Dopaminergic toxicity of rotenone and the 1-methyl-4-phenylpyridinium ion after their stereotaxic administration to rats: implication for the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity.
The 1-methyl-4-phenyl-pyridinium ion (MPP+) is the four electron oxidation product of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine (MPTP). MPP+ can be formed by the oxidation of MPTP by monoamine oxidase B to the intermediate dihydropyridinium species, MPDP+, which is spontaneously transformed to MPP+. In the present study, MPP+, like the mitochondrial toxin rotenone, inhibited pyruvate-malate respiration in isolated mitochondrial preparations. Moreover, the stereotaxic administration of both MPP+ and rotenone caused damage to the dopaminergic nigrostriatal pathway. These data clearly demonstrate that a mitochondrial toxin, administered stereotaxically, is extremely neurotoxic. The data lend support to the concept that MPTP-induced neurotoxicity may be due to the detrimental actions of enzymatically formed MPP+ on mitochondrial function.
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D008928:Mitochondria / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity; D010101:Oxygen Consumption / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage / Q000633:toxicity*; D011726:Pyridinium Compounds / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012402:Rotenone / Q000008:administration & dosage / Q000633:toxicity*; D013238:Stereotaxic Techniques; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D013386:Succinates / Q000378:metabolism; D019802:Succinic Acid
D009498:Neurotoxins; D011725:Pyridines; D011726:Pyridinium Compounds; D013386:Succinates; D012402:Rotenone; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D019802:Succinic Acid; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine