Neurorestorative Therapy of Stroke with Statins

描述(申请人提供)：HMG-CoA还原酶抑制剂(他汀类)，广泛用于降低胆固醇，具有多效性作用。基于稳健的初步数据，我们寻求利用他汀类药物开发一种新的缺血性中风的神经恢复性治疗方法。这些药物在中风后一天或更多天给药，可以增强大脑的可塑性，并显著减少缺血性中风后的功能缺陷。通过建立大脑中动脉闭塞(MCAO)的临床前啮齿动物模型，设计了以下特定的目标和相关的假说，以开发这种恢复性疗法并探讨其细胞机制：目的1观察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脑可塑性的影响。需要检验的假设是，在中风发病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的可塑性。目的2研究他汀类药物对脑缺血后血管生成的时间分布和诱导作用，他汀类药物诱导的血管生成与功能恢复的关系，以及可能的下游分子靶点，包括突触蛋白的表达和前体细胞在缺血脑血管生成部位的定位。血管内皮生长因子、血管内皮细胞生长因子2和内皮型一氧化氮合酶在他汀类药物诱导的脑可塑性中的作用将通过使用针对血管内皮生长因子2和内皮型一氧化氮合酶基因敲除小鼠的特异性抗体来检验。其基本假设是：他汀类药物通过促进脑组织中VEGF/VEGFR2和eNOS的表达和激活来促进卒中后功能的恢复；VEGF/VEGFR2和eNOS通过诱导血管生成而促进脑的可塑性，并在脑内提供微环境，进一步增强突触蛋白的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。这项研究为治疗中风提供了一种新的、高效的方法，并可能将他汀类药物在实验性中风中的恢复性治疗益处转化为患者。

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.