MPTP TOXICITY AND ANIMAL MODELS OF PARKINSON'S DISEASE

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1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin which causes selective destruction of dopaminergic neurones of the nigro-striatal pathway in monkeys, but is less specific in mice requiring higher doses and affecting other areas as well. A hemiparkinsonian model has been developed by infusion of MPTP into the internal carotid artery of monkeys. The behavioral effects (turning in the direction of the lesioned side) provide a useful means for functional evaluation of agonists (which reverse the turning) and of effects of procedures to stimulate regeneration or replace by implantation dopamine-producing cells. The involvement of the dopaminergic neurones and changes in receptor properties as a result of neuronal damage are being examined using biochemical techniques for measurement of dopamine, norepinephrine, and serotonin and their metabolites as well as binding of radiolabelled ligands to receptors and immunohistofluorescence of tyrosine hydroxylase. These confirm unilateral destruction of dopamine innervation of the caudate-putamen in hemiparkinsonian monkeys and increased D2 receptors in this area in these animals. PET scanning with 18F-DOPA is being planned to follow the degeneration-regeneration process in monkey brain after MPTP treatment. The mechanisms of toxicity involve metabolism to its pyridium derivative (MPP+) which is accumulated in dopaminergic neurones. Toxicity of MPP+ may involve free radicals and affinity to neuromelanin. In mice, drugs which potentiate (e.g., copper chelators) or alleviate (e.g., reducing agents) MPTP toxicity provide evidence for involvement of superoxide free-radicals in causing the toxic damage to the amine accumulating neurones.