Capela João Paulo, Meisel Andreas, Abreu Artur Reis, Branco Paula Sério, Ferreira Luísa Maria, Lobo Ana Maria, Remião Fernando, Bastos Maria Lurdes, Carvalho Félix
REQUIMTE, Toxicology Department, Faculty of Pharmacy, University of Porto, Rua Aníbal Cunha 164, 4099-030 Porto, Portugal.
J Pharmacol Exp Ther. 2006 Jan;316(1):53-61. doi: 10.1124/jpet.105.092577. Epub 2005 Sep 23.
3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") is a widely abused, psychoactive recreational drug. There is growing evidence that the MDMA neurotoxic profile may be highly dependent on both its hepatic metabolism and body temperature. 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, both of which are catechols that can undergo oxidation to the corresponding ortho-quinones. In the presence of glutathione (GSH), ortho-quinones may be conjugated with GSH to form glutathionyl adducts. In this study, we evaluated the neurotoxicity of MDMA and three of its metabolites obtained by synthesis, N-Me-alpha-MeDA, alpha-MeDA, and 5-(GSH)-alpha-MeDA [5-(glutathion-S-yl)-alpha-methyldopamine] in rat cortical neuronal serum-free cultures under normal (36.5 degrees C) and hyperthermic (40 degrees C) conditions. Cell viability was assessed, and the mechanism of cell death was also evaluated. Our study shows that these metabolites are more neurotoxic [5-(GSH)-alpha-MeDA being the most toxic] than the parent compound MDMA. The neurotoxicity of MDMA metabolites was partially prevented by the antioxidants N-acetylcystein and also, in a minor extent, by alpha-phenyl-N-tert-butyl nitrone. All the tested compounds induced apoptotic cell death in cortical neurons, and their neurotoxic effect was potentiated under hyperthermic conditions. These data suggest that MDMA metabolites, especially under hyperthermic conditions, contribute to MDMA-induced neurotoxicity.
3,4-亚甲基二氧甲基苯丙胺（摇头丸或“迷幻药”）是一种被广泛滥用的精神活性娱乐性药物。越来越多的证据表明，摇头丸的神经毒性特征可能高度依赖于其肝脏代谢和体温。摇头丸的代谢包括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），这两种都是儿茶酚，可氧化为相应的邻醌。在谷胱甘肽（GSH）存在的情况下，邻醌可与GSH结合形成谷胱甘肽加合物。在本研究中，我们评估了摇头丸及其三种合成代谢产物N-Me-α-MeDA、α-MeDA和5-(GSH)-α-MeDA [5-(谷胱甘肽-S-基)-α-甲基多巴胺]在正常（36.5摄氏度）和高温（40摄氏度）条件下对大鼠皮质神经元无血清培养物的神经毒性。评估了细胞活力，并对细胞死亡机制进行了评估。我们的研究表明，这些代谢产物比母体化合物摇头丸具有更强的神经毒性[5-(GSH)-α-MeDA毒性最强]。抗氧化剂N-乙酰半胱氨酸部分预防了摇头丸代谢产物的神经毒性，α-苯基-N-叔丁基硝酮在较小程度上也有预防作用。所有测试化合物均诱导皮质神经元凋亡性细胞死亡，并且在高温条件下它们的神经毒性作用增强。这些数据表明，摇头丸代谢产物，尤其是在高温条件下，会导致摇头丸诱导的神经毒性。
