Vascular Cognitive Impairment Induced by Ischemic Stroke: mechanism and therapy

描述(申请人提供)：缺血性中风是血管性痴呆的主要原因。流行病学研究表明，缺血性中风后痴呆症是一个进行性的病程。在本申请中提出的初步研究一致地表明，在短暂性局灶性脑缺血后，大鼠表现出延迟的显著认知功能下降。此外，在远离原始缺血区的海马区有延迟的突触交替。认知功能障碍和海马区突触交替的出现相对较慢，这表明缺血性卒中后应用治疗性干预可以防止血管性认知功能障碍的进展。在这一应用中，我们建议进一步确定短暂性局灶性脑缺血对大鼠各种感觉运动和认知功能的长期影响，并利用行为学、分子生化和电生理学的方法，描述该模型中血管性认知损害的神经病理机制，重点是海马区突触的变化。此外，172-雌二醇和一种非女性化雌激素类似物的治疗干预效果将在这个实验模型中进行测试。为了实现这一目标，将解决以下目标：具体目标1。表征短暂性局灶性脑缺血后的血管认知功能障碍。在拟议的研究中，将使用广泛的行为组件来确定短暂性局灶性脑缺血对大鼠大脑中动脉短暂性闭塞模型的长期感觉运动功能、认知功能和焦虑相关行为的影响。具体目的2.探讨短暂性局灶性脑缺血后认知功能进行性下降的机制。我们将重点关注在认知功能中起关键作用的海马区的神经病理变化，因为在大鼠大脑中动脉短暂性闭塞后，在远离原发梗死区的这一区域发现了迟发性突触改变。具体目的3.采用行为学、生化和电生理学方法，确定172-雌二醇和非女性化雌激素类似物对短暂性局灶性脑缺血所致血管认知功能障碍进展的干预作用。总之，提出的研究将为血管性痴呆的发病机制提供新的见解，并确定预防脑缺血后认知功能下降的潜在治疗靶点。公共卫生相关性：在这项应用中，我们建议确定短暂性局灶性脑缺血对大鼠各种感觉运动和认知功能的长期影响，并利用行为学、分子生化和电生理学方法，在该模型中确定血管认知损害的神经病理机制，重点是海马区突触的变化。此外，172-雌二醇和一种非女性化雌激素类似物的治疗干预效果将在这个实验模型中进行测试。这些研究将为血管性痴呆的发病机制提供新的认识，并为预防脑缺血后认知功能减退寻找潜在的治疗靶点。

DESCRIPTION (provided by applicant): Ischemic stroke is the major cause of vascular dementia. Epidemiological studies have suggested a progressive course of dementia after ischemia stroke. Consistently, the preliminary study presented in this application indicates that, following a transient focal cerebral ischemia, rats exhibit a delayed significant decline of cognitive function. Furthermore, a delayed synaptic alternation was indicated in the hippocampus remote to the primary ischemic area. The relatively slow onset of cognitive dysfunction and synaptic alternation in the hippocampus suggest that therapeutic interventions applied after ischemic stroke could prevent progression of vascular cognitive impairment. In this application, we propose to further determine the long-term effects of transient focal cerebral ischemia on various sensorimotor and cognitive functions of rats, and to delineate the neuropathological mechanisms underlying the vascular cognitive impairment in this model with a focus on the hippocampus synaptic alternation, using behavioral, molecular biochemical, and electrophysiological approaches. In addition, the effects of therapeutic intervention with 172-estradiol and a non-feminizing estrogen analogue will be tested in this experimental model. To achieve this objective, the following aims will be addressed: Specific Aim 1. To characterize vascular cognitive impairment after transient focal cerebral ischemia. In the proposed studies, an extensive behavioral battery will be employed to determine the impact of transient focal cerebral ischemia on long-term sensorimotor functions, cognitive functions, and anxiety-related behavior in a transient middle cerebral artery occlusion model in rats. Specific Aim 2. To determine the mechanisms contributing to the progressive decline of cognitive function after transient focal cerebral ischemia. We will focus on the neuropathological change in hippocampus, which plays a critical role in cognitive function, since delayed synaptic alternation has been identified in this area remote to the primary infarct area after transient middle cerebral artery occlusion in rats. Specific Aim 3. To determine the effects of therapeutic intervention with 172-estradiol and a non-feminizing estrogen analogue on the progression of vascular cognitive impairment induced by transient focal cerebral ischemia, using behavioral, biochemical, and electrophysiological approaches. Collectively, the studies proposed will provide new insight in the mechanism of vascular dementia and identify potential therapeutic target for the prevention of cognitive decline following cerebral ischemia. PUBLIC HEALTH RELEVANCE: In this application, we propose to determine the long-term effects of transient focal cerebral ischemia on various sensorimotor and cognitive functions of rats, and to determine the neuropathological mechanisms underlying the vascular cognitive impairment in this model with a focus on the hippocampus synaptic alternation, using behavioral, molecular biochemical, and electrophysiological approaches. In addition, the effects of therapeutic intervention with 172-estradiol and a non-feminizing estrogen analogue will be tested in this experimental model. The studies proposed will provide new insight on the mechanism of vascular dementia and identify potential therapeutic target for the prevention of cognitive decline following cerebral ischemia.