NEURAL DEGENERATION INDUCED BY TETRAHYDROPYRIDINE ANALOGS

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1-Methy1-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can be formed as a by-product in the synthesis of 1-methy1-4-phenyl-4- propionoxypiperidine (MPPP), a potent analgesic agent structurally similar to other widely use analgesics including meperidine. It was reported a few years ago that the ingestion of MPTP, mixed with varying amounts of MPPP and perhaps other agents, caused an irreversible parkinsonism in several young adults who were most likely attempting to simulate the actions of heroin with MPPP. It was also reported that the injection of MPTP alone to monkeys caused symptoms and pathology consistent with parkinsonism. It thus appears that the agent responsible for the parkinsonism observed in the young drug abusers was MPTP or a metabolite. The discovery that a simple substance administered systemically can reproduce so closely the pathology of Parkinson's disease has enormous implications for the etiology of human parkinsonism. It suggests that a similar neurotoxin, exogenous or endogenous, may be involved in the pathogenesis of the disease. It was previously reported that MPTP administration did not produce parkinsonian symptoms in certain other species including rats. However, we discovered that MPTP administration to mice produced features of dopaminergic neuronal destruction, including a loss of nerve cells in the zona compacta of the substantia nigra and large and long-lasting decrements: 1) in neostriatal levels of dopamine and its metabolites, 2) in the capacity of neostriatal brain tissue to accumulate 3H-dopamine, and 3) in neostriatal tyrosine hydroxylase activity. In the present study we hope to further develop the MPTP-treated mouse as an animal model of parkinsonism. A second and more important goal is to learn as much as possible about the basic features of the action of MPTP and many of its structural analogs. We have recently found several MPTP analogs to be neurotoxic, some more so than MPTP itself. All of these findings with MPTP and its analogs are relatively recent, and anything that we discover concerning the actions of MPTP or its analogs can potentially be important. We hope to be able to determine the exact mode of action of MPTP. An overall goal underlying this entire project is to determine if there are similarities in the etiology of parkinsonism caused in experimental animals by MPTP and the etiology of idiopathic parkinsonism in humans.