OXIDATION CHEMISTRY OF INDOLES

吲哚的氧化化学

• 批准号: 6385498
• 负责人: GLENN DRYHURST
• 金额: $ 33.63万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-09-15 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6385498
• 关键词: 3,4 methylenedioxymethamphetamine; brain metabolism; dopamine; endotoxins; free radical oxygen; glutathione; indoles; laboratory rat; methamphetamine; microdialysis; neurotoxicology; neurotoxins; neurotransmitter metabolism; oxidation; oxidative stress; pharmacokinetics; protein glutamine gamma glutamyltransferase; serotonin

DESCRIPTION (Adapted From The Applicant's Abstract): The goal of this project is to contribute to an understanding of the chemical and biochemical mechanisms that underlie the dopaminergic and/or serotonergic neurotoxicity of methamphetamine (MA) and 3,4-methylenedioxymethampetamine (MDMA). The project is based on the hypothesis that glutathione (GSH), released from both neurons and glia, and extracellular conditions that influence the activity of gamma-glutamyl transpeptidase (g-GT), are key factors in MA- and MDMA-induced neurotoxicity. It is proposed that extracellular conditions evoked by a MA-induced neuronal energy impairment, notably excessive HO* generation, cause upregulation of g-GT and hydrolysis of GSH to glutamate (Glu), glycine (Gly) and cysteine (CySH). Dopaminergic neuronal damage evoked by MA in the rat is proposed to be dependent on the intraneuronal oxidation of DA by O2-*, generated by NMDA receptor activation by elevated extracellular Glu, in the presence of translocated CySH forming dihydrobenzothiazine (DHBT) and benzothiazine (BT) mitochondrial (mt) toxicants. Similarly, serotonergic neuronal damage may be caused by intraneuronal oxidation of 5-HT by O-2-* in the presence of translocated CySH to give endotoxic metabolites. Mechanisms are proposed by which MDMA, because of its HO* scavenging properties, inhibits g-GT and hence hydrolysis of released GSH. Thus, not only is Glu-mediated NMDA receptor activation and intraneuronal O-2-* generation attenuated, CySH, essential for DHBT/BT formation, is not available and DA neurons are spared. In contrast, the O-2-* mediated oxidation of 5-HT generates tryptamine-4,5-dione that in the absence of CySH inhibits mt enzymes and, hence, MDMA evokes selective serotonergic neurotoxicity. Specific aims are to: (1) monitor extracellular changes of DA, 5-HT and their metabolites, thiols/disulfides, and Glu, Asp and Gly in rat brain in response to MA and MDMA using microdialysis; (2) search for unusual products of oxidation of extracellular DA/5-HT/metabolites by HO* that might contribute to MA/MDMA toxicity, also using microdialysis; (3) study the influence of hypothermia, astroglial ablation, and the glucose metabolism inhibitor 2-deoxy-D-glucose, on MA/MDMA-induced extracellular neurochemical changes; (4) investigate the effects of MA/MDMA on brain thiol/disulfide concentrations and g-GT activity; (5) study the effects of g-GT inhibition, manipulations of brain GSH, 5-S-cysteinyldopamine (DHBT/BT precursor), and glial ablation on MA/MDMA-induced neurotoxicity; (6) analyze brain tissue for evidence of putative endotoxic metabolites and covalently modified proteins; (7) study interactions of putative endotoxins with mt and other enzymes; (8) assay rat brain for activities of mt and other enzymes, following MA/MDMA administration.

描述（改编自申请人的摘要）： 该项目的目标是促进对化学品的理解 以及多巴胺能和/或多巴胺能神经递质 甲基苯丙胺和3，4-亚甲二氧基甲基苯丙胺的神经毒性 （MDMA）。该项目是基于假设，谷胱甘肽（GSH），释放 从神经元和神经胶质细胞，和细胞外条件，影响 γ-谷氨酰转肽酶（g-GT）的活性是MA的关键因素， MDMA诱导的神经毒性。有人提出，细胞外条件诱发 通过MA诱导的神经元能量损伤，特别是过量的HO* 产生， 引起g-GT的上调和GSH水解为谷氨酸（Glu）、甘氨酸 (Gly)和半胱氨酸（CySH）。MA对大鼠多巴胺能神经元的损伤作用 被认为依赖于O2-* 对DA的神经元内氧化， 由NMDA受体激活产生的细胞外谷氨酸升高，在 存在易位的CySH形成二氢苯并噻嗪（DHBT）， 苯并噻嗪（BT）线粒体（MT）毒物。同样， 神经元损伤可能是由O-2-* 在神经元内氧化5-HT所致。 存在移位的CySH以产生内毒素代谢物。机制 MDMA，由于其HO* 清除特性，抑制g-GT 并因此水解释放的GSH。因此，不仅Glu介导的NMDA 受体激活和神经元内O-2-* 生成减弱，CySH， 对于DHBT/BT形成至关重要的是不可用的，并且DA神经元被保留。在 相反，O-2-* 介导的5-HT氧化生成色胺-4，5-二酮 在缺乏CySH的情况下，抑制mt酶，因此，MDMA引起 选择性肾上腺素能神经毒性具体目标是：（1）监测 DA、5-HT及其代谢物、硫醇/二硫化物的细胞外变化，以及 用微透析法研究MA和MDMA对大鼠脑内Glu、Asp和Gly的影响 (2)寻找不寻常的产品氧化的细胞外 DA/5-HT/HO* 代谢产物可能导致MA/MDMA毒性， （3）研究低温对星形胶质细胞的影响， 消融，和葡萄糖代谢抑制剂2-脱氧-D-葡萄糖， MA/MDMA诱导的细胞外神经化学变化;（4）研究MA/MDMA诱导的细胞外神经化学变化。 MA/MDMA对脑巯基/二硫键浓度和g-GT活性的影响; (5)研究g-GT抑制、脑GSH操作、 5-S-半胱氨酰多巴胺（DHBT/BT前体），和神经胶质消融， MA/MDMA诱导的神经毒性;（6）分析脑组织中的证据， 推定的内毒素代谢物和共价修饰的蛋白质;（7）研究 推定内毒素与mt和其他酶的相互作用;（8）测定速率 MA/MDMA给药后，大脑中MT和其他酶的活性。