On the mechanisms underlying 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity: the effect of perinigral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, its metabolite and their analogs in the rat
The discovery that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism in humans and other primates by selective destruction of substantia nigra dopaminergic neurons has spurred research to define the mechanisms underlying its toxicity. To avoid variables such as tissue distribut...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 241; no. 2; pp. 669 - 676 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Bethesda, MD
American Society for Pharmacology and Experimental Therapeutics
01.05.1987
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Subjects | |
Online Access | Get full text |
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Summary: | The discovery that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism in humans and other primates by
selective destruction of substantia nigra dopaminergic neurons has spurred research to define the mechanisms underlying its
toxicity. To avoid variables such as tissue distribution, extracerebral metabolism and blood-brain barrier permeability, the
authors studied the neurochemical and morphologic effects of direct perinigral infusions of various concentrations of MPTP,
its metabolites and analogs in the rat. MPTP, in the highest dose used, 1000 nmol, decreased dopamine and its metabolites
in ipsilateral striatum by approximately 75%, whereas 3,3-dimethyl-MPTP (which is oxidized to 1,3,3-trimethyl-4-phenyl-2,3-dihydropyridinium
cation but not to a pyridinium species) had no effect. The 2,2 and 3,3-dimethyl analogs of 1-methyl-4-phenyl-2,3-dihydropyridinium
cation which also cannot be oxidized to pyridinium species, reduced striatal dopamine, suggesting that these compounds are
toxic in their own right. 1-Methyl-4-phenylpyridinium cation (MPP+) and its 4-(4-fluorophenyl) and 4-(2-pyridyl) analogs that
have less negative reduction potentials than MPP+, were most potent in decreasing striatal dopamine and metabolites, with
MPP+ being 5 to 10 times more effective than its two analogs and approximately 100 times more potent than MPTP and the two
dimethyl 1-methyl-4-phenyl-2,3-dihydropyridinium cation analogs. These findings suggest that MPP+ is ultimately responsible
for MPTP toxicity but does not act via oxidant stress mechanisms. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 |
ISSN: | 0022-3565 1521-0103 |