The effects of pyridinium salts, structurally related compounds of 1-methyl-4-phenylpyridinium ion (MPP+), on tyrosine hydroxylation in rat striatal tissue slices.

We had previously reported that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces Parkinson's disease in humans and animals, inhibited tyrosine hydroxylation, the rate-limiting step of dopamine synthesis, in striatal tissue slices after its conversion to 1-methyl-4-phenylpyridinium ion by monoamine oxidase. In this report, structurally related compounds of 1-methyl-4-phenylpyridinium ion (MPP+) were synthesized and tested for their ability to inhibit tyrosine hydroxylation in rat striatal tissue slices. The following pyridinium salts showed inhibitory effect on tyrosine hydroxylation: pyridinium salts that substituted the alkyl group for the methyl group of MPP+ (1-ethyl-, 1-propyl-, 1-isopropyl-4-phenylpyridinium ions); pyridinium salts that changed the position of the phenyl group (1-methyl-2-phenyl-, 1-methyl-3-phenylpyridinium ions); pyridinium salts that modified the phenyl ring at 4 position (1-methyl-4-tolylpyridinium ion, 1-methyl-4-(4'-methoxyphenyl)pyridinium ion); and N-methylisoquinolinium ion. In contrast, pyridinium salts in which the phenyl group was replaced with hydrogen, methyl or methoxycarbonyl group, paraquat (1,1'-dimethyl-4,4'-dipyridinium chloride, one of bipyridinium compounds and a widely used herbicide), and N-methylquinolinium ion, showed no inhibitory effect. Nomifensine, an inhibitor of dopamine uptake, prevented the inhibition caused by 1-methyl-2-phenylpyridinium ion. The result suggests that the effective pyridinium salts are taken up into dopaminergic neurons likewise MPP+ by the dopamine transport system and inhibit tyrosine hydroxylation in striatal tissue slices. N-methylisoquinolinium ion could be one of the candidates of endogenous or environmental factors that produce Parkinson's disease.