Potential environmental neurotoxins related to 1-methyl-4-phenylpyridinium: selective toxicity of 1-methyl-4-(4'-acetamidophenyl)-pyridinium and 1-methyl-4-cyclohexylpyridinium for dopaminergic neurons in culture.
Mesencephalic cells in culture were exposed to various compounds which we hypothesized to be selective toxins for dopaminergic neurons. The culture system was previously shown suitable for assessing selective dopaminergic neurotoxicity, since 1-methyl-4-phenyl-pyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium, destroyed dopaminergic neurons without affecting other cells. Some compounds tested were selected to fulfill two criteria believed to underly the selective dopaminergic neurotoxicity of MPP+, i.e., to be a potential substrate for the uptake carrier for dopamine and to possess a strong delocalized positive charge to inhibit the mitochondrial respiratory system. Other compounds were chosen on the basis of clinical or anecdotal evidence linking them to Parkinson's disease. Among the tested compounds two pyridinium analogs, 1-methyl-4-(4'-acetamidophenyl)pyridinium (MACPP+) and 1-methyl-4-cyclohexylpyridinium (MCP+) were found to be selectively toxic toward dopaminergic neurons. Incubation of cultures with both MACPP+ and MCP+ produced a dramatic reduction in the number of tyrosine hydroxylase-positive cells and the uptake of [3H]dopamine without reducing the number of cells visualized by phase-contrast microscopy or the uptake of [3H]aminobutyric acid. Besides MACPP+ and MCP+ none of the tested compounds exhibited any selective dopaminergic neurotoxicity. Together with earlier findings, these data suggest that the structural requirements are rather strict for a chemical to be a selective dopaminergic neurotoxin and make it unlikely that there is a wide spectrum of environmental dopaminergic toxins.
Michel
P P
PP
Andrus Gerontology Center, University of Southern California, Los Angeles 90089.
Dandapani
B K
BK
Efange
S M
SM
Hefti
F
F
D015655:1-Methyl-4-phenylpyridinium / Q000031:analogs & derivatives* / Q000506:poisoning; D000470:Alkaloids / Q000506:poisoning; D000818:Animals; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism*; D004781:Environmental Exposure; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology*; D012701:Serotonin / Q000031:analogs & derivatives
D000470:Alkaloids; D009498:Neurotoxins; C064036:1-methyl-4-(4'-acetamidophenyl)pyridinium; C064037:1-methyl-4-cyclohexylpyridinium; D012701:Serotonin; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine