Pharmacological properties of the MPTP analog trans-1-methyl-4-[4-dimethylaminophenylethenyl]-1,2,3,6-tetrahydropyridine and its pyridinium metabolite in mouse brain synaptosomes: a potential visual marker for substrates of MPTP-induced neurotoxicity

Abstract

1. The tetrahydropyridine trans-1-methyl-4-[4-dimethylaminophenylethenyl]-1,2,3,6-tetrahydropyridine ( t-THP), like MPTP, can undergo monoamine oxidase (MAO)-mediated conversion to a dihydropyridinium intermediate and subsequent metabolism to a pyridinium species. t-THP is also a better substrate for MAO B than MAO A. In contrast to the metabolism of MPTP, the pyridinium ion derived from t-THP is highly fluorescent. This endows t-THP with potential as an in vivo visual probe for localizing the substrates of MPTP-like neurotoxicity. As a prelude to in vivo labeling studies, we examined the metabolism and uptake kinetics of t-THP and its metabolites in mouse striatal and cortical synaptosomes. 2. T-THP was found to induce a concentration-dependent and saturable fluorescence within striatal and cortical synaptosomes that was also MAO-dependent. Like MPP +, the fluorescent pyridinium ion t-P +, derived from t-THP, inhibited the uptake and facilitated the release of monoamines from synaptosomes in a concentration-dependent fashion. The ion did not rely on sodium-dependent membrane transporters for its concentration-dependent uptake into synaptosomes, although it may have an irreversible affinity for the dopamine transporter. 3. These data suggest that t-THP could be appropriate for use as a visual marker for micro-environments where MPTP-like compounds are taken up and converted to potentially neurotoxic pyridinium species. Such a marker could be employed to address some of the issues regarding the selectivity of MPTP-induced neurotoxicity.