Vascular Cognitive Impairment Induced by Ischemic Stroke: mechanism and therapy

描述（由申请人提供）：缺血性卒中是血管性痴呆的主要原因。流行病学研究表明缺血性卒中后痴呆的进展过程。因此，本申请中提出的初步研究表明，在短暂的局灶性脑缺血后，大鼠表现出延迟的认知功能显著下降。此外，在远离原发性缺血区的海马中显示了延迟的突触交替。海马中认知功能障碍和突触改变的相对缓慢的发作表明，缺血性卒中后应用的治疗干预可以预防血管性认知障碍的进展。在本申请中，我们建议进一步确定短暂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，并采用行为、分子生物化学和电生理方法，以海马突触交替为重点，阐明该模型中血管性认知障碍的神经病理学机制。此外，将在该实验模型中测试172-雌二醇和非雌性化雌激素类似物的治疗干预效果。为实现这一目标，将致力于实现以下目标：具体目标1。描述短暂性局灶性脑缺血后血管性认知障碍的特征。在拟议的研究中，将采用广泛的行为电池来确定短暂局灶性脑缺血对大鼠短暂大脑中动脉闭塞模型中长期感觉运动功能、认知功能和焦虑相关行为的影响。具体目标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。我们将集中在海马的神经病理学变化，这在认知功能中起着至关重要的作用，因为延迟的突触交替已被确定在这个地区远离原发性脑梗死后，短暂的大脑中动脉闭塞的大鼠。具体目标3。采用行为学、生物化学和电生理学方法，确定172-雌二醇和非雌性化雌激素类似物治疗干预对短暂性局灶性脑缺血诱导的血管性认知障碍进展的影响。总之，这些研究将为血管性痴呆的发病机制提供新的见解，并为预防脑缺血后认知功能下降确定潜在的治疗靶点。公共卫生相关性：在本申请中，我们建议确定短暂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，并确定该模型中血管性认知障碍的神经病理学机制，重点是海马突触交替，使用行为，分子生物化学和电生理学方法。此外，将在该实验模型中测试172-雌二醇和非雌性化雌激素类似物的治疗干预效果。这些研究将为血管性痴呆的发病机制提供新的见解，并为预防脑缺血后认知功能下降提供潜在的治疗靶点。

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.