Activation of ERK and Akt Signaling in Focal Cerebral Ischemia: Modulation by TGF-α 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-α (TGF-α), 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-α 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-α, but it was enhanced in the nucleus and cytoplasm by MK-801. Also, MK-801 but not TGF-α increased p-Akt. Results suggest that preventing ERK activation is related to the protective effect of TGF-α, 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.