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首页> 外文期刊>Chemical research in toxicology >Serotonergic Neurotoxicity of 3,4-(+/-)-Methylenedioxyamphetamine and 3,4-(+/-)-Methylendioxymethamphetamine (Ecstasy) Is Potentiated by Inhibition of gamma-Glutamyl Transpeptidase.
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Serotonergic Neurotoxicity of 3,4-(+/-)-Methylenedioxyamphetamine and 3,4-(+/-)-Methylendioxymethamphetamine (Ecstasy) Is Potentiated by Inhibition of gamma-Glutamyl Transpeptidase.

机译：3,4-（+/-）-亚甲基二氧基苯丙胺和3,4-（+/-）-甲基二氧甲基苯丙胺（迷魂药）的血清素神经毒性通过抑制γ-谷氨酰转肽酶来增强。

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Reactive metabolites play an important role in 3,4-(+/-)-methylenedioxyamphetamine (MDA) and 3,4-(+/-)-methylenedioxymethamphetamine (MDMA; ecstasy)-mediated serotonergic neurotoxicity, although the specific identity of such metabolites remains unclear. 5-(Glutathion-S-yl)-alpha-methyldopamine (5-GSyl-alpha-MeDA) is a serotonergic neurotoxicant found in the bile of MDA-treated rats. The brain uptake of 5-GSyl-alpha-MeDA is decreased by glutathione (GSH), but sharply increases in animals pretreated with acivicin, an inhibitor of gamma-glutamyl transpeptidase (gamma-GT) suggesting competition between intact 5-GSyl-alpha-MeDA and GSH for the putative GSH transporter. gamma-GT is enriched in blood-brain barrier endothelial cells and is the only enzyme known to cleave the gamma-glutamyl bond of GSH. We now show that pretreatment of rats with acivicin (18 mg/kg, ip) inhibits brain microvessel endothelial gamma-GT activity by 60%, and potentiates MDA- and MDMA-mediated depletions in serotonin (5-HT) and 5-hydroxylindole acidic acid (5-HIAA) concentrations in brain regions enriched in 5-HT nerve terminal axons (striatum, cortex, hippocampus, and hypothalamus). In addition, glial fibrillary acidic protein (GFAP) expression increases in the striatum of acivicin and MDA (10 mg/kg) treated rats, but remains unchanged in animals treated with just MDA (10 mg/kg). Inhibition of endothelial cell gamma-GT at the blood-brain barrier likely enhances the uptake into brain of thioether metabolites of MDA and MDMA, such as 5-(glutathion-S-yl)-alpha-MeDA and 2,5-bis-(glutathion-S-yl)-alpha-MeDA, by increasing the pool of thioether conjugates available for uptake via the intact GSH transporter. The data indicate that thioether metabolites of MDA and MDMA contribute to the serotonergic neurotoxicity observed following peripheral administration of these drugs.
机译：反应性代谢产物在3,4-（+/-）-亚甲基二氧基苯丙胺（MDA）和3,4-（+/-）-亚甲基二氧基甲基苯丙胺（MDMA;摇头丸）介导的血清素能神经毒性中起重要作用，尽管这类代谢物具有特定的特性还不清楚。 5-（谷胱甘肽-S-基）-α-甲基多巴胺（5-GSyl-α-MeDA）是在MDA治疗的大鼠的胆汁中发现的一种血清素能神经毒剂。谷胱甘肽（GSH）可以降低5-GSyl-α-MeDA的大脑摄取量，但是在用阿维西林预处理的动物中，其急剧增加，阿西维奇是一种γ-谷氨酰转肽酶（γ-GT）抑制剂，表明完整的5-GSyl-α-MeDA之间存在竞争。 MeDA和GSH用于假定的GSH转运蛋白。 γ-GT富含血脑屏障内皮细胞，并且是已知唯一可切割GSHγ-谷氨酰胺键的酶。我们现在显示，用阿西维汀（18 mg / kg，腹膜内）对大鼠进行预处理可将脑微血管内皮gamma-GT活性抑制60％，并增强5-羟色胺（5-HT）和5-羟吲哚酸性的MDA和MDMA介导的消耗富含5-HT神经末梢轴突（纹状体，皮层，海马和下丘脑）的大脑区域中的酸（5-HIAA）浓度。另外，用阿维西林和MDA（10 mg / kg）处理的大鼠纹状体中神经胶质纤维酸性蛋白（GFAP）的表达增加，但仅用MDA（10 mg / kg）处理的动物中胶质原纤维酸性蛋白（GFAP）的表达保持不变。在血脑屏障上抑制内皮细胞γ-GT可能会增强MDA和MDMA的硫醚代谢物（如5-（谷胱甘肽-S-基）-α-MeDA和2,5-双-（谷胱甘肽-S-基）-α-MeDA，通过增加可用于完整GSH转运蛋白摄取的硫醚共轭物的库。数据表明，在外周给药这些药物后，MDA和MDMA的硫醚代谢物有助于血清素能神经毒性。

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