Role of Nogo-A in neuronal survival in the reperfused ischemic brain


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Kilic E., Elali A., Kilic L., Guo Z., Ugur M., Uslu Ü., ...More

JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, vol.30, no.5, pp.969-984, 2010 (Peer-Reviewed Journal) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 30 Issue: 5
  • Publication Date: 2010
  • Doi Number: 10.1038/jcbfm.2009.268
  • Journal Name: JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
  • Journal Indexes: Science Citation Index Expanded, Scopus
  • Page Numbers: pp.969-984

Abstract

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. Journal of Cerebral Blood Flow & Metabolism (2010) 30, 969-984; doi: 10.1038/jcbfm.2009.268; published online 20 January 2010