{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T05:12:52Z","timestamp":1790485972732,"version":"4.1.0"},"reference-count":54,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2011,3,17]],"date-time":"2011-03-17T00:00:00Z","timestamp":1300320000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2011,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective:<\/jats:title><jats:p>Brief systemic hypoxia protects the rodent brain from subsequent ischemic injury, although the protection wanes within days. We hypothesized that the duration of ischemic tolerance could be extended from days to months by repeated intermittent hypoxia of varying magnitude and duration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods:<\/jats:title><jats:p>Infarction volumes following a 60\u2010minute transient middle cerebral artery occlusion were determined in adult male mice 2 days through 8 weeks after completion of a 2\u2010week repetitive hypoxic preconditioning (RHP) protocol. Separate cohorts were studied for the protective effects of RHP on postischemic and cytokine\u2010induced cerebrovascular inflammation, and for potential deleterious effects of the RHP stimulus itself.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p>RHP protection against transient focal stroke persisted for 8 weeks. Leukocyte adherence to cortical venules was attenuated in response to stroke, as well as following tumor necrosis factor\u2010\u03b1 administration, indicating that reductions in postischemic inflammation were not secondary to smaller infarct volumes. RHP reduced poststroke leukocyte diapedesis concomitant with a long\u2010lasting downregulation of endothelial adhesion molecule mRNAs, and also reduced postischemic blood\u2013brain barrier permeability to endogenous immunoglobulin G. RHP was without effect on hippocampal CA1 pyramidal cell viability, only transiently elevated hematocrit, and did not affect the magnitude of cerebral blood flow during and after ischemia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation:<\/jats:title><jats:p>Taken together, our findings reveal a novel form of epigenetic neurovascular plasticity characterized by a prominent anti\u2010inflammatory phenotype that provides protection against stroke many weeks longer than previously established windows of preconditioning\u2010induced tolerance. Translating these endogenous protective mechanisms into therapeutics could afford sustained periods of cerebroprotection in subpopulations of individuals at identified risk for stroke. 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