INHIBITION OF ACETYLCHOLINESTERASE BY THE NEUROTOXICANT, 1-METHYL-4-PHENYL-2,3-DIHYDROPYRIDINIUM ION

The effect of the neurotoxicant 1-methyl-4-phenyl-2,3-dihydropyridiniu m ion (MPDP(+)) on acetylcholinesterase (AchE) activity was investigat ed. The MPDP(+) was found to inhibit the enzyme in a dose-dependent ma nner. The kinetic parameter, K-m, for the substrate acetylthiocholine was found to be 0.22 mM, and the K-is, and K-ii for MPDP(+) inhibition of AChE were found to be 0.265 and 0.578 mM, respectively. It was fou nd that MPDP(+) is neither a substrate of AChE nor a time-dependent in activator. The studies of reaction kinetics indicate the inhibition of AChE to be a noncompetitive inhibition. The inhibition of AchE by MPD P(+) was virtually reversed by either dilution or gel exclusion chroma tography, These data suggest that once MPDP(+) enters the basal gangli a of the brain, it can inhibit the AChE and thereby increase the acety lcholine level in the basal ganglia, leading to potential cell dysfunc tion. It appears likely that the nigrostriatal toxicity by MPDP(+) lea ding to Parkinson's disease-like syndrome may, at least in part, be me diated via the AChE inhibition. (C) 1996 Academic Press, Inc.