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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Corriveau, Roderick A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Georgia
Schools of Pharmacy
United States
Zip Code
Ishrat, Tauheed; Soliman, Sahar; Eldahshan, Wael et al. (2018) Silencing VEGF-B Diminishes the Neuroprotective Effect of Candesartan Treatment After Experimental Focal Cerebral Ischemia. Neurochem Res 43:1869-1878
Hafez, Sherif; Abdelsaid, Mohammed; Fagan, Susan C et al. (2018) Peroxynitrite-Induced Tyrosine Nitration Contributes to Matrix Metalloprotease-3 Activation: Relevance to Hyperglycemic Ischemic Brain Injury and Tissue Plasminogen Activator. Neurochem Res 43:259-266
Fouda, Abdelrahman Y; Alhusban, Ahmed; Ishrat, Tauheed et al. (2017) Brain-Derived Neurotrophic Factor Knockdown Blocks the Angiogenic and Protective Effects of Angiotensin Modulation After Experimental Stroke. Mol Neurobiol 54:661-670
Fouda, Abdelrahman Y; Newsome, Andrea S; Spellicy, Samantha et al. (2017) Minocycline in Acute Cerebral Hemorrhage: An Early Phase Randomized Trial. Stroke 48:2885-2887
Alhusban, Ahmed; Kozak, Anna; Pillai, Bindu et al. (2017) Mechanisms of acute neurovascular protection with AT1 blockade after stroke: Effect of prestroke hypertension. PLoS One 12:e0178867
Fouda, Abdelrahman Y; Pillai, Bindu; Dhandapani, Krishnan M et al. (2017) Role of interleukin-10 in the neuroprotective effect of the Angiotensin Type 2 Receptor agonist, compound 21, after ischemia/reperfusion injury. Eur J Pharmacol 799:128-134
Li, Weiguo; Ward, Rebecca; Valenzuela, John Paul et al. (2017) Diabetes Worsens Functional Outcomes in Young Female Rats: Comparison of Stroke Models, Tissue Plasminogen Activator Effects, and Sexes. Transl Stroke Res :
Hafez, Sherif; Abdelsaid, Mohammed; El-Shafey, Sally et al. (2016) Matrix Metalloprotease 3 Exacerbates Hemorrhagic Transformation and Worsens Functional Outcomes in Hyperglycemic Stroke. Stroke 47:843-51
Alhusban, Ahmed; Kozak, Anna; Eldashan, Wael et al. (2016) Artery reopening is required for the neurorestorative effects of angiotensin modulation after experimental stroke. Exp Transl Stroke Med 8:4
Coucha, Maha; Abdelsaid, Mohammed; Li, Weiguo et al. (2016) Nox4 contributes to the hypoxia-mediated regulation of actin cytoskeleton in cerebrovascular smooth muscle. Life Sci 163:46-54

Showing the most recent 10 out of 55 publications