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) scavenging action of nitric oxide (NO*), 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* donors such as S-nitroso-N-acetylpenicillamine (SNAP), 3-morpholinosydnonimine hydrochloride (SIN-1), sodium nitroprusside (SNP) and nitroglycerin (NG) on in vitro *OH generation in a Fenton-like reaction involving ferrous citrate, as well as in MPP+-induced *OH production in the mitochondria. We also tested whether co-administration of NO* donor and MPP+ could protect against MPP+-induced dopaminergic neurotoxicity in rats. While NG, SNAP and SIN-1 attenuated MPP+-induced *OH generation in the mitochondria, and in a Fenton-like reaction, SNP caused up to 18-fold increase in *OH 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*, 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 in the nigrostriatal degeneration caused by MPP+, indicate the *OH scavenging ability of NO*, and demonstrate protection by NO* donors against MPP+-induced dopaminergic neurotoxicity in rats.
Banerjee
Rebecca
R
Division of Cell Biology & Physiology, Laboratory of Clinical and Experimental Neuroscience, Indian Institute of Chemical Biology, 4, Raja S C Mullick Road, Kolkata 700 032, India.
Saravanan
Karuppagounder S
KS
Thomas
Bobby
B
Sindhu
Kizhake M
KM
Mohanakumar
Kochupurackal P
KP
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012459:Salicylates / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism
D018696:Neuroprotective Agents; D009498:Neurotoxins; D020030:Nitric Oxide Donors; D012459:Salicylates; D017665:Hydroxyl Radical; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine