Intracerebroventricular administration of 1-methyl-4-phenylpyridinium ion in mice: effects of simultaneously administered nomifensine, deprenyl, and 1-t-butyl-4,4-diphenylpiperidine.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) destroys nigrostriatal dopaminergic pathways and thereby produces a syndrome similar to Parkinson's disease. MPTP is oxidized by monoamine oxidase B (MAO B) to the 1-methyl-4-phenylpyridinium ion (MPP+), which is taken up in dopaminergic neurons through the dopamine (DA) uptake system, where it develops its toxic effect. Our observations show a new aspect of the MPP+ mode of action, in which deprenyl in mice has a partially protective effect against MPP+. Furthermore budipine, a therapeutic agent for Parkinsonism, is also able to partially prevent MPP+ toxicity. A MAO B-inhibitory component of budipine, as shown in receptor binding studies previously, could contribute to this effect. Comparable experiments with nomifensine do not exclude the possibility of budipine as an effect as a DA uptake inhibitor. An unexplained after effect of budipine leads to a large increase in 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels five weeks after the last administration.
D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002395:Catecholamines / Q000378:metabolism; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D007276:Injections, Intraventricular; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009069:Movement Disorders / Q000139:chemically induced; D009627:Nomifensine / Q000008:administration & dosage / Q000494:pharmacology*; D010627:Phenethylamines / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D012642:Selegiline / Q000008:administration & dosage / Q000494:pharmacology*; D012701:Serotonin / Q000378:metabolism
D002395:Catecholamines; D008996:Monoamine Oxidase Inhibitors; D010627:Phenethylamines; D010880:Piperidines; D011726:Pyridinium Compounds; D009627:Nomifensine; D012642:Selegiline; D012701:Serotonin; C026710:budipine; D015655:1-Methyl-4-phenylpyridinium