Activation of ERK and Akt signaling in focal cerebral ischemia: modulation by TGF-alpha and involvement of NMDA receptor.
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.
Friguls
Bibiana
B
Departament de Farmacologia i Toxicologia, Institut d'Investigacions Biomèdiques de Barcelona, CSIC-IDIBAPS, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain.
Petegnief
Valérie
V
Justicia
Carles
C
Pallàs
Mercè
M
Planas
Anna M
AM
D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism*; D003720:Densitometry; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016211:Transforming Growth Factor alpha / Q000008:administration & dosage / Q000378:metabolism*
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D016211:Transforming Growth Factor alpha; D016291:Dizocilpine Maleate; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases