PARP-1 Inhibitors as Therapy for the Treatment of Stroke

描述（由申请人提供）：中风是美国发病率和死亡率的主要原因。对脑卒中病理生理基础的研究已经产生了预防和治疗的新范式，但将这些方法转化为改善的临床结果被证明是非常缓慢的。预防战略主要侧重于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；对于严重狭窄的患者，可能需要行颈动脉内膜切除术。研究中使用了脑血管成形术，但冠状动脉成形术后观察到的高再狭窄率表明该方法可能对许多患者构成不可接受的风险。治疗策略主要集中于急性治疗，以减少缺血半暗带的损伤，即梗死周围可逆受损组织的区域。溶栓治疗已被证明可以改善缺血半暗带的灌注，但必须在梗死发作后3小时内给予。然而，新的临床有用的药物必须在缺血发作后相当长的时间间隔内有效，因为大多数中风患者不是到达药物治疗，而是几个小时，比其他药物（如溶栓药物）的短暂有效窗口要晚得多。在缺血性卒中的情况下，靶向聚（adp -核糖）聚合酶（PARP-1）可能在很长一段时间内提供治疗益处，因为研究表明，PARP-1抑制将保护神经元细胞免受原发性缺血性损伤，并在随后因诱导炎症反应而导致额外细胞死亡时保护神经元细胞。公共卫生相关性：中风是美国发病率和死亡率的主要原因。对脑卒中病理生理基础的研究为脑卒中的预防和治疗提供了新的范式。在缺血性卒中的情况下，抑制酶，聚（ADP-核糖）聚合酶（PARP-1）的药物可能在更长的时间窗口内提供治疗益处，因为研究表明，PARP-1抑制将保护神经元细胞免受原发性缺血性损伤，并在后来当额外的细胞因诱导的炎症反应而死亡时也能保护神经元细胞

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 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. PUBLIC HEALTH RELAVANCE: 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