Capela J P, Macedo C, Branco P S, Ferreira L M, Lobo A M, Fernandes E, Remião F, Bastos M L, Dirnagl U, Meisel A, Carvalho F
REQUIMTE (Rede de Química e Tecnologia), Toxicology Department, Faculty of Pharmacy, University of Porto, Rua Aníbal Cunha, 164, 4099-030 Porto, Portugal.
Neuroscience. 2007 Jun 8;146(4):1743-57. doi: 10.1016/j.neuroscience.2007.03.028. Epub 2007 Apr 30.
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-methyl-alpha-methyldopamine (N-Me-alpha-MeDA) and alpha-methyldopamine (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, alpha-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-alpha-MeDA and alpha-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.
3,4-亚甲基二氧甲基苯丙胺（摇头丸或“迷魂药”）是一种被广泛滥用的精神活性娱乐性药物，已知会诱发神经毒性作用。摇头丸在人和大鼠肝脏中的代谢涉及N-去甲基化生成3,4-亚甲基二氧苯丙胺（MDA），MDA也是一种滥用药物。摇头丸和MDA分别经O-去亚甲基化生成N-甲基-α-甲基多巴胺（N-Me-α-MeDA）和α-甲基多巴胺（α-MeDA），二者均为儿茶酚，可氧化为相应的邻醌。邻醌可与谷胱甘肽（GSH）结合形成谷胱甘肽加合物，该加合物可转运至脑内并代谢为相应的N-乙酰半胱氨酸（NAC）加合物。在本研究中，我们评估了通过合成获得的9种摇头丸代谢产物的神经毒性：N-Me-α-MeDA、α-MeDA及其相应的GSH和NAC加合物。研究在大鼠皮质神经元培养物中进行，暴露6小时，分别在正常（36.5℃）和高温（40℃）条件下。我们的研究结果表明，硫醚类摇头丸代谢产物是强神经毒素，比其相应的母体儿茶酚毒性大得多。另一方面，N-Me-α-MeDA和α-MeDA比摇头丸的神经毒性更大。N-Me-α-MeDA和α-MeDA的GSH和NAC缀合物诱导浓度依赖性延迟神经元死亡，伴有半胱天冬酶3的激活，在高温条件下更早发生。此外，硫醚类摇头丸代谢产物随时间依赖性增加活性物质的产生，浓度依赖性消耗细胞内GSH并增加蛋白结合醌。最后，硫醚类摇头丸代谢产物诱导神经元死亡，抗氧化剂和GSH前体NAC可预防氧化应激。本研究为硫醚类摇头丸代谢产物的神经毒性机制提供了新的见解，并突出了它们在“摇头丸”神经毒性中的重要性。
