Neurorestorative Therapy of Stroke with Statins

描述（由申请人提供）：HMG-CoA还原酶抑制剂（他汀类药物）广泛用于降低胆固醇，具有多效性。基于可靠的初步数据，我们寻求开发一种使用他汀类药物治疗缺血性中风的新型神经恢复性治疗方法。这些药物在脑卒中后1天或多天使用，可增强脑可塑性并显著减少缺血性脑卒中后的功能缺陷。以下具体目标和相关假设旨在开发这种恢复性治疗，并在临床前啮齿动物大脑中动脉闭塞（MCAo）模型中研究细胞机制：目的1将测量不同剂量的他汀类药物（辛伐他汀或阿托伐他汀）对老年和年轻成年小鼠中风后功能恢复和大脑可塑性的影响。要验证的假设是，在中风发作后一天开始使用他汀类药物治疗中风，可以改善神经功能恢复并增强大脑可塑性。目的2将测量他汀类药物治疗缺血性脑血管生成的时间分布和诱导，他汀类药物诱导的血管生成与功能恢复之间的关系，以及潜在的下游分子靶点，包括突触蛋白表达和缺血脑血管生成部位祖细胞的定位。VEGF、VEGFR2和eNOS对他汀类药物诱导的脑可塑性的贡献将分别通过VEGFR2和eNOS敲除小鼠的特异性抗体和他汀类药物治疗来检测。潜在的假设是：他汀类药物通过促进脑组织内VEGF/VEGFR2和eNOS的表达和激活来促进脑卒中后功能恢复；VEGF/VEGFR2和eNOS通过诱导血管生成激活脑可塑性，并在脑内提供微环境，进一步增强突触蛋白表达和祖细胞的存在，从而促进他汀类药物治疗后的功能恢复。本研究为脑卒中治疗提供了一种新的、高效的方法，并可能将他汀类药物在实验性脑卒中患者中的恢复性治疗效果转化为患者。

DESCRIPTION (provided by applicant): HMG-CoA reductase inhibitors (statins), widely used in the reduction of cholesterol, have pleiotropic effects. Based on robust preliminary data, we seek to develop a novel neuro-restorative treatment of ischemic stroke using statins. These agents, when administered one or more days after stroke, enhance brain plasticity and significantly reduce functional deficits after ischemic stroke. The following specific aims and associated hypotheses are designed to develop this restorative therapy and to investigate the cellular mechanisms in a pre-clinical rodent model of middle cerebral artery occlusion (MCAo): Aim 1 will measure the effects of different doses of statins (simvastatin or atorvastatin) on functional recovery and brain plasticity in old and young adult mice after stroke. The hypothesis to be tested is that treatment of stroke with statins, initiated at one day after stroke onset, improves neurological functional recovery and enhances brain plasticity. Aim 2 will measure the temporal profile and induction of angiogenesis in ischemic brain treated with statins, the relationship between statin-induced angiogenesis and functional recovery, and potential downstream molecular targets, including synaptic protein expression and the localization of progenitor cells at sites of angiogenesis in ischemic brain. The contribution of VEGF, VEGFR2 and eNOS to statin-induced brain plasticity will be examined by using a specific antibody to VEGFR2 and eNOS knockout mice subjected to stroke and treated with statins, respectively. The underlying hypotheses are that: statins foster functional recovery after stroke by promoting the expression and activation of VEGF/VEGFR2 and eNOS within cerebral tissue; VEGF/VEGFR2 and eNOS instigate brain plasticity via the induction of angiogenesis and provide a microenvironment in brain to further enhance synaptic protein expression and presence of progenitor cells, which augment functional recovery after statin treatment. This study provides a new and highly effective way to treat stroke and may permit translation our finding of restorative therapeutic benefit of statin in experimental stroke to the patient.