MPTP-INDUCED OXIDATIVE STRESS AND NEUROTOXICITY ARE AGE-DEPENDENT - EVIDENCE FROM MEASURES OF REACTIVE OXYGEN SPECIES AND STRIATAL DOPAMINELEVELS

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes marked depl etion of dopamine (DA) levels and reduction in the activity of tyrosin e hydroxylase (TH) in the nigrostriatal DA pathway. In the brain, the enzyme monoamine oxidase B converts MPTP to 1-methyl-4-phenylpyridiniu m (MPP(+)) which enters DA terminals via DA uptake sites. Within the D A terminals, MPP(+) blocks the mitochondrial complex I and causes ATP depletion. This is thought to be the main cause of MPTP-induced termin al degeneration. In addition, reactive oxygen species (ROS) generated after blockade of the complex I as well as those generated due to DA o xidation may participate in MPTP-induced dopaminotoxicity. The present study sought to determine if a single injection of a large dose of MP TP generates ROS. We also sought to determine if these changes as well as changes in DA levels were correlated and age-dependent. Toward tha t end, we have used C57/B6N male mice that were 22 days or 12 months o ld. These animals were injected with a single dose of MPTP (40 mg/kg, ip). Animals were sacrificed at various times after drug administratio n. MPTP produced no significant increase in ROS nor decreases in DA or HVA concentrations in the striatum of the younger mice. However, DOPA C concentrations were significantly decreased from 15-120 min after dr ug administration. In the older mice, MPTP caused significant increase s in ROS from the beginning to the end of the study period. DA concent rations were decreased from 60 min onward. DOPAC concentrations were d ecreased significantly after 15-120 min while HVA concentrations were significantly increased after 60 and 120 min. These data demonstrate t hat in older mice, a single dose of MPTP can cause increases of ROS wh ich were associated with subsequent decreases in DA concentrations. Yo unger mice were not similarly affected. These results suggest that MPT P-induced neurotoxicity is age-dependent and may be mediated by oxidat ive stress. (C) 1994 Wiley-Liss, Inc.