Novel Therapeutic Opportunity in Stroke

描述（由申请人提供）：中风是美国死亡和残疾的主要原因，但广泛有效的治疗方法仍然难以捉摸，除了长期的康复计划外，没有有效的治疗缺血性中风的方法。因此，迫切需要新的治疗方法，最大限度地保护缺血半暗区，促进功能恢复。在过去的二十年里，人们在开发抗中风药物方面投入了大量的努力，但这些努力并没有产生临床有效的中风治疗方法。这些失败强调需要发展新的治疗理念和方法来预防继发于缺血和中风的神经元损伤。在可能的策略中，有效的卒中后治疗与广泛的治疗窗口可能是最有价值的，因为中风的意外性质。现有文献和初步数据表明，激活7种尼古丁乙酰胆碱受体（nAChRs）可显著减轻脑损伤和缺血性损伤引起的神经功能缺损。一种新的治疗模式已经被引入，通过使用ii型阳性变张力调节剂（即pam - ii）（如PNU-120596）抑制7 nAChR脱敏，将内源性胆碱/乙酰胆碱转化为有效的脑缺血治疗药物。我们的初步数据表明，PNU-120596在局灶性脑缺血发作后6小时内静脉注射可显著减少脑梗死面积，改善脑缺血大鼠大脑中动脉闭塞（MCAO）模型的神经功能，这表明新型PAM-II药物代表了脑卒中治疗的新机遇。发现和概念验证阶段的路径包括：A)合成具有适当钙通量活性、稳定性、选择性、溶解度和药物样特征的新型候选分子，最终用于体内疗效研究；B)急性大鼠脑切片中PAM-II候选谱的详细功能活动评估。我们期望找到具有合适药物样特性的新线索来测试这一新概念

DESCRIPTION (provided by applicant): Stroke is a leading cause of death and disability in the USA, yet widely effective treatments remain elusive and, except for a lengthy program of rehabilitation, no effective treatment for cerebral ischemic stroke is available. Therefore, there s a critical need in new therapeutic approaches which can maximally preserve ischemic penumbra and facilitate functional recovery. In the last two decades substantial efforts have been invested in developing anti-stroke medicine, but these efforts have not resulted in clinically-efficacious therapies for stroke. These failures highlight the need for development of new therapeutic ideas and approaches for prevention of neuronal injury secondary to ischemia and stroke. Among possible strategies, effective post-stroke treatments with broad therapeutic windows are likely to be the most valuable because of the unexpected nature of stroke. The existing literature and preliminary data presented indicate that activation of 7 nicotinic acetylcholine receptors (nAChRs) can significantly reduce brain injury and neurological deficits caused by ischemic injury. A novel therapeutic paradigm has been introduced that converts endogenous choline/ACh into potent therapeutic agents in cerebral ischemia by inhibiting 7 nAChR desensitization using Type-II positive allosteric modulators (i.e. PAMs-II), such as PNU-120596. Our preliminary data demonstrate that PNU-120596 administered intravenously up to 6 hours after the onset of focal cerebral ischemia significantly reduces infarct volume and improves neurological function in a middle cerebral artery occlusion (MCAO) model of cerebral ischemic stroke in rats and suggest that novel PAM-II agents represent a novel therapeutic opportunity in cerebral stroke. The path for discovery and proof-of-concept phases includes: A) synthesis of novel candidate molecules with appropriate calcium flux activity, stability, selectivity, solubility and drug-like characteristics for eventual use in in vivo efficacy studies;and B) a detailed functional activity assessment of PAM-II candidate profiles in acute rat brain slices We expect to identify novel leads with suitable drug-like properties for testing this novel concept in the context of a new therapy for cerebral ischemic stroke.