Novel Neuroprotective/Anti-inflammatory Therapy for Ischemic Stroke

描述（由申请方提供）：卒中是美国发病率和死亡率的主要原因。对中风病理生理学基础的研究已经产生了预防和治疗的新范例，但是将这些方法转化为改善的临床结果被证明是痛苦的缓慢。预防策略主要集中在减少或控制风险因素，如糖尿病，高血压，心血管疾病和生活方式;在严重狭窄的患者中，可能需要颈动脉内膜切除术。脑血管成形术用于研究，但冠状动脉成形术后观察到的高再狭窄率表明，这种方法可能对许多患者造成不可接受的风险。治疗策略主要集中在急性治疗，以减少缺血半暗带的损伤，缺血半暗带是梗死周围可逆性损伤组织的区域。溶栓治疗已被证明可以改善缺血半暗带的灌注，但必须在梗死发生后3小时内给药。然而，当在缺血发作后以相当长的间隔给予时，新的临床上有用的药剂必须是有效的，因为大多数中风患者不是到达进行医学治疗而是几个小时，比其他药剂如溶栓剂的短的有效窗口晚得多。在缺血性卒中背景下靶向聚（ADP-核糖）聚合酶（PARP-1）可能在长时间窗内提供治疗获益，因为研究表明，PARP-1抑制将保护神经血管系统免受原发性缺血性损伤，并且在诱导的炎症反应导致额外细胞死亡时也是如此。在这项拟议的研究中，我们将研究我们的先导化合物ANG-2864在暂时性和永久性缺血性中风大鼠模型中的急性和长期作用。 公共卫生相关性：卒中是美国发病率和死亡率的主要原因。对中风病理生理基础的研究为预防和治疗提供了新的范例。在缺血性卒中的情况下，抑制酶聚（ADP-核糖）聚合酶（PARP-1）的药物可以在较长的时间窗内提供治疗益处，因为研究已经证明，PARP-1抑制将保护神经元细胞免受原发性缺血性损伤，并且当诱导的炎症反应导致额外的细胞死亡时也会保护神经元细胞。

DESCRIPTION (provided by applicant): Stroke is leading cause of morbidity and mortality in the US. Research on the pathophysiological basis of stroke has produced new paradigms for prevention and treatment, but translation of these approaches into improved clinical outcomes has proved to be painfully slow. Preventive strategies focus primarily on reducing or controlling risk factors such as diabetes, hypertension, cardiovascular disease, and lifestyle; in patients with severe stenosis, carotid endarterectomy may be indicated. Cerebral angioplasty is used investigationally, but the high restenosis rates observed following coronary angioplasty suggest this approach may pose unacceptable risk for many patients. Therapeutic strategies focus primarily on acute treatment to reduce injury in the ischemic penumbra, the region of reversibly damaged tissue surrounding an infarct. Thrombolytic therapy has been shown to improve perfusion to the ischemic penumbra, but it must be administered within three hours of the onset of infarction. However, new clinically useful agents must be efficacious when given at considerably longer intervals after the onset of ischemia as most stroke patients do not arrive for medical treatment but for several hours, much later than the short, efficacious window of other agents such as the thrombolytics. Targeting Poly (ADP-ribose) polymerase (PARP-1) in the setting of ischemic stroke may provide therapeutic benefit over a long time window, as research studies have demonstrated that PARP-1 inhibition will protect the neurovasculature from the primary ischemic insult and also later when additional cells die as the result of the induced inflammatory response. In this proposed study we will investigate the acute and long-term effects of our lead compound, ANG-2864 in rat models of temporary and permanent ischemic stroke. PUBLIC HEALTH RELEVANCE: Stroke is leading cause of morbidity and mortality in the US. Research on the pathophysiological basis of stroke has produced new paradigms for prevention and treatment. Drugs that inhibit the enzyme, Poly (ADP- ribose) polymerase (PARP-1) in the setting of ischemic stroke may provide therapeutic benefit over a longer time window, as studies have demonstrated that PARP-1 inhibition will protect neuronal cells from the primary ischemic insult and also later when additional cells die as the result of the induced inflammatory response