AGE-RELATED SUSCEPTIBILITY TO MPTP-INDUCED NEUROTOXICITY IN MICE

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is known to cause neurotoxicity in rodents and nonhuman primates. In this study the ontogeny of MPTP-induced DA depletion and formation of reactive oxygen species (ROS) were evaluated in mouse striatum. C57/B6N mice were injected four times with 0 or 10 mg/kg MPTP (i.p.) at two-hour intervals on either postnatal day 23, at about 7 months of age, and at one year of age. Animals were sacrificed 1, 2, 4, 8, 12, 24, 48 and 72 hours after the last dose. Brains were rapidly removed and striata were dissected for neurochemical analysis. Dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured by HPLC/EC. ROS formation was measured by a fluorescence probe, 2,7'-dichlorofluorescein-diacetate (DCFH-DA). MPTP produced a slight but significant decrease of DA only 4 hours post dosing on PND 23. DOPAC and HVA levels decreased up to 4 and 8 hours post dosing respectively and returned to control values thereafter. At 7 months of age, MPTP produced a 50-65 % decrease of DA and its metabolites (DOPAC and HVA) in striatum 24 hours post dosing. In one year old mice MPTP produced an 80 % decrease of DA and 60 - 80 % decrease of DOPAC and HVA in striatum. In contrast, ROS formation in striatum was not significantly increased by MPTP treatment at any age but was decreased at 1 hour only in PND 23 and 7 month old mice. These studies suggest that MPTP-induced neurotoxicity is age-dependent in the mouse. The lack of effect on ROS formation suggests that, if MPTP neurotoxicity is mediated via oxidative stress it cannot be measured by fluorescence probe techniques used in these experiments. (C) 1993 Intox Press, Inc.