Manipulation of the renin-angiotensin-aldosterone (RAS) system has been shown to be extremely effective in reducing the impact of cardiovascular disease. In particular, angiotensin receptor blockers (ARBs) are known to reduce stroke risk in humans and be robustly neuroprotective in experimental stroke. The angiotensin II Type 2 (AT2) receptor agonist, compound 21 (C21) is likely to demonstrate all the neurovascular benefits of the ARBs without the potentially dangerous blood pressure (BP) lowering characteristic of these AT1 receptor blockers. The objective of this application is to obtain preclinical in vivo efficacy data on C21 as a candidate therapeutic in ischemic stroke. We plan to achieve this through the following two aims:
AIM 1 : Optimize the regimen of C21 in young male rats to improve short- and long-term stroke outcome without affecting BP. We will optimize the dosing of C21 with frequency, effects on BP and function. We will use this regimen to then test in Aim 2. We will monitor BP by telemetry, cerebral blood flow (CBF), functional outcome and assess infarct size and hemorrhagic transformation (HT). An embolic model of stroke, with and without tPA, will be employed with 48 hour and 28 day endpoints.
AIM 2 : Determine the effectiveness of the optimal C21 regimen in hypertensive rats. In this aim, we will again measure the effect on BP and CBF in the acute phase and long-term functional and histologic outcomes at 28 days. We will achieve these aims by administration of an AT2 receptor agonist (C21) and optimizing the dose, time window and duration, with and without tPA, in a clinically relevant embolic stroke model. Our addition of continuous monitoring of BP with telemetry adds an addition degree of rigor to the evaluation in both normotensive and hypertensive rat strains. Our group has the unique track record and expertise necessary to complete this project and move the compound on to a translational effort to humans.

Public Health Relevance

There is a need to develop new drugs for stroke patients that allow them to recover brain function in the long-term. Compound 21 is a new agent that has been shown to lessen brain injury when given after stroke in rats. We will determine the optimal dose and timing of administration in order to have a long-lasting effect in rats that could be tested later in human patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Koenig, James I
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University of Georgia
Schools of Pharmacy
United States
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Jackson, LaDonya; Eldahshan, Wael; Fagan, Susan C et al. (2018) Within the Brain: The Renin Angiotensin System. Int J Mol Sci 19:
Ishrat, Tauheed; Fouda, Abdelrahman Y; Pillai, Bindu et al. (2018) Dose-response, therapeutic time-window and tPA-combinatorial efficacy of compound 21: A randomized, blinded preclinical trial in a rat model of thromboembolic stroke. J Cereb Blood Flow Metab :271678X18764773
Ward, Rebecca; Valenzuela, John Paul; Li, Weiguo et al. (2018) Post Stroke Cognitive Impairment and Hippocampal Neurovascular Remodeling: The Impact of Diabetes and Sex. Am J Physiol Heart Circ Physiol :
Ahmed, Heba A; Ishrat, Tauheed; Pillai, Bindu et al. (2018) Role of angiotensin system modulation on progression of cognitive impairment and brain MRI changes in aged hypertensive animals - A randomized double- blind pre-clinical study. Behav Brain Res 346:29-40
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; 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