Neuroprotective effects of DETA-NONOate, a nitric oxide donor, on hydrogenperoxide-induced neurotoxicity in cortical neurones

Nitric oxide (NO) has been proposed to exert neuroprotective actions agains t oxidative damage acting directly as an antioxidant; in addition, it has a lso been suggested that NO might be cytoprotective by increasing cyclic GMP concentrations via activation of soluble guanylate cyclase. In this contex t, we have previously shown that cyclic GMP elevations confer cytoprotectio n against the neurotoxicity induced by SIN-1 in the presence of superoxide dismutase, conditions in which cell death seems to be a consequence of hydr ogen peroxide (H2O2) formation. We have now found that H2O2 (20-100 mu M) c auses neurotoxicity in 1-week-old rat cortical neurones and that this effec t is inhibited by the NO donor DETA-NONOate (1-10 mu M). We have also found that 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ), a selective inhib itor of soluble guanylate cyclase, reverses the effect induced by DETA-NONO ate, and that this action of ODQ is mimicked by 8-(4-chlorophenylthio)guano sine-3',5'-monophosphorothioate (Rp-8-pCPT-cGMPS), an inhibitor of cyclic G MP-dependent protein kinase, suggesting that the pathway affording protecti on involves activation of this kinase by cyclic GMP elevations. Simultaneou sly, ODQ inhibits the elevation of cyclic GMP concentrations induced by DET A-NONOate (1-3 mu M) in cortical cells. Finally, we have also shown that th e cyclic GMP mimetic, 8-bromoguanosine 3':5'-cyclic monophosphate (8-Br-cyc lic GMP) inhibits the neurotoxicity induced by H2O2 (30-40 mu M). Taken tog ether, these data demonstrate that NO-induced cyclic GMP elevations confer cytoprotection against H2O2-induced neuronal cell death. (C) 1999 Elsevier Science Ltd. All rights reserved.