Copper/Zinc Superoxide Dismutase Attenuates Neuronal Cell Death by Preventing Extracellular Signal-Regulated Kinase Activation after Transient Focal Cerebral Ischemia in Mice

Abstract

Recent studies have revealed that activation of extracellular signal-regulated kinase (ERK) may contribute to apoptosis, a cell death process involved in oxidative stress. We examined phosphorylation of ERK1/2 and oxidative stress after transient focal cerebral ischemia (FCI) using transgenic (Tg) mice that overexpress copper/zinc superoxide dismutase (SOD1). The mice were subjected to 60 min of middle cerebral artery (MCA) occlusion by intraluminal suture blockade followed by 1, 4, and 24 hr of reperfusion. Immunohistochemistry and Western blot analysis showed that phospho-ERK1 was markedly increased in the cortex within the MCA territory at 1 hr of reperfusion (p < 0.01), followed by a decrease at 24 hr in wild-type mice. Double staining with phospho-ERK1/2 and neuron-specific nuclear protein showed that phospho-ERK1/2 was primarily expressed in neurons. In SOD1 Tg mice, phospho-ERK1/2 was prominently reduced compared with nonischemic controls, shown by immunohistochemistry. Western blot analysis confirmed a significant decrease in phospho-ERK1/2 1 hr 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/ERK pathway.

ATM deficiency induces oxidative stress and endoplasmic reticulum stress in astrocytes

“…Activation of ERK by growth factors or oxidants can promote either cell proliferation [55][56][57] or cell death, especially in neuronal cells. [58][59][60][61] These effects can be blocked by antioxidants. 62 Recent work by others also shows marked ERK1/2 activation in oxidatively stressed neurons.…”

Neuronal death/survival signaling pathways in cerebral ischemia

“…1,6 Experimental ischemia and reperfusion models, such as transient focal/global ischemia in rodents, have been thoroughly studied and the cumulative evidence suggests the involvement of cell survival/death signaling pathways in the pathogenesis of apoptotic cell death in the ischemic lesions. [7][8][9][10][11] In these models, reoxygenation during reperfusion provides a substrate for numerous enzymatic oxidation reactions. 1,2 In this review, the mechanisms of cell death/survival signaling pathways after ischemia and the involvement of oxygen radicals in these pathways will be discussed.…”

ERK1/2-p90RSK-mediated Phosphorylation of Na+/H+ Exchanger Isoform 1

“…However, the role of the activation of the ERK pathway in cerebral ischemia remains equivocal. Whereas activation of the ERK1/2 signaling pathway is involved in cell survival in programmed cell death (11) and ischemia (12), there is growing evidence indicating a role for ERK1/2 in neuronal cell death during cerebral ischemia (13). Such multiple functions of ERK1/2 pathways may result from variation in intensity of stimuli, their subcellular localization, and the interplay with other pathways or cellular energy state.…”