Inhibition of the Tyrosine Hydroxylase System by MPTP, 1-Methyl-4-phenylpyridinium Ion (MPP+) and the Structurally Related Compounds in vitro and in vivo

Abstract

MPTP, l-methyl-4-phenyl-pyridinium ion (MPP⁺) and the structurally related compounds including N-methyltetrahydroisoquinilinium ion inhibited the tyrosine hydroxylase (TH) system in tissue slices of rat striatum at 10^–5M. Mouse striatum is more susceptible to MPTP than rat striatum. A similar degree of inhibition by MPP⁺ was observed in the absence or presence of 1 mM dibutyryi cyclic adenosine monophosphate (DBcAMP) which stimulated the TH system about 3-fold. The results with the structurally related compounds of MPP⁺ indicate that both the pyridinium and the phenyl group are required for the inhibition of the TH system in tissue slices or rat striatum. Tetrahydroisoquinoline, a pyridinium compound related to dopamine (DA), was found to decrease TH and 3,4-dihydroxyphenyl-acetic acid in the striatum of mice after administration at a dose of 60 mg/kg/day s.c. for 8 days. It is suggested that either tetrahydroisoquinoline or N-methyltetrahydroisoquinoline, which is a DA-related pyridinium compound, could be one of the environmental or endogenous compounds inducing Parkinson’s disease.