Comparative testing of tatCN19o for neuroprotection in rodent tMCAo

项目摘要/摘要 局灶性脑缺血(中风)每年困扰着近80万美国人，通常会导致永久性的 认知障碍或死亡。开发脑保护性中风疗法的努力在很大程度上取得了成果 失望：唯一被批准的药物疗法是组织纤溶酶原溶血疗法 激活剂(tPA；alteplase)。在这个项目中，我们将进一步开发我们优化的CaMKII抑制物肽 在NINDS卒中中进行对比试验的TATCN19o作为脑保护性卒中的治疗 临床前评估网络(SPAN)。该30个氨基酸的多肽具有选择性、稳定性、强效、水性。 易溶，具有优异的化学、制造和控制(CMC)性能。重要的是，talCN19o 在活体内对小鼠和猪(后者)的全脑缺血(GCI)模型都非常有效 未发表)，即使在极低剂量的0.01-0.02 mg/kg静脉注射。母体化合物也有效 在急性缺血性中风(短暂性大脑中动脉闭塞；tMCAo)小鼠模型中进行体内实验。 甚至在迄今为止测试的最新时间点，在各种缺血/兴奋毒性之后也看到了神经保护 损伤(全脑缺血0.5h；卒中模型1h；神经元培养6h)。在这里，斯潘将 在啮齿动物tMCAo模型中提供严格、公正的talCN19o测试，以便与其他 候选干预措施。提出了几个tMCAo条件供网络考虑： 与溶血性tPA治疗(目前的护理标准)的兼容性和各种侮辱后的疗效 持续时间。为了最恰当地代表临床人群，我们建议在成人和老年人中进行平行测试。 两性动物都有。

Project Summary/Abstract Focal cerebral ischemia (stroke) afflicts nearly 800,000 Americans each year and often results in permanent cognitive impairment or death. Efforts in developing a cerebroprotective stroke therapy have largely resulted in disappointment: the only approved pharmacological therapy is hemolytic treatment with tissue plasminogen activator (tPA; alteplase). In this project, we will further develop our optimized CaMKII inhibitor peptide tatCN19o as a cerebroprotective stroke treatment through comparative testing within the NINDS Stroke Preclinical Assessment Network (SPAN). The 30 amino-acid peptide is selective, stable, potent, water soluble, and has excellent chemistry, manufacturing, and control (CMC) properties. Importantly, tatCN19o was highly effective in vivo in global cerebral ischemia (GCI) models in both mouse and pig (the latter unpublished), even at extremely low doses of 0.01-0.02 mg/kg i.v.. The parent compound was also effective in vivo in a mouse model of acute ischemic stroke (transient middle cerebral artery occlusion; tMCAo). Neuroprotection was seen even at the latest time points tested so far after the various ischemic/excitotoxic insults (0.5h after global cerebral ischemia; 1h after stroke model; 6h in neuronal cultures). Here, SPAN will provide rigorous, unbiased testing of tatCN19o in rodent tMCAo models for direct comparison to other candidate interventions. Several tMCAo conditions are proposed for consideration by the network: compatibility with hemolytic tPA treatment (the current standard of care) and efficacy after varied insult duration. To most appropriately represent clinical populations, we propose parallel testing in adult and older animals of both sexes.