Role of Nogo-A in neuronal survival in the reperfused ischemic brain.
Nogo-A is an oligodendroglial neurite outgrowth inhibitor, the deactivation of which enhances brain plasticity and functional recovery in animal models of stroke. Nogo-A's role in the reperfused brain tissue was still unknown. By using Nogo-A(-/-) mice and mice in which Nogo-A was blocked with a neutralizing antibody (11C7) that was infused into the lateral ventricle or striatum, we show that Nogo-A inhibition goes along with decreased neuronal survival and more protracted neurologic recovery, when deactivation is constitutive or induced 24 h before, but not after focal cerebral ischemia. We show that in the presence of Nogo-A, RhoA is activated and Rac1 and RhoB are deactivated, maintaining stress kinases p38/MAPK, SAPK/JNK1/2 and phosphatase-and-tensin homolog (PTEN) activities low. Nogo-A blockade leads to RhoA deactivation, thus overactivating Rac1 and RhoB, the former of which activates p38/MAPK and SAPK/JNK1/2 via direct interaction. RhoA and its effector Rho-associated coiled-coil protein kinase2 deactivation in turn stimulates PTEN, thus inhibiting Akt and ERK1/2, and initiating p53-dependent cell death. Our data suggest a novel role of Nogo-A in promoting neuronal survival by controlling Rac1/RhoA balance. Clinical trials should be aware of injurious effects of axonal growth-promoting therapies. Thus, Nogo-A antibodies should not be used in the very acute stroke phase.
Kilic
Ertugrul
E
Department of Neurology, University Hospital Essen, Essen, Germany.
ElAli
Ayman
A
Kilic
Ulkan
U
Guo
Zeyun
Z
Ugur
Milas
M
Uslu
Unal
U
Bassetti
Claudio L
CL
Schwab
Martin E
ME
Hermann
Dirk M
DM
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology*; D002560:Cerebrovascular Circulation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism*; D017078:Laser-Doppler Flowmetry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D000070798:Nogo Proteins; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015424:Reperfusion; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D020743:rhoB GTP-Binding Protein / Q000378:metabolism
D000906:Antibodies; D009185:Myelin Proteins; D000070798:Nogo Proteins; C000603201:Rtn4 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D020743:rhoB GTP-Binding Protein