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，脑缺血后痴呆有进行性病程。与此一致，本应用程序中提出的初步研究表明，在短暂局灶性脑缺血后，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体中显示了延迟的突触交替。相对缓慢的认知功能障碍和海马突触交替提示缺血性卒中后的治疗干预可以防止血管性认知障碍的进展。在本研究中，我们拟采用行为学、分子生化和电生理等方法，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，并以海马突触交替为重点，阐述该模型中血管性认知障碍的神经病理机制。此外，172-雌二醇和一种非雌性化雌激素类似物的治疗干预效果将在该实验模型中进行测试。为实现这一目标，将处理以下目标：具体目标1。目的探讨短暂性局灶性脑缺血后血管性认知障碍的特征。在拟建的研究中，将采用广泛的行为电池来确定短暂性局灶性脑缺血对大鼠短暂性大脑中动脉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。具体目标2。目的探讨短暂性局灶性脑缺血后认知功能进行性下降的机制。我们将重点关注海马体的神经病理改变，海马体在认知功能中起着关键作用，因为在大鼠短暂性大脑中动脉闭塞后，在远离原发性梗死区的这一区域发现了延迟的突触交替。具体目标3。采用行为学、生物化学和电生理方法，确定172-雌二醇和非雌性雌激素类似物治疗干预对短暂性局灶性脑缺血引起的血管性认知障碍进展的影响。总的来说，所提出的研究将为血管性痴呆的机制提供新的见解，并确定预防脑缺血后认知能力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、分子生化和电生理方法，以海马突触交替为重点，确定该模型中血管性认知障碍的神经病理机制。此外，172-雌二醇和一种非雌性化雌激素类似物的治疗干预效果将在该实验模型中进行测试。这些研究将为血管性痴呆的机制提供新的见解，并为预防脑缺血后认知能力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.