Neuroprotective effects of DETA-NONOate, a nitric oxide donor, on hydrogen peroxide-induced neurotoxicity in cortical neurones.
Nitric oxide (NO) has been proposed to exert neuroprotective actions against oxidative damage acting directly as an antioxidant; in addition, it has also been suggested that NO might be cytoprotective by increasing cyclic GMP concentrations via activation of soluble guanylate cyclase. In this context, we have previously shown that cyclic GMP elevations confer cytoprotection against the neurotoxicity induced by SIN-1 in the presence of superoxide dismutase, conditions in which cell death seems to be a consequence of hydrogen peroxide (H2O2) formation. We have now found that H2O2 (20-100 microM) causes neurotoxicity in 1-week-old rat cortical neurones and that this effect is inhibited by the NO donor DETA-NONOate (1-10 microM). We have also found that 1H-[1,2,4]oxadiazolo[4,3,-alpha]quinoxalin-1-one (ODQ), a selective inhibitor of soluble guanylate cyclase, reverses the effect induced by DETA-NONOate, and that this action of ODQ is mimicked by 8-(4-chlorophenylthio)guanosine-3',5'-monophosphorothioate (Rp-8-pCPT-cGMPS), an inhibitor of cyclic GMP-dependent protein kinase, suggesting that the pathway affording protection involves activation of this kinase by cyclic GMP elevations. Simultaneously, ODQ inhibits the elevation of cyclic GMP concentrations induced by DETA-NONOate (1-3 microM) in cortical cells. Finally, we have also shown that the cyclic GMP mimetic, 8-bromoguanosine 3':5'-cyclic monophosphate (8-Br-cyclic GMP) inhibits the neurotoxicity induced by H2O2 (30-40 microM). Taken together, these data demonstrate that NO-induced cyclic GMP elevations confer cytoprotection against H2O2-induced neuronal cell death.
Fernández-Tomé
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P
Instituto de Farmacologia y Toxicologia, Consejo Superior de Investigaciones Cientificas, Facultad de Medicina, Universidad Complutense de Madrid, Spain.
Lizasoain
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I
Leza
J C
JC
Lorenzo
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P
Moro
M A
MA
D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors* / Q000633:toxicity; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D013873:Thionucleotides / Q000494:pharmacology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C090860:8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D010069:Oxadiazoles; D011810:Quinoxalines; D013873:Thionucleotides; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; C016276:8-bromocyclic GMP; D006861:Hydrogen Peroxide; D006152:Cyclic GMP