a-Meda及其相应的GSH和NAC加合物的神经毒性。这些研究是在大鼠皮质神经元培养中进行的，暴露时间为6小时，在正常(36.5摄氏度)和高温(40摄氏度)条件下进行。我们的研究结果表明，硫醚MDMA代谢物是一种强烈的神经毒素，显著高于其相应的母儿茶酚。另一方面，N-me-a-Meda和a-Meda比MDMA具有更强的神经毒性。N-Me-α-Meda和α-Meda的GSH和NAC偶联物诱导了浓度依赖性的迟发性神经元死亡，并伴随着caspase 3的激活，这在高温条件下发生得更早。此外，硫醚MDMA代谢物呈时间依赖性地增加活性物种的产生，依赖于浓度而耗尽细胞内的GSH，并增加蛋白结合的苯二酚。最后，硫醚MDMA代谢产物诱导的神经元死亡和氧化应激可被抗氧化剂和GSH前体NAC预防。这项研究为硫醚MDMA代谢物的神经毒性机制提供了新的见解，并强调了它们在“摇头丸”神经毒性中的重要性。(C)2007年IBRO。爱思唯尔有限公司出版。保留所有权利。
3,4-Methylenedioxymethamphetamine (MDMA or "ecstasy"), is a widely abused, psychoactive recreational drug that is known to induce neurotoxic effects. Human and rat hepatic metabolism of MDMA involves N-demethylation to 3,4-methylenedioxyamphetamine (MDA), which is also a drug of abuse. MDMA and MDA are O-demethylenated to N-methyla-methyidopamine (N-Me-alpha-MeDA) and alpha-methyidopamine (alpha-MeDA), respectively, which are both catechols that can undergo oxidation to the corresponding ortho-quinones. Ortho-quinones may be conjugated with glutathione (GSH) to form glutathionyl adducts, which can be transported into the brain and metabolized to the correspondent N-acetylcysteine (NAC) adducts. In this study we evaluated the neurotoxicity of nine MDMA metabolites, obtained by synthesis: N-Me-alpha-MeDA, a-MeDA and their correspondent GSH and NAC adducts. The studies were conducted in rat cortical neuronal cultures, for a 6 h of exposure period, under normal (36.5 degrees C) and hyperthermic (40 degrees C) conditions. Our findings show that thioether MDMA metabolites are strong neurotoxins, significantly more than their correspondent parent catechols. On the other hand, N-Me-a-MeDA and a-MeDA are more neurotoxic than MDMA. GSH and NAC conjugates of N-Me-alpha-MeDA and alpha-MeDA induced a concentration dependent delayed neuronal death, accompanied by activation of caspase 3, which occurred earlier in hyperthermic conditions. Furthermore, thioether MDMA metabolites time-dependently increased the production of reactive species, concentration-dependently depleted intracellular GSH and increased protein bound quinones. Finally, thioether MDMA metabolites induced neuronal death and oxidative stress was prevented by NAC, an antioxidant and GSH precursor. This study provides new insights into the neurotoxicity mechanisms of thioether MDMA metabolites and highlights their importance in "ecstasy" neurotoxicity. (C) 2007 IBRO. Published by Elsevier Ltd. All rights reserved.