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 onto geny of MPTP-induced DA depletion and formation of reactive oxygen spe cies (ROS) were evaluated in mouse striatum. C57/B6N mice were injecte d four times with 0 or 10 mg/kg MPTP (i.p.) at two-hour intervals on e ither postnatal day 23, at about 7 months of age, and at one year of a ge. 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-dihy droxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measur ed 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 a nd HVA levels decreased up to 4 and 8 hours post dosing respectively a nd returned to control values thereafter. At 7 months of age, MPTP pro duced 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 8 0 % decrease of DA and 60 - 80 % decrease of DOPAC and HVA in striatum . In contrast, ROS formation in striatum was not significantly increas ed by MPTP treatment at any age but was decreased at 1 hour only in PN D 23 and 7 month old mice. These studies suggest that MPTP-induced neu rotoxicity is age-dependent in the mouse. The lack of effect on ROS fo rmation 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.