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.
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