Regional biotransformation of MPTP in the CNS of rodents and its relation to neurotoxicity.
The concentrations of the catecholamine neurotoxin 1-methyl-4-phenyl-1, 2,3,6-tetrahydropridine (MPTP) and its oxidized metabolite 1-methyl-4-phenylpyridine (MPP+) were determined by liquid chromatography in various regions of brains from NMRI and C57 BL/6 mice and from Sprague-Dawley rats after systemic administration of MPTP. Peak levels of MPTP were reached within 5 min after i.v. injections, and the substance was not detectable after 20-30 min. The MPP+ levels peaked between 20-40 min, while the elimination differed between regions. The tissue concentration of MPP+ appeared not to be the determining factor for vulnerability of dopamine and noradrenaline neurons to MPTP, equal concentrations of MPP+ were found in regions showing marked as well as no neurotoxic effects of MPTP. High concentrations of MPP+ were detected in striatum of rats in spite of the absence of degenerative effects. By studying the dose-response of the acute MPTP-induced depletion of 3,4-dihydroxyphenyl acetic acid (DOPAC), it was confirmed that MPTP does enter the brain of all species. Neither previous lesions of catecholamine terminals in striatum or the frontal cortex, nor pretreatment with a dopamine uptake blocker affected the synthesis of MPP+, showing that the conversion of MPTP to MPP+ is taking place outside both dopaminergic and noradrenergic neurons. It is concluded that MPTP enters the brain parenchyma and is metabolized to MPP+ outside the catecholamine neurons, but that the regional distribution of MPTP and MPP+ does not explain the vulnerability of different catecholamine neurons in the rodents studied.
Nwanze
E
E
Department of Clinical Neuroscience and Family Medicine, Karolinska Institute, Huddinge University Hospital, Sweden.
Souverbie
F
F
Jonsson
G
G
Sundström
E
E
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000493:pharmacokinetics*; D015655:1-Methyl-4-phenylpyridinium / Q000493:pharmacokinetics; D000818:Animals; D001711:Biotransformation; D002395:Catecholamines / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley
D002395:Catecholamines; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium