Activation of ERK and Akt signaling in focal cerebral ischemia: modulation by TGF-alpha and involvement of NMDA receptor

Abstract

Cerebral ischemia activates ERK and Akt pathways. We studied whether these activations were affected by treatment with the protective growth factor transforming growth factor-alpha (TGF-alpha), and whether they were mediated through N-methyl D-aspartate (NMDA) receptors. The middle cerebral artery was occluded in rats and signaling was studied 1 h later. Noncompetitive NMDA receptor antagonist MK-801 was injected i.p. before the occlusion, whereas in other rats TGF-alpha was given intraventricularly before and after occlusion. Ischemia caused ERK phosphorylation in the nucleus, localized in the endothelium and neurons. Phosphorylation of ERK was prevented by TGF-alpha, but it was enhanced in the nucleus and cytoplasm by MK-801. Also, MK-801 but not TGF-alpha increased p-Akt. Results suggest that preventing ERK activation is related to the protective effect of TGF-alpha, whereas the protective effect of MK-801 is associated with activation of pro-survival Akt. While results support that NMDA receptor signaling precludes Akt activation, we did not find evidence to support that it underlies ischemia-induced ERK phosphorylation. This study illustrates that neuroprotection results from a fine balance between death and survival signaling pathways.