MPTP, BETA-CARBOLINES AND THE ETIOLOGY OF PARKINSONISM

黑质纹状体的毒性 N-甲基-4-苯基-1，2，5，6-四氢吡啶（MPTP）可能提供见解 潜在的内源性毒性因素的化学性质 特发性帕金森综合征（帕金森病）。 MPTP仅相差一个 原子，吲哚氮桥，从 N-甲基-1，2，3，4-四氢-β-咔啉（2M-THBC）， 在大脑中发现的“哺乳动物”生物碱可能来源于 吲哚化合物与代谢醛的缩合。 经过初步 实验验证了我们的假设，即内源性MPTP样 β-咔啉是引起多巴胺细胞损失的病原体， 帕金森氏病，我们看到的迹象，纹状体多巴胺能损伤， 2M-THBC处理的小鼠和猴。 为了进一步研究我们的假设， 该提案有三个顺序相关的目标。 第一个目标， 利用知识，MPTP的毒性取决于其转化为 氧化形式，然后由多巴胺摄取系统，是 确定哪些类型的β-咔啉代谢物可能出现在 体内可通过突触体中的多巴胺摄取系统积累， 通过体外代谢途径形成。 在第二个目标中， 与氧化的MPTP相比， 检查C57/B1小鼠的神经毒性作用。 血脑屏障 将首先测定渗透，之后将测定生物碱。 通过最适当的途径（中枢或 外围设备）。 将通过生物源性单胺评估黑质纹状体损失 以及生物酸水平和3H-单胺摄取和组织学。 一 然后将研究导致小鼠多巴胺能损伤的β-咔啉 在非人类灵长类动物中（Aim III）。 生物碱将通过以下途径给药： 在6个月的时间里， 行为和神经化学（CSF代谢物水平）参数将 密切监视。 处死时，多巴胺能损失将评估为 用老鼠 这种系统的方法应该提供明确的证据， 或反对MPTP样生物碱代谢物之间的联系 它可能在体内形成和帕金森氏病。

The potent nigrostriatal toxicity of N-methyl-4-phenyl-1,2,5,6-tetrahydro-pyridine (MPTP) may provide insight into the chemical nature of possible endogenous toxic factors underlying idiopathic parkinsonism (Parkinson's disease). MPTP differs by only one atom, an indolic nitrogen bridge, from N-methyl-1,2,3,4-tetrahydro-beta-carboline (2M-THBC), one of several 'mammalian' alkaloids found in brain that are probably derived from condensation of indole compounds with metabolic aldehydes. After initial experiments testing our hypothesis that endogenous MPTP-like beta-carbolines are etiologic agents causing dopamine cell loss in Parkinson's disease, we saw indications of striatal dopaminergic damage in 2M-THBC treated mice and monkeys. To further pursue our hypothesis, this proposal has three sequentially-related aims. The first aim, which makes use of knowledge that toxicity by MPTP depends upon its conversion to oxidized forms that are then taken up by dopamine uptake systems, is to determine what types of beta-carbolinium metabolites potentially arising in vivo can be accumulated by dopamine uptake systems in synaptosomes and can be formed by metabolic routes in vitro. In the second aim, alkaloids which undergo uptake by dopamine systems comparable to oxidized MPTP will then be examined for neurotoxic effects in C57/B1 mice. Blood-brain barrier penetration will first be determined, after which the alkaloids will be administered chronically by the most appropriate route (central or peripheral). Nigrostriatal loss will be assessed via biogenic monoamine and biogenic acid levels and 3H-monoamine uptake, and histology. A beta-carboline that causes dopaminergic damage in mice will then be studied in nonhuman primates (Aim III). The alkaloid(s) will be administered via minipumps to squirrel monkeys over a 6 month period, during which time behavioral and neurochemical (CSF metabolite levels) parameters will be closely monitored. At sacrifice, dopaminergic loss will be assessed as with mice. This systematic approach should provide definitive evidence for or against the proposed connection between MPTP-like alkaloid metabolites which may form in vivo and Parkinson's disease.