title: Ischemic post-conditioning facilitates brain recovery after stroke by promoting Akt/mTOR activity in nude rats.
abstract: While pre-conditioning is induced before stroke onset, ischemic post-conditioning (IPostC) is performed after reperfusion, which typically refers to a series of mechanical interruption of blood reperfusion after stroke. IPostC is known to reduce infarction in wild-type animals. We investigated if IPostC protects against brain injury induced by focal ischemia in Tcell-deficient nude rats and to examine its effects on Akt and the mammalian target of rapamycin (mTOR) pathway. Although IPostC reduced infarct size at 2 days post-stroke in wild-type rats, it did not attenuate infarction in nude rats. Despite the unaltered infarct size in nude rats, IPostC increased levels of phosphorylated Akt (p-Akt) and Akt isoforms (Akt1, Akt2, Akt3), and p-mTOR, p-S6K and p-4EBP1 in the mTOR pathway, as well as growth associated Protein 43 (GAP43), both in the peri-infarct area and core, 24 h after stroke. IPostC improved neurological function in nude rats 1-30 days after stroke and reduced the extent of brain damage 30 days after stroke. The mTOR inhibitor rapamycin abolished the long-term protective effects of IPostC. We determined that IPostC did not inhibit acute infarction in nude rats but did provide long-term protection by enhancing Akt and mTOR activity during the acute post-stroke phase. Post-conditioning did not attenuate infarction in nude rats measured 2 days post-stroke, but improved neurological function in nude rats and reduced brain damage 30 days after stroke. It resulted in increased-activities of Akt and mTOR, S6K and p-4EBP1. The mTOR inhibitor rapamycin abolished the long-term protective effects of IPostC.
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA; Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China; Department of Neurosurgery, Shanghai Jingan District Central Hospital, Shanghai, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Xie
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.forename: Xunming
authors.initials: X
authors.lastname: Ji
authors.forename: Heng
authors.initials: H
authors.lastname: Zhao
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D007166:Immunosuppressive Agents / Q000494:pharmacology; D057775:Ischemic Postconditioning / Q000379:methods*; D008297:Male; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D011923:Rats, Nude; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000502:physiology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D020521:Stroke / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy*; D013601:T-Lymphocytes / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D007166:Immunosuppressive Agents; C546845:mTOR protein, rat; C494920:Akt1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448959:ribosomal protein S6 kinase, 70kD, polypeptide 2; D020123:Sirolimus
keywords: Akt; T cells; ischemic post-conditioning; mTOR; stroke