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 deteremined 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 MPT P were reached within 5 min after iv injections, and the substance was not detectable after 20-30 min. The MPP(+) levels peaked between 20-4 0 min, while the elimination differed between regions. The tissue conc entration of MPP(+) appeared not to be the determining factor for vuln erability of dopamine and noradrenaline neurons to MPTP, equal concent rations of MPP(+) were found in regions showing marked as well as no n eurotoxic 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 catechola mine terminals in striatum or the frontal cortex, nor pretreatment wit h a dopamine uptake blocker affected the synthesis of MPP(+), showing that the con version of MPTP to MPP(+) is taking place outside both do paminergic and noradrenergic neurons. It is concluded that MPTP enters the brain parenchyma and is metabolized to MPP(+) outside the catecho lamine neurons, but that the regional distribution of MPTP and MPP(+) does not explain the vulnerability of different catecholamine neurons in the rodents studied. (C) 1995 Intox Press, Inc.