[3H]1-methyl-4-phenyl-2,3-dihydropyridinium ion binding sites in mouse brain: pharmacological and biological characterization.
Because 1-methyl-4-phenyl-2,3-dihydropyridinium ion (MPP+) appears to damage the dopaminergic neuron and cause neuronal death, we characterized [3H]MPP+ binding sites in mouse brain membranes. Among several compounds tested, debrisoquin [3,4-dihydro-2(1H)-isoquinolinecarboxamidine] and some analogues were able to antagonize [3H]MPP+ binding. Debrisoquin is able to block adrenergic transmission and inhibit the activity of monoamine oxidase A (MAO-A). We found a certain correlation between the ability of these agents to displace [3H]MPP+ from its binding sites and their capacity to inhibit MAO-A activity. These data and the finding of a higher number of [3H]MPP+ binding sites in human placenta compared to mouse brain suggest that these sites may correspond to MAO-A enzymes. Recently it has been demonstrated in human brain that neurons in regions rich in catecholamines are positive for MAO-A. Accordingly, we suggest MAO-A as a possible accumulation site of MPP+ within the dopaminergic neuron. We also indicate the chemical structural requirement associated with the best binding of debrisoquin analogues with [3H]MPP+ sites. It would be reasonable to test the effects of debrisoquin-like drugs able to pass the blood-brain barrier on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity.
Del Zompo
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Department of Neurosciences, University of Cagliari, Italy.
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D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D055598:Chemical Phenomena; D002621:Chemistry; D003647:Debrisoquin / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D007477:Ions; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008995:Monoamine Oxidase / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011726:Pyridinium Compounds / Q000378:metabolism*; D014316:Tritium
D007477:Ions; D011726:Pyridinium Compounds; D014316:Tritium; C044755:1-methyl-4-phenyl-2,3-dihydropyridinium; D008995:Monoamine Oxidase; D003647:Debrisoquin