Acetylcholinesterase inhibition by 1-methyl-4-phenylpyridinium ion, a bioactivated metabolite of MPTP.

The effect of the neurotoxicant, 1-methyl-4-phenylpyridinium ion (MPP+) on acetylcholinesterase (AchE) activity was investigated. The MPP+ was found to inactivate the enzyme in a dose dependent manner. The kinetic parameter, Km for the substrate (acetylthiocholine), was found to be 0.216 mM and Ki for MPP+ for the inactivation of AChE was found to be 0.197 mM. It was found that MPP+ is neither a substrate of AChE nor the time-dependent inactivator. The studies of reaction kinetics indicate the inactivation of AChE to be a linear mixed-type inhibition. The inactivation of AChE by MPP+ was partially recovered by either dilution or gel exclusion chromatography. These data suggest that once MPP+ enters the basal ganglia of the brain, it can inactivate 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 MPP+ leading to Parkinson's disease-like syndrome may, in part, be mediated via the AChE inactivation.