MPTP, BETA-CARBOLINES AND THE ETIOLOGY OF PARKINSONISM

强效的黑质纹状体毒性 N-甲基-4-苯基-1，2，5，6-四氢吡啶(MPTP) 可能的内源性毒性因素的化学性质 特发性帕金森症(帕金森氏症)。MPTP只有一处不同 原子，一个惰性的氮桥，来自 N-甲基-1，2，3，4-四氢-β-卡宾(2M-THBC) 在大脑中发现的哺乳动物生物碱，可能来自 吲哚化合物与代谢醛的缩合。在首字母之后 验证我们的假设的实验内源性MPTP样蛋白 β-卡波林是导致多巴胺细胞丢失的病原体。 帕金森氏病，我们看到纹状体多巴胺能损伤的迹象 2M-THBC治疗小鼠和猴子。为了进一步推进我们的假设，这一点 提案有三个顺序相关的目标。第一个目标，它使 了解MPTP的毒性取决于其转化为 氧化形式，然后被多巴胺摄取系统吸收，是 确定哪些类型的β-碳氢化合物代谢物可能出现在 VIVO可以通过突触体内的多巴胺摄取系统积累，并可以 在体外通过代谢途径形成。在第二个目标中，生物碱 通过与氧化MPTP相当的多巴胺系统摄取，然后 对C57/B1小鼠进行神经毒性试验。血脑屏障 首先测定渗透性，然后再测定生物碱 通过最合适的途径(中心或 外围设备)。黑质纹状体丢失将通过生物单胺进行评估 以及生物酸水平和~3H-单胺摄取，以及组织学。一个 然后将研究导致小鼠多巴胺能损伤的β-卡宾 在非人类灵长类动物中(目标III)。生物碱(S)将通过 在6个月的时间里，对松鼠猴子进行了小型泵浦 行为和神经化学(脑脊液代谢物水平)参数将为 受到严密监视。在牺牲时，多巴胺能损失将被评估为 和老鼠在一起。这种系统化的方法应该提供明确的证据 或反对MPTP类生物碱代谢物之间的联系 这可能在体内形成和帕金森氏症。

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.