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 inhi biting mitochondrial respiration. However, astrocytic injuries are als o observed in MPTP/MPP+-treated rats. Because nitric oxide (NO.) is su ggested to be cytoprotective, we examined the effects of nitroprusside (SNP), S-nitroso-N-acetylpenicillamine (SNAP), and 3-morpholinosydnon imine (SIN-1) on MPP+ induced toxicity in astrocytes. Incubation of as trocytes with MPP+ for 2 days produced a dose-dependent toxicity, incl uding increase in lactate level and lipid peroxidation, decrease of me tabolic activity and cell damage. SNP, SNAP, and SIN-1 all attenuated MPP+-induced toxicity. The same protection was not achieved with N-ace tylpenicillamine or ferrocyanide, structural analogues of SNAP or SNP but devoid of NO.. Further, the effect was not attributed to the incre ased cGMP levels or blockade of MPP+ accumulation in astrocytes. Notab ly, catalase, dimethyl sulfoxide and ferricyanide, an extracellular el ectron acceptor, were also effective in inhibiting MPP+ damage. NO. do nors and analogues were also tested against damage produced by rotenon e, an irreversible complex I inhibitor. Only ferricyanide and SNP effe ctively 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 allev iate MPP+-induced toxicity. (C) 1998 Elsevier Science Inc.