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-dihydropyridinium ion (MPDP+) on acetylcholinesterase (AchE) activity was investigated. The MPDP+ was found to inhibit the enzyme in a dose-dependent manner. The kinetic parameter, Km, for the substrate acetylthiocholine was found to be 0.22 mM, and the Kis and Kii for MPDP+ inhibition of AChE were found to be 0.265 and 0.578 mM, respectively. It was found that MPDP+ is neither a substrate of AChE nor a time-dependent inactivator. The studies of reaction kinetics indicate the inhibition of AChE to be a noncompetitive inhibition. The inhibition of AchE by MPDP+ was virtually reversed by either dilution or gel exclusion chromatography. These data suggest that once MPDP+ enters the basal ganglia of the brain, it can inhibit the AChE and thereby increase the acetylcholine level in the basal ganglia, leading to potential cell dysfunction. It appears likely that the nigrostriatal toxicity by MPDP+ leading to Parkinson's disease-like syndrome may, at least in part, be mediated via the AChE inhibition.