Department of Physiology and Functional Genomics, McKnight Brain Institute, University of Florida, Gainesville, FL, U.S.A.
IMM - Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark.
Clin Sci (Lond). 2018 May 25;132(10):1055-1067. doi: 10.1042/CS20171549. Print 2018 May 31.
Stroke is a devastating disease that afflicts millions of people each year worldwide. Ischemic stroke, which accounts for ~88% of cases, occurs when blood supply to the brain is decreased, often because of thromboembolism or atherosclerotic occlusion. This deprives the brain of oxygen and nutrients, causing immediate, irreversible necrosis within the core of the ischemic area, but more delayed and potentially reversible neuronal damage in the surrounding brain tissue, the penumbra. The only currently approved therapies for ischemic stroke, the thrombolytic agent recombinant tissue plasminogen activator (rtPA) and the endovascular clot retrieval/destruction processes, are aimed at restoring blood flow to the infarcted area, but are only available for a minority of patients and are not able in most cases to completely restore neurological deficits. Consequently, there remains a need for agents that will protect neurones against death following ischemic stroke. Here, we evaluate angiotensin II (Ang II) type 2 (AT) receptor agonists as a possible therapeutic target for this disease. We first provide an overview of stroke epidemiology, pathophysiology, and currently approved therapies. We next review the large amount of preclinical evidence, accumulated over the past decade and a half, which indicates that AT receptor agonists exert significant neuroprotective effects in various animal models, and discuss the potential mechanisms involved. Finally, after discussing the challenges of delivering blood-brain barrier (BBB) impermeable AT receptor agonists to the infarcted areas of the brain, we summarize the evidence for and against the development of these agents as a promising therapeutic strategy for ischemic stroke.
中风是一种毁灭性的疾病，每年在全球范围内影响数百万人。缺血性中风占病例的~88%，发生在大脑供血减少时，通常是由于血栓栓塞或动脉粥样硬化性闭塞。这会剥夺大脑的氧气和营养物质，导致缺血区域核心立即发生不可逆转的坏死，但周围脑组织（半影区）会发生更延迟和潜在可逆转的神经元损伤。目前唯一批准的缺血性中风治疗方法，溶栓剂重组组织纤溶酶原激活剂（rtPA）和血管内血栓清除/破坏过程，旨在恢复梗死区域的血流，但仅适用于少数患者，在大多数情况下无法完全恢复神经功能缺损。因此，仍然需要能够保护神经元免受缺血性中风后死亡的药物。在这里，我们评估血管紧张素 II（Ang II）类型 2（AT）受体激动剂作为该疾病的可能治疗靶点。我们首先提供中风流行病学、病理生理学和目前批准的治疗方法的概述。接下来，我们回顾了过去十五年积累的大量临床前证据，这些证据表明 AT 受体激动剂在各种动物模型中具有显著的神经保护作用，并讨论了涉及的潜在机制。最后，在讨论了将血脑屏障（BBB）不可渗透的 AT 受体激动剂递送到大脑梗死区域的挑战之后，我们总结了这些药物作为缺血性中风有前途的治疗策略的证据。
