CV-2619 protects cultured astrocytes against reperfusion injury via nerve growth factor production

In this study, we examined the effect of the neuroprotective agent 2,3-dime thoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone (CV-2619) on reperfusio n injury in cultured rat astrocytes after exposure to hydrogen peroxide (H2 O2)-containing medium. CV-2619 (10 nM to 10 muM) significantly attenuated t he reperfusion-induced decrease in cell viability. The compound showed an a nti-apoptotic effect in this astrocyte injury model. Antioxidants such as a scorbic acid, alpha -tocopherol and reduced glutathione also inhibited H2O2 exposure-induced cytotoxicity. CV-2619 did not affect the levels of reacti ve oxygen species, but it increased nerve growth factor (NGF) production. T he effect of CV-2619 on H2O2 exposure-induced cytotoxicity was blocked by c ycloheximide and anti-NGF antibody. The protective effect of CV-2619 was an tagonized by the mitogen-activated protein (MAP)/extracellular signal-regul ated kinase (ERK) kinase inhibitor 2'-amino-3'-methoxyflavone and the phosp hatidylinositol-3 kinase inhibitor wortmannin. These findings suggest that the effect of CV-2619 is mediated at least partly by NGF production in astr ocytes and that ERK and phosphatidylinositol-3 kinases play a role in the d ownstream mechanism. (C) 2000 Elsevier Science B.V. All rights reserved.