NEUROPROTECTION BY S-NITROSOGLUTATHIONE OF BRAIN DOPAMINE NEURONS FROM OXIDATIVE STRESS

The proposed anti- and prooxidant effects of nitric oxide (NO) derivat ives, such as S-nitrosoglutathione (GSNO) and peroxynitrite, were inve stigated in the rat nigrostriatal dopaminergic system. Intranigal infu sion of freshly prepared GSNO (0-16.8 nmol, i.n.) prevented iron-induc ed (4.2 nmol, i.n.) oxidative stress and nigral injury, reflected by a decrease in striatal dopamine levels. This neuroprotective effect of GSNO was verified by ex vivo imaging of brain dopamine uptake sites us ing I-125-labeled RTI-55. In addition, in vitro data indicate that GSN O concentration-dependently inhibited iron-evoked hydroxyl radical gen eration and brain lipid peroxidation. In this iron-induced oxidant str ess model, GSNO was approximately 100-fold more potent than the antiox idant glutathione (GSH). Light-exposed, NO-exhausted GSNO produced nei ther antioxidative nor neuroprotective effects, which indicates that N O may mediate at least part of GSNO's effects. Moreover, GSNO complete ly (and GSH only partially) inhibited the weak pro-oxidant effect of p eroxynitrite, which produced little injury to nigral neurons in vivo. This study provides relevant in vivo evidence suggesting that nanomol GSNO can protect brain dopamine neurons from iron-induced oxidative st ress and degeneration. In conclusion, S-nitrosylation of GSH by NO and oxygen may be part of the antioxidative cellular defense system.