Novel Therapeutic Opportunity in Stroke

描述(申请人提供)：在美国，中风是导致死亡和残疾的主要原因，然而，仍然缺乏广泛有效的治疗方法，而且，除了漫长的康复计划外，还没有有效的治疗脑缺血性中风的方法。因此，S迫切需要新的治疗方法，能够最大限度地保留缺血半暗带，促进功能恢复。在过去的二十年里，在开发抗中风药物方面投入了大量的努力，但这些努力并没有导致中风的临床有效治疗。这些失败突显出需要开发新的治疗思想和方法来预防继发性脑缺血和中风引起的神经元损伤。在可能的策略中，由于中风的意外性质，具有广泛治疗窗口的有效的中风后治疗可能是最有价值的。现有的文献和初步数据表明，激活7种烟碱型乙酰胆碱受体(NAChRs)可以显著减轻脑缺血损伤和神经功能障碍。一种新的治疗模式被引入，通过使用II型正性变构调节剂(即PAMS-II)，如PNU-120596，抑制7nAChR脱敏，将内源性胆碱/ACh转化为有效的脑缺血治疗剂。我们的初步数据表明，在大鼠局灶性脑缺血后6小时内静脉注射PNU-120596可显著缩小脑梗塞体积和改善神经功能，提示新型PAM-II类药物为脑中风的治疗提供了新的机会。发现和概念验证阶段的途径包括：A)合成具有合适的钙通量活性、稳定性、选择性、溶解性和类药物特性的新的候选分子，最终用于体内疗效研究；以及B)对急性大鼠脑片中PAM-II候选分子的功能活性进行详细的评估。我们期望确定具有合适的类药物特性的新的先导，以测试这一新概念。 在一种治疗脑缺血中风的新疗法的背景下。

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.