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.
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 microenvironments 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.
Klein
B G
BG
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, 24061-0442, USA. bklein@vt.edu
Kirby
M L
ML
Freeborn
E R
ER
Bloomquist
J R
JR
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008996:Monoamine Oxidase Inhibitors / Q000493:pharmacokinetics; D009498:Neurotoxins / Q000378:metabolism / Q000494:pharmacology*; D010293:Pargyline / Q000493:pharmacokinetics; D012701:Serotonin / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
C101344:1-methyl-4-(4-dimethylaminophenylethenyl)-1,2,3,6-tetrahydropyridine; D008996:Monoamine Oxidase Inhibitors; D009498:Neurotoxins; D012701:Serotonin; D005680:gamma-Aminobutyric Acid; D010293:Pargyline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine