Ischemic tolerance is a powerful cerebroprotective mechanism by which a sublethal injury protects from a subsequent lethal ischemic insult. Studies over the last funding period have revealed that the inducible or """"""""immunological"""""""" isoform of nitric oxide synthase (iNOS;NOS II) is essential for the development of the ischemic tolerance induced by systemic administration of the proinflammatory mediator lipopolysaccharide. However, the mechanisms by which iNOS participates in ischemic preconditioning have not been defined. Preconditioning induces cellular and molecular changes that are thought to ultimately increase the resistance of brain pells to ischemia. However, preservation of brain tissue depends not only on protection of neurons and glia, but also on safeguarding cerebral blood vessels. Therefore, it is conceivable that both """"""""cytoprotective"""""""" and """"""""vasoprotective"""""""" mechanisms contribute to the development of ischemic tolerance. The goal of this renewal application is to test the hypothesis that INOS-derived NO contributes to ischemic tolerance by preserving post-ischemic vascular function (vasoprotection). as well as increasing the resistance of brain cells to ischemia (cvtoprotection). First, we will determine whether preconditioning with lipopolysaccharide leads to better preservation of cerebral perfusion after middle cerebral artery occlusion in mice (vasoprotection). Second, we will test the hypothesis that iNOS-derived NO is responsible for the vasoprotective component of preconditioning. Third, we will use a model of NMDA-mediated neocortical injury to test the hypothesis that iNOS is also involved in the tolerance to excitotoxicity induced by lipopolysaccharide (cytoprotection). Fourth, considering that NO exerts many of its actions through peroxynitrite, its reaction product with superoxide, we will test the hypothesis that reactive oxygen species produced by NADPH oxidase are needed for the cytoprotective and vasoprotective effects of iNOS-derived NO. The proposed studies will provide insight into poorly understood aspects of the mechanisms of ischemic preconditioning that may have important implications for the prevention and treatment of ischemic stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034179-15
Application #
7738484
Study Section
Special Emphasis Panel (ZRG1-BINP-L (01))
Program Officer
Bosetti, Francesca
Project Start
1995-03-20
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
15
Fiscal Year
2010
Total Cost
$363,826
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Neurology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Gorelick, Philip B; Furie, Karen L; Iadecola, Costantino et al. (2017) Defining Optimal Brain Health in Adults: A Presidential Advisory From the American Heart Association/American Stroke Association. Stroke 48:e284-e303
Kamel, Hooman; Gialdini, Gino; Baradaran, Hediyeh et al. (2017) Cryptogenic Stroke and Nonstenosing Intracranial Calcified Atherosclerosis. J Stroke Cerebrovasc Dis 26:863-870
Murthy, Santosh B; Gupta, Ajay; Merkler, Alexander E et al. (2017) Restarting Anticoagulant Therapy After Intracranial Hemorrhage: A Systematic Review and Meta-Analysis. Stroke 48:1594-1600
Demuth, Hans-Ulrich; Dijkhuizen, Rick M; Farr, Tracy D et al. (2017) Recent progress in translational research on neurovascular and neurodegenerative disorders. Restor Neurol Neurosci 35:87-103
Iadecola, Costantino (2017) The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease. Neuron 96:17-42
Gialdini, Gino; Parikh, Neal S; Chatterjee, Abhinaba et al. (2017) Rates of Spinal Cord Infarction After Repair of Aortic Aneurysm or Dissection. Stroke 48:2073-2077
Rollins, Nancy; Braga, Bruno; Hogge, Amy et al. (2017) Dynamic Arterial Compression in Pediatric Vertebral Arterial Dissection. Stroke 48:1070-1073
Fisher, Marc; Iadecola, Costantino; Sacco, Ralph (2017) Introduction to the Stroke Compendium. Circ Res 120:437-438
Merkler, Alexander E; Gialdini, Gino; Yaghi, Shadi et al. (2017) Safety Outcomes After Percutaneous Transcatheter Closure of Patent Foramen Ovale. Stroke 48:3073-3077
Garcia-Bonilla, Lidia; Faraco, Giuseppe; Moore, Jamie et al. (2016) Spatio-temporal profile, phenotypic diversity, and fate of recruited monocytes into the post-ischemic brain. J Neuroinflammation 13:285

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