Attenuation of neuronal cell death by SOD1 is associated with extracellular signal-regulated kinase after transient focal cerebral ischemia in mice

Abstract

Recent studies revealed that activation of extracellular signal-regulated kinase (ERK) may contribute to apoptosis, a cell death process involved in oxidative stress. We investigated phosphorylation of ERK1/2 and oxidative stress after transient focal cerebral ischemia (FCI) using transgenic (Tg) mice that overexpress copper/zinc-superoxide dismutase (SOD1). Mice were subjected to 60 min of middle cerebral artery (MCA) occlusion by intraluminal suture blockade followed by 1, 4 and 24 h of reperfusion. Immunohistochemistry showed that phospho-ERK1/2 was markedly increased in the cortex within the MCA territory at 1 h of reperfusion, followed by a decrease at 24 h. In SOD1 Tg mice, phospho-ERK1/2 was prominently reduced compared with non-ischemic controls, shown by immunohistochemistry. Western blot analysis confirmed a significant decrease in phospho-ERK1/2 1 h after FCI in the ischemic cortex ( P<0.005). Apoptotic-related DNA fragmentation was reduced in the ischemic cortex of SOD1 Tg mice compared with wild-type mice using a cell death assay. These results suggest that phosphorylation of ERK1/2 may be involved in apoptosis or cell death after transient FCI, and that SOD1 may attenuate apoptotic cell death mediated by the mitogen-activated protein kinase (MAPK)/ERK pathway.