Contradictory effects of sodium nitroprusside and S-nitroso-N-acetylpenicillamine on oxidative stress in brain dopamine neurons in vivo.
To investigate whether nitric oxide (*NO) is neurotoxic or neuroprotective in the brain, we compared the in vivo role of S-nitroso-N-acetylpenicillamine (SNAP) with that of sodium nitroprusside (SNP) on ferrous citrate-induced oxidative stress and neuronal loss in the rat nigrostriatal dopaminergic system. It is known that light irradiation releases *NO from its donor compounds; these irradiated *NO donors were used as sham controls in this study. Intranigral infusion of ferrous citrate (4.2 nmol) into the rat midbrain substantia nigra compacta area caused acute lipid peroxidation in the substantia nigra and chronic dopamine depletion in the caudate nucleus. Coinfusion of freshly prepared SNAP (0-8.4 nmol) or *NO (about 2 nmol), but not SNP, rescued iron-induced dopamine depletion in the rat brain in vivo. In fact, SNP produced prooxidative effects similar to ferrous citrate both in vivo and in vitro, since SNP is a redox iron complex. Consistently, *NO and SNAP inhibited, whereas SNP potentiated, *OH generation and lipid peroxidation evoked by ferrous citrate in vitro. We previously reported that freshly prepared, but not irradiated, S-nitroso-L-glutathione (GSNO) protected brain dopamine neurons against oxidative stress in vivo. As well as these antioxidative properties, our recent reports (see (Ref. 1)) indicate that *NO/GSNO activated guanylyl cyclase, increased cGMP and that could lead to PKG-mediated expression of MnSOD, Bcl-2, and thioredoxin for preconditioning neuroprotection against 1-methyl-4-phenylpyridinium (MPP(+)).(1) In conclusion, *NO and S-nitrosothiols (e.g., GSNO and SNAP) can scavenge reactive oxygen species and activate the heme moiety of guanylyl cyclase, resulting in protection of brain dopamine neurons through both antioxidative and antiapoptotic mechanisms.
Rauhala
Pekka
P
Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland. pekka.rauhala@helsinki.fi
Andoh
Tsugunobu
T
Yeh
Kevin
K
Chiueh
Chuang C
CC
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D019343:Citric Acid; D004298:Dopamine / Q000378:metabolism*; D005296:Ferrous Compounds / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology*
D005296:Ferrous Compounds; D018696:Neuroprotective Agents; D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; D009599:Nitroprusside; D019343:Citric Acid; D009569:Nitric Oxide; C016600:ferrous citrate; D026423:S-Nitroso-N-Acetylpenicillamine; D007501:Iron; D004298:Dopamine