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-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone (CV-2619) on reperfusion injury in cultured rat astrocytes after exposure to hydrogen peroxide (H(2)O(2))-containing medium. CV-2619 (10 nM to 10 microM) significantly attenuated the reperfusion-induced decrease in cell viability. The compound showed an anti-apoptotic effect in this astrocyte injury model. Antioxidants such as ascorbic acid, alpha-tocopherol and reduced glutathione also inhibited H(2)O(2) exposure-induced cytotoxicity. CV-2619 did not affect the levels of reactive oxygen species, but it increased nerve growth factor (NGF) production. The effect of CV-2619 on H(2)O(2) exposure-induced cytotoxicity was blocked by cycloheximide and anti-NGF antibody. The protective effect of CV-2619 was antagonized by the mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase inhibitor 2'-amino-3'-methoxyflavone and the phosphatidylinositol-3 kinase inhibitor wortmannin. These findings suggest that the effect of CV-2619 is mediated at least partly by NGF production in astrocytes and that ERK and phosphatidylinositol-3 kinases play a role in the downstream mechanism.