Vascular Cognitive Impairment Induced by Ischemic Stroke: mechanism and therapy

缺血性中风引起的血管性认知障碍：机制和治疗

• 批准号: 7752511
• 负责人: SHAOHUA YANG
• 金额: $ 31.19万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7752511
• 关键词: Address; Adult; Affect; Antithrombins; Anxiety; Area; Attention; Attenuated; Behavior; Behavioral; Biochemical; Blood Coagulation Factor; Blood Coagulation Factor VII; Blood Vessels; Brain; C-reactive protein; CREB1 gene; Cerebral Ischemia; Conjugated Equine Estrogens; Contralateral; Critiques; Data; Dementia; Disease; Elements; Epidemiologic Studies; Estradiol; Estrogen Analogues; Estrogen Receptors; Estrogens; Exhibits; Experimental Models; Future; Hepatocyte; Hippocampus (Brain); Hormonal; Human; Impaired cognition; Infarction; Ipsilateral; Ischemia; Ischemic Stroke; Lead; Long-Term Effects; Mediating; Menopause; Middle Cerebral Artery Occlusion; Modeling; Molecular; Nerve Degeneration; Oral; Pathology; Patients; Phosphorylation; Plasma; Play; Postmenopause; Prevention; Principal Investigator; Process; Protein C; Published Comment; Rattus; Research; Role; Sensorimotor functions; Side; Stroke; Suggestion; Synapses; TFPI; Testing; Therapeutic Intervention; Vascular Dementia; Woman; Women' s Health; Yang; activated Protein C; age related; aged; aging brain; analog; brain volume; clinically relevant; cognitive function; improved; insight; nerve stem cell; neurogenesis; neuroinflammation; novel; prevent; programs; public health relevance; research study; response; senescence; subventricular zone; therapeutic target; transdermal estrogen; treatment effect; young adult; Address; Adult; Affect; Antithrombins; Anxiety; Area; Attention; Attenuated; Behavior; Behavioral; Biochemical; Blood Coagulation Factor; Blood Coagulation Factor VII; Blood Vessels; Brain; C-reactive protein; CREB1 gene; Cerebral Ischemia; Conjugated Equine Estrogens; Contralateral; Critiques; Data; Dementia; Disease; Elements; Epidemiologic Studies; Estradiol; Estrogen Analogues; Estrogen Receptors; Estrogens; Exhibits; Experimental Models; Future; Hepatocyte; Hippocampus (Brain); Hormonal; Human; Impaired cognition; Infarction; Ipsilateral; Ischemia; Ischemic Stroke; Lead; Long-Term Effects; Mediating; Menopause; Middle Cerebral Artery Occlusion; Modeling; Molecular; Nerve Degeneration; Oral; Pathology; Patients; Phosphorylation; Plasma; Play; Postmenopause; Prevention; Principal Investigator; Process; Protein C; Published Comment; Rattus; Research; Role; Sensorimotor functions; Side; Stroke; Suggestion; Synapses; TFPI; Testing; Therapeutic Intervention; Vascular Dementia; Woman; Women' s Health; Yang; activated Protein C; age related; aged; aging brain; analog; brain volume; clinically relevant; cognitive function; improved; insight; nerve stem cell; neurogenesis; neuroinflammation; novel; prevent; programs; public health relevance; research study; response; senescence; subventricular zone; therapeutic target; transdermal estrogen; treatment effect; young adult

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.

描述（由申请人提供）：缺血性中风是血管性痴呆的主要原因。流行病学研究表明，缺血性疾病后，痴呆症的逐渐逐渐发展。一致地，本应用中提出的初步研究表明，在短暂的局灶性脑缺血之后，大鼠表现出认知功能的显着下降延迟。此外，海马遥控区与原发性缺血区域有延迟的突触交替。海马中认知功能障碍和突触交替的相对较慢的发作表明，缺血性中风后采用的治疗干预措施可以防止血管认知障碍的进展。在此应用中，我们建议进一步确定瞬态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，并使用河马突触层的hippocussentical anderical and praveny BioChem和Molecolar BioChem Chemalical和Molecorlical Chemcolal and Molecorlical Chemchem and Molecolal BioChem Chemalical和Molecolar BioChem Chemoral and Molecolal BioChem Chemalical and Solecull BioChem Chemoral and Solecull BioChem Chame the Modial and Cognitive Imagiraugh的神经病理学机制。此外，将在此实验模型中测试对172-雌二醇和非雌激素类似物的治疗干预的影响。为了实现这一目标，将解决以下目标：特定目的1。表征短暂局灶性脑缺血后的血管认知障碍。在拟议的研究中，将采用广泛的行为电池来确定瞬态脑缺血对长期感觉运动功能，认知功能和与焦虑相关的行为的影响。具体目的2。确定瞬时局灶性脑缺血后认知功能逐渐下降的机制。我们将重点关注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，因为在大鼠瞬时中大脑动脉闭塞后，在该区域距离该区域延迟突触交替。具体目的3。确定使用172-雌二醇和非雌激素类似物对治疗性干预的影响，对使用行为，生物化学和电生理学方法的瞬时局灶性脑缺血引起的血管认知障碍的进展。总的来说，提出的研究将提供有关血管性痴呆机理的新见解，并确定脑缺血后预防认知能力下降的潜在治疗靶标。公共卫生相关性：在此应用中，我们建议确定短期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认知型的神经病理学机制，其重点是使用Hippocampussentaptic synaptic antiraper anderaptial Biocly BioChem Chemchem和Solecult BioChem Chemolal BioChem Chemofic and Solecult BioChem and Solecult and Molecult and Mortakoly BioChem。此外，将在此实验模型中测试对172-雌二醇和非雌激素类似物的治疗干预的影响。提出的研究将提供有关血管痴呆机制的新见解，并确定预防脑缺血后认知能力下降的潜在治疗靶标。