Nitric Oxide Donors Protect Cultured Rat Astrocytes From 1-Methyl-4-Phenylpyridinium-Induced Toxicity

MPP+ is thought to mediate MPTP’s toxicity on dopamine neurons by inhibiting mitochondrial respiration. However, astrocytic injuries are also observed in MPTP/MPP+-treated rats. Because nitric oxide (NO•) is suggested to be cytoprotective, we examined the effects of nitroprusside (SNP), S-nitroso-N-acetylpenicillamine (SNAP), and 3-morpholinosydnonimine (SIN-1) on MPP+-induced toxicity in astrocytes. Incubation of astrocytes with MPP+ for 2 days produced a dose-dependent toxicity, including increase in lactate level and lipid peroxidation, decrease of metabolic activity and cell damage. SNP, SNAP, and SIN-1 all attenuated MPP+-induced toxicity. The same protection was not achieved with N-acetylpenicillamine or ferrocyanide, structural analogues of SNAP or SNP but devoid of NO•. Further, the effect was not attributed to the increased cGMP levels or blockade of MPP+ accumulation in astrocytes. Notably, catalase, dimethyl sulfoxide and ferricyanide, an extracellular electron acceptor, were also effective in inhibiting MPP+ damage. NO• donors and analogues were also tested against damage produced by rotenone, an irreversible complex I inhibitor. Only ferricyanide and SNP effectively protected rotenone’s toxicity. These results concluded that (1) NO• may protect astrocytes from MPP+-induced free radical formation, and (2) prevention of energy depletion/free radicals production alleviate MPP+-induced toxicity.