Toxic effects of potential environmental neurotoxins related to 1-methyl-4-phenylpyridinium on cultured rat dopaminergic neurons.
Dopaminergic rat mesencephalic neurons in culture were exposed to a group of potential environmental neurotoxins. These cultures, which contained 0.5 to 1% dopaminergic neurons, were a suitable tool for determining nonselective and selective dopaminergic cytotoxicity. Selective toxicity was quantitated as the concentration which destroyed half of the population of dopaminergic neurons as visualized by tyrosine hydroxylase immunocytochemistry. Nonselective toxicity was defined as the concentration of test drug which destroyed half of the entire population of cultured cells as visualized by phase contrast microscopy. The compounds tested were selected to fulfill two molecular criteria underlying the toxic activity of 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toward dopaminergic cells: 1) to be a substrate for the selective uptake system of the dopaminergic neurons and 2) to possess a delocalized positive charge related to their ability to inhibit mitochondrial electron transport. Of a total number of 29 compounds tested, MPP+ and its close derivatives, 2'-methyl-MPP+ and p-amino-MPP+, exhibited highly selective dopaminergic toxicity, hence the requirements for a selective dopaminergic neurotoxin are rather strict.
Michel
P P
PP
Department of Neurology, University of Miami, Florida.
Dandapani
B K
BK
Sanchez-Ramos
J
J
Efange
S
S
Pressman
B C
BC
Hefti
F
F
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D001562:Benzimidazoles / Q000633:toxicity; D002478:Cells, Cultured; D004785:Environmental Pollutants / Q000633:toxicity*; D019791:Guanidine; D006146:Guanidines / Q000633:toxicity; D007546:Isoquinolines / Q000633:toxicity; D009498:Neurotoxins / Q000633:toxicity*; D011725:Pyridines / Q000633:toxicity*; D011726:Pyridinium Compounds / Q000633:toxicity; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects*; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D004785:Environmental Pollutants; D006146:Guanidines; D007546:Isoquinolines; D009498:Neurotoxins; D011725:Pyridines; D011726:Pyridinium Compounds; D011954:Receptors, Dopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D019791:Guanidine; D015655:1-Methyl-4-phenylpyridinium