The Nitric Oxide Donor NOC12 Protects Cultured Astrocytes Against Apoptosis via a cGMP-Dependent Mechanism.

  • Takuma Kazuhiro
    Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences and High Technology Research Center, Kobe Gakuin University
  • Phuagphong Patamawan
    Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University
  • Lee Eibai
    Department of Pharmacology, Faculty of Pharmaceutical Sciences and High Technology Research Center, Kobe Gakuin University
  • Enomoto Riyo
    Department of Pharmacology, Faculty of Pharmaceutical Sciences and High Technology Research Center, Kobe Gakuin University
  • Mori Koichi
    Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences and High Technology Research Center, Kobe Gakuin University
  • Baba Akemichi
    Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University
  • Matsuda Toshio
    Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University

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Abstract

We examined the effect of 3-ethyl-3-(ethylaminoethyl)-1-hydroxy-2-oxo-1-triazene (NOC12), a nitric oxide (NO) donor, on apoptosis in cultured astrocytes. Reperfusion after hydrogen peroxide (H2O2) exposure caused a decrease in cell viability, loss of mitochondrial membrane potential, caspase-3 activation, DNA ladder formation, and nuclear condensation. NOC12 at 10 – 100 μM significantly attenuated these apoptotic changes, while the NO donor at 1 mM caused cell injury and exacerbated the H2O2-induced cell injury. NOC12 increased intracellular cGMP levels in a dose dependent manner with the maximal effect at 100 μM. The protective effect of NOC12 was mimicked by the NO-independent guanylate cyclase activator 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole, and was attenuated by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and the cGMP-dependent protein kinase inhibitor KT5823. ODQ and KT5823 did not block but rather exacerbated the cytotoxic effect of NOC12 at 1 mM. These findings demonstrate that lower concentrations of NOC12 inhibit the H2O2-induced apoptosis of astrocytes in a cGMP-dependent way, but higher concentrations of NOC12 show a toxic effect on astrocytes in a cGMP-independent way.

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