Repetitive hypoxia extends endogenous neurovascular protection for stroke

• Published in: Annals of neurology Vol. 69; no. 6; pp. 975 - 985
• Main Authors: Stowe, Ann M., Altay, Tamer, Freie, Angela B., Gidday, Jeffrey M.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-06-2011; Wiley-Liss; Wiley Subscription Services, Inc
• Subjects: Analysis of Variance; Animals; Biological and medical sciences; Blood-Brain Barrier - physiopathology; Cerebrovascular Circulation - drug effects; Cerebrovascular Circulation - physiology; Disease Models, Animal; E-Selectin - genetics; E-Selectin - metabolism; Functional Laterality; Green Fluorescent Proteins - genetics; Hematocrit - methods; Hippocampus - metabolism; Hippocampus - pathology; Hypoxia; Infarction, Middle Cerebral Artery - complications; Infarction, Middle Cerebral Artery - pathology; Infarction, Middle Cerebral Artery - prevention & control; Ischemic Preconditioning; L-Selectin - genetics; L-Selectin - metabolism; Leukocytes - pathology; Male; Medical research; Medical sciences; Mice; Mice, Transgenic; Neurology; Rodents; Time Factors; Tumor Necrosis Factor-alpha - adverse effects; Vascular Cell Adhesion Molecule-1 - genetics; Vascular Cell Adhesion Molecule-1 - metabolism; Vascular diseases and vascular malformations of the nervous system; Vascular disease; Oxygen; Stroke; Nervous system diseases; Central nervous system disease; Cardiovascular disease; Hypoxia; Cerebrovascular disease; Cerebral disorder
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.22367

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.
Interpretation:
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. ANN NEUROL 2011