Evidence for generation of oxidative stress in brain by MPTP: in vitro and in Research report vivo studies in mice

The role of oxidative stress in I-methyl-4-phenyl1 .2,3,6tetrahydropyridine (MPTPJ-mediated neurotoxicity is as yet unclear and the evidence for generation of oxygen free radicals as a primary event in the neurotoxicity is yet to be demonstrated. The present study was unoertaken to ascertain the potential role of oxidative damage. and the protective role, if any, of the antioxidant, glutathione (GSH), in MFI’P-induced neurotoxicity. Exposure of sagittal slices of mouse brain to MPTP resulted in significant increases of reactive oxygen species (ROS) and malondialdehyde (MDA. the product of lipid peroxidation) and decreases in GSH content. Pretreatment of mouse brain slices, in vitro, with GSH or GSH isopropyl ester attenuated MPTP toxicity as assessed by the tissue activity of the mitochondrial enzyme, NADH-dehydrogensse (NADH-DH), and by leakage of the cytosolic enzyme. lactate dehydrogenase (LDH). from the slice into the medium. In vivo administration of MPTP (30 mg/kg body weight, s.c.), to mice resulted in significant lowering of GSH in the striatum and midbrain , 2 h after dosage; ROS levels in the striatum and midbrain increased after 4 and 8 h. respectively. In the striatum significant inhibition of rotenone-sensilive NADH ubiquinone-1 oxido-reductase (Complex I) was observed transiently 1 h after MPTP administration. The enzyme activity recovered thereafter; significant inhibition of mitochondrial Complex I was obberved in the striatum only I8 h after MPTP dose. In the midbrain. mitochondrial Complex I was inhibited only I8 h after MPTP dose: no change was observed at the early time points examined. Thus. the depletion of GSH and incrcascd ROS fornlatiorl prc~cdcd the inhibirion ol’ the mitochondriul enzyme in the midbrain. Evidcncc presented herein from both in vitro and in viva srudies support lhut MPTP exposure guncrates ROS resulting in oxidative stress. Kqwwrcls: MYTP: Oxidutivc stress: Gluruthwne; Reactive oxygen species; Brain slice; Brain: Neurotoxicity; Complex I