title: Repetitive hypoxia extends endogenous neurovascular protection for stroke.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Infarction volumes following a 60-minute transient middle cerebral artery occlusion were determined in adult male mice 2 days through 8 weeks after completion of a 2-week repetitive hypoxic preconditioning (RHP) protocol. Separate cohorts were studied for the protective effects of RHP on postischemic and cytokine-induced cerebrovascular inflammation, and for potential deleterious effects of the RHP stimulus itself.
  
  
  RESULTS
  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-α administration, indicating that reductions in postischemic inflammation were not secondary to smaller infarct volumes. RHP reduced poststroke leukocyte diapedesis concomitant with a long-lasting downregulation of endothelial adhesion molecule mRNAs, and also reduced postischemic blood--brain 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.
  
  
  CONCLUSIONS
  Taken together, our findings reveal a novel form of epigenetic neurovascular plasticity characterized by a prominent anti-inflammatory phenotype that provides protection against stroke many weeks longer than previously established windows of preconditioning-induced tolerance. Translating these endogenous protective mechanisms into therapeutics could afford sustained periods of cerebroprotection in subpopulations of individuals at identified risk for stroke.
authors: Department of Neurological Surgery, Washington University School of Medicine, St Louis, MO 63110, USA.
authors: Ann M
authors: AM
authors: Stowe
authors: Tamer
authors: T
authors: Altay
authors: Angela B
authors: AB
authors: Freie
authors: Jeffrey M
authors: JM
authors: Gidday
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D007839:Functional Laterality; D049452:Green Fluorescent Proteins / Q000235:genetics; D006400:Hematocrit / Q000379:methods; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications* / Q000473:pathology / Q000517:prevention & control*; D019194:Ischemic Preconditioning; D019041:L-Selectin / Q000235:genetics / Q000378:metabolism; D007962:Leukocytes / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D019040:E-Selectin; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C485184:enhanced green fluorescent protein; D019041:L-Selectin; D049452:Green Fluorescent Proteins