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.
Tsai
M J
MJ
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, The Republic of China.
Lee
E H
EH
D015655:1-Methyl-4-phenylpyridinium / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects*; D002478:Cells, Cultured; D005609:Free Radicals; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000494:pharmacology
D000975:Antioxidants; D005609:Free Radicals; D018696:Neuroprotective Agents; C110881:S-nitro-N-acetylpenicillamine; D012402:Rotenone; D009599:Nitroprusside; D009569:Nitric Oxide; C002385:linsidomine; D008981:Molsidomine; D010396:Penicillamine; D015655:1-Methyl-4-phenylpyridinium