Astrocytes as a primary locus for the conversion MPTP into MPP+.
The enzymatic conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to 1-methyl-4-phenylpyridinium ion by monoamine oxidase-B is an essential step mediating the dopaminergic neurotoxicity. Since monoamine oxidase-B is located primarily in serotonergic neurons and astrocytes, the production of 1-methyl-4-phenylpyridinium ion is thought to be extra-dopaminergic. This study provides evidence in support of this conclusion. Pretreating mice with fluoxetine (a serotonergic uptake inhibitor) before the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine attenuated the dopaminergic neurotoxicity. This was not the result of a nonspecific inhibition of dopaminergic uptake, as fluoxetine pretreatment did not attenuate the dopaminergic neurotoxicity resulting from the intrastriatal administration of the 1-methyl-4-phenylpyridinium ion. Further localization of the primary site of 1-methyl-4-phenylpyridinium ion production as being astrocytes was provided by the failure of 5,7-dihydroxytryptamine-induced serotonergic lesions to attenuate the neurotoxicity produced by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, whereas, fluoxetine pretreatment in similarly lesioned subjects, continued to attenuate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity. These results are consistent with the hypothesis that astrocytes are a principle site of 1-methyl-4-phenylpyridinium ion production.
Brooks
W J
WJ
Department of Psychology, Rutgers, State University, New Brunswick, New Jersey.
Jarvis
M F
MF
Wagner
G C
GC
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001711:Biotransformation; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008995:Monoamine Oxidase / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism*; D011725:Pyridines / Q000378:metabolism* / Q000633:toxicity; D011726:Pyridinium Compounds / Q000378:metabolism* / Q000633:toxicity; D012016:Reference Values; D012701:Serotonin / Q000378:metabolism
D009498:Neurotoxins; D011725:Pyridines; D011726:Pyridinium Compounds; D005473:Fluoxetine; D012701:Serotonin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine