Enhanced N-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Toxicity in Mice Deficient in CuZn-Superoxide Dismutase or Glutathione Peroxidase

摘要: Administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mammals causes damage the nigrostriatal dopaminergic pathway similar that observed in Parkinson disease (PD). Reactive oxygen species (ROS) are thought be involved pathogenesis MPTP-mediated neurodegeneration. To further clarify role superoxide anion radical (.O 2 and study possible involvement hydroperoxides neurodegeneration, MPTP neurotoxicity was induced mice deficient either CuZn dismutase (SOD), a scavenger enzyme for.O , or cellular glutathione peroxidase (GSHPx-1), for hydroperoxides. Littermate control homozygous were injected intraperitoneally with total cumulative dose 0, 75, 150 mg/kg delivered over 5 d. All killed d after last injection brains processed immunohistological analysis tyrosine hydroxylase (TH) striatum substantia nigra pars compacta (SNc), as well direct measurements dopamine concentrations striatum. The intensity TH immunoreactivity evaluated by measuring relative optical density (OD) NIH IMAGE, expressed Log (OD striatum)/Log white matter). Degeneration TH-containing neurons assessed counting TH-positive SNc. We found this exposure protocol produced dose-dependent depletion littermate both strains knockout mice; however, reduction content significantly greater CuZn-SOD GSHPx- I compared controls. did not alter number SNc mice. These data suggest some deleterious effects on striatal nerve terminals mediated both.O hydroperoxides, they occur prior neurodegeneration similarity between model PD raises possibility types ROS may play significant early PD.