Evidence for hydroxyl radical scavenging action of nitric oxide donors in the protection against 1-methyl-4-phenylpyridinium-induced neurotoxicity in rats

In the present study we provide evidence for hydroxyl radical ((OH)-O-center dot) scavenging action of nitric oxide (NO center dot), and subsequent dopaminergic neuroprotection in a hemiparkinsonian rat model. Reactive oxygen species are strongly implicated in the nigrostriatal dopaminergic neurotoxicity caused by the parkinsonian neurotoxin, 1-methyl-4-phenylpyridinium (MPP+). Since the role of this free radical as a neurotoxicant or neuroprotectant is debatable, we investigated the effects of some of the NO center dot donors such as S-nitroso-N-acetylpenicillamine (SNAP), 3-morpholinosydnonimine hydrochloride (SIN-1), sodium nitroprusside (SNP) and nitroglycerin (NG) on in vitro (OH)-O-center dot generation in a Fenton-like reaction involving ferrous citrate, as well as in MPP+-induced (OH)-O-center dot production in the mitochondria. We also tested whether co-administration of NO center dot donor and MPP+ could protect against MPP+-induced dopaminergic neurotoxicity in rats. While NG, SNAP and SIN-1 attenuated MPP+-induced (OH)-O-center dot generation in the mitochondria, and in a Fenton-like reaction, SNP caused up to 18-fold increase in (OH)-O-center dot production in the latter reaction. Striatal dopaminergic depletion following intranigral infusion of MPP+ in rats was significantly attenuated by NG, SNAP and SIN-1, but not by SNP. Solutions of NG, SNAP and SIN-1, exposed to air for 48 h to remove NO center dot, when administered similarly failed to attenuate MPP+-induced neurotoxicity in vivo. Conversely, long-time air-exposed SNP solution when administered in rats intranigrally, caused a dose-dependent depletion of the striatal dopamine. These results confirm the involvement of (OH)-O-center dot in the nigrostriatal degeneration caused by MPP+, indicate the (OH)-O-center dot scavenging ability of NO center dot, and demonstrate protection by NO center dot donors against MPP+-induced dopaminergic eurotoxicity in rats.