Angiotensin receptor agonism to promote recovery after stroke

描述(申请人提供)：肾素-血管紧张素-醛固酮(RAS)系统的操作已被证明在减少心血管疾病的影响方面极其有效。特别是，血管紧张素受体阻滞剂(ARB)被认为可以降低人类中风的风险，并在实验性中风中具有强大的神经保护作用。血管紧张素II 2型(AT2)受体激动剂化合物21(C21)可能展示ARB的所有神经血管益处，而不具有这些AT1受体阻滞剂潜在的降低血压(BP)的特性。该应用的目的是获得C21作为治疗缺血性卒中的候选药物的临床前体内疗效数据。我们计划通过以下两个目标来实现这一目标：目标1：优化年轻雄性大鼠的C21方案，在不影响血压的情况下改善短期和长期卒中结果。我们将根据频率、对血压的影响和功能来优化C21的剂量。然后我们将使用该方案在目标2中进行测试。我们将通过遥测监测血压、脑血流量(CBF)、功能结果，并评估梗塞面积和出血转化(HT)。有或没有tPA的卒中栓子模型将采用48小时和28天的终点。目的2：确定最佳C21方案对高血压大鼠的疗效。为此，我们将再次测量急性期对BP和CBF的影响以及28天后的长期功能和组织学结果。我们将通过给予AT2受体激动剂(C21)和优化剂量、时间窗口和持续时间，在有和没有tPA的情况下，在临床相关的栓塞性卒中模型中实现这些目标。我们的遥测血压连续监测增加了对正常血压和高血压大鼠品系的严格程度的评估。我们的团队拥有完成这一项目并将化合物转移到人类身上所需的独特记录和专业知识。

DESCRIPTION (provided by applicant): 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.