Of the more than 600,000 acute ischemic strokes treated annually in the United States, 98% of patients receive no acute therapy. Patients with co-morbid vascular diseases, like diabetes and uncontrolled hypertension, have worse outcomes and have historically been underrepresented in preclinical studies. Long-term recovery is limited by the brain's inherent plasticity and ability to actively remodel after injury. The brain vasculature is undoubtedly a key component of recovery and therapeutic strategies that are vascular protective are likely to promote better function. The facilitation of natural recovery mechanisms, especially when cerebral ischemia is layered on preexisting vascular compromise, has great promise as a therapeutic strategy. The objective of this application is to further elucidate the mechanisms involved in vascular protection after cerebral ischemia. The central hypothesis for the proposed research is that neurovascular protection after cerebral ischemia and reperfusion can be achieved by optimization of oxidative stress and activation of remodeling. We plan to achieve this objective through the following three specific aims:
Aim #1 : Determine the contribution of oxidative stress and MMP modulation to the beneficial effects of angiotensin antagonism on experimental ischemic stroke outcome.
Aim #2 : Determine the extent to which premorbid vascular damage impacts the neurovascular protective effects of angiotensin antagonism after acute ischemic stroke.
Aim #3 : Determine whether reperfusion is essential for optimal vascular protection with candesartan after cerebral ischemia We will achieve these aims using normotensive, hypertensive and hyperglycemic rat models of temporary cerebral ischemia, continuous BP monitoring via telemetry, laser Doppler flowmetry, BP lowering and pharmacologic MMP and oxidative stress modulation. In addition, we will employ MMP zymography, and quantitative measures of microvascular integrity and oxidative damage using ELISA and immunoblotting and a sensitive battery of neurobehavioral tests at 3, 7 and 30 days. Lastly, we will use brain microvascular endothelial cell culture studies. At the completion of 12 experiments over 5 years, we expect that changes in oxidative stress and MMP activity will contribute to the vascular protection afforded by angiotensin blockade in the acute stroke period. We expect that the presence of prior hypertension, hyperglycemia, endogenous vascular protectors and the method and timing of treatment in relation to reperfusion status will be important in the ultimate degree of neurovascular damage. This is important because it will provide impetus and guidance for a clinical trial to improve outcome of human stroke patients.

Public Health Relevance

Most stroke patients recover some brain function in the long-term but not enough to return to normal. Development of treatments that protect the blood vessels during a stroke may promote functional recovery. This project will determine the mechanisms of vascular protection after stroke and develop a medication treatment likely to work in stroke patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS063965-05
Application #
8429498
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Corriveau, Roderick A
Project Start
2009-07-15
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2013
Total Cost
$265,194
Indirect Cost
$48,193
Name
University of Georgia
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602
Soliman, Sahar; Ishrat, Tauheed; Pillai, Anilkumar et al. (2014) Candesartan induces a prolonged proangiogenic effect and augments endothelium-mediated neuroprotection after oxygen and glucose deprivation: role of vascular endothelial growth factors A and B. J Pharmacol Exp Ther 349:444-57
Ergul, Adviye; Abdelsaid, Mohammed; Fouda, Abdelrahman Y et al. (2014) Cerebral neovascularization in diabetes: implications for stroke recovery and beyond. J Cereb Blood Flow Metab 34:553-63
Coucha, Maha; Li, Weiguo; Johnson, Maribeth H et al. (2014) Reply to "Letter to the editor: 'Targeting cerebrovascular myogenic dysfunction in stroke'". Am J Physiol Heart Circ Physiol 306:H1483
Hafez, Sherif; Coucha, Maha; Bruno, Askiel et al. (2014) Hyperglycemia, acute ischemic stroke, and thrombolytic therapy. Transl Stroke Res 5:442-53
Kelly-Cobbs, Aisha I; Prakash, Roshini; Li, Weiguo et al. (2013) Targets of vascular protection in acute ischemic stroke differ in type 2 diabetes. Am J Physiol Heart Circ Physiol 304:H806-15
Boudreau, Denise M; Guzauskas, Greg; Villa, Kathleen F et al. (2013) A model of cost-effectiveness of tissue plasminogen activator in patient subgroups 3 to 4.5 hours after onset of acute ischemic stroke. Ann Emerg Med 61:46-55
Prakash, Roshini; Johnson, Maribeth; Fagan, Susan C et al. (2013) Cerebral neovascularization and remodeling patterns in two different models of type 2 diabetes. PLoS One 8:e56264
Fagan, Susan C; Lapchak, Paul A; Liebeskind, David S et al. (2013) Recommendations for preclinical research in hemorrhagic transformation. Transl Stroke Res 4:322-7
Alhusban, Ahmed; Kozak, Anna; Ergul, Adviye et al. (2013) AT1 receptor antagonism is proangiogenic in the brain: BDNF a novel mediator. J Pharmacol Exp Ther 344:348-59
Ishrat, Tauheed; Pillai, Bindu; Ergul, Adviye et al. (2013) Candesartan reduces the hemorrhage associated with delayed tissue plasminogen activator treatment in rat embolic stroke. Neurochem Res 38:2668-77

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