The mechanism of action and the metabolism of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is being studied in several animal species. 14C6-MPTP has been prepared and is being used to characterize metabolic differences between effected and resistant animal species. In mouse brain, identified metabolites include 4-phenyl-1,2,3,6-tetrahydropyridine (PTP) and 1-methyl-4-phenyl-2-pyridone. Rabbit antibodies to MPTP and MPP+ have been raised using bovine serum albumin diazolinked to 3'- and 4'-amino MPTP and MPP+ analogues as antigens. No differences in specificity of the antibodies was found with regard to the 3'- or 4'-linkage. An enzyme-linked immunoassay procedure has been devised using a second antigen, and commercial horseradish peroxidase linked to goat-antirabbit antibody. Anti-MPTP antibodies detected MPTP in mouse brain extracts derived from as little as 5 Mug of tissue. The hypothesis that Parkinson's disease is caused by a neurotoxin structurally related to MPTP will be tested with these antibodies and extracts from brains of patients with Parkinson's disease. Structure activity relationships of MPTP analogs have been tested in mice and dogs. Of the three amine substituted analogs (2'-, 3'-, and 4'-amino MPTP), the 4'-NH2 MPTP caused some depletion of striatal dopamine in the mouse, but no cell loss. In the dog, a dose three times that required for MPTP causes loss of dopamine and cell death in the substantia nigra. Because of the 4'-NH2 MPTP does not appear to be metabolized in the same way as MPTP, new insights into the mechanism of action of these dopaminergic neurotoxins should result.
