Effect of exogenous and endogenous antioxidants on 3-nitropropionic acid-induced in vivo oxidative stress and striatal lesions: Insights into Huntington's disease

3-Nitropropionic acid (3-NP) is an irreversible inhibitor of complex ii in the mitochondria, 3-NP toxicity has gained acceptance as an animal model of Huntington's disease (HD). In the present study, we confirmed that rats in jected with 3-NP (20 mg/kg, i.p., daily for 4 days) exhibit increased oxida tive stress in both striatum and cortical synaptosomes as well as lesions i n the striatum, Synaptosomal membrane proteins from rats injected with 3-NP exhibited a decrease in W/S ratio, the relevant electron paramagnetic reso nance (EPR) parameter used to determine levels of protein oxidation, and we stern blot analysis for protein carbonyls revealed direct evidence of incre ased synaptosomal protein oxidation. Treatment of rats with the brain-acces sible free radical spin trap 5-diethoxyphosphoryl-5-methyl-1-pyrrolin N-oxi de (DEPMPO; 30 mg/kg, i.p., daily 2 h before 3-NP injection) or with N-acet ylcysteine (NAC; 100 mg/kg, i.p,, daily 2 h before 3-NP injection), a known glutathione precursor, before 3-NP treatments protects against oxidative d amage induced by 3-NP as measured by EPR and western blot analysis for prot ein carbonyls, Furthermore, both DEPMPO and NAC treatments before 3-NP admi nistration significantly reduce striatal lesion volumes. These data suggest oxidative damage is a prerequisite for striatal lesion formation and that antioxidant treatment may be a useful therapeutic strategy against 3-NP neu rotoxicity and perhaps against HD as well.