Combination Therapy for Chronic Stroke-Induced Impairment

慢性中风引起的损伤的联合治疗

• 批准号: 7315114
• 负责人: J. Leigh Leasure
• 金额: $ 17.8万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7315114
• 关键词: Address; Age; Aging; Animals; Area; Axon; Basic Science; Behavioral; Biological Models; Blood flow; Brain; Brain Injuries; Cell Nucleus; Cerebral Ischemia; Cerebrum; Chondroitin ABC Lyase; Chondroitin Sulfate Proteoglycan; Chondroitin Sulfates; Chronic; Chronic Phase; Combined Modality Therapy; Complex; Denervation; Deposition; Distal; Elderly; Elements; Endothelin-1; Environment; Enzymes; Exploratory/Developmental Grant; Exposure to; Fiber; Forelimb; Glycosaminoglycans; Growth; Housing; Human; Impairment; Infarction; Injury; Ipsilateral; Ischemia; Lesion; Measurable; Measures; Mission; Modeling; Natural regeneration; Nature; Neuraxis; Neurological Models; Neurons; Personal Satisfaction; Pontine structure; Predictive Value; Prevalence; Public Health; Rattus; Recommendation; Recovery of Function; Red nucleus structure; Rehabilitation therapy; Research; Research Support; Societies; Spinal Cord; Spinal cord injury; Staging; Standards of Weights and Measures; Stroke; Survivors; System; Testing; Therapeutic; Tissues; Vasoconstrictor Agents; Western Blotting; aged; aging brain; axon regeneration; behavior test; brain tissue; central nervous system injury; chronic stroke; improved; injured; ischemic lesion; motor deficit; motor impairment; nervous system disorder; pre-clinical; preclinical study; prevent; relating to nervous system; research study; social; tissue processing; treatment program

DESCRIPTION (provided by applicant): The objective of the proposed experiment is to determine whether chronic stroke-induced impairment in aged animals can be ameliorated with a combination of two plasticity-enhancing treatments; exposure to environmental enrichment and treatment with chondroitinase ABC (cABC), which has been previously shown to enhance axonal outgrowth after spinal cord injury. This proposal seeks to break new ground in three under-explored areas. First, the potential of cABC to promote axonal plasticity after stroke has not been investigated. Second, the combination of cABC and environmental enrichment has not been attempted in any model of neurological disease. Third, very little research has addressed stroke injury in an aged system, despite the prevalence of stroke among elderly humans, and the special considerations inherent to the aged central nervous system. We propose, therefore, to examine aged rats and to address stroke-related motor impairment in the chronic phase of injury. This objective conforms to NINDS's mission to reduce the burden of neurological disease by realizing the translational potential of basic research findings. Focal cerebral ischemic lesions will be made in aged rats with the vasoconstrictor endothelin-1 (ET-1). Subsequently, animals will remain in standard social housing for one month in order to model chronic, untreated impairment in humans. Animals will then be transferred to enriched housing and treated with cABC. Behavioral testing will continue for an additional three months in order to determine whether the combination of enriched housing and cABC can ameliorate chronic stroke-induced impairment. Finally, animals will be sacrificed and brain tissue processed for markers of axonal outgrowth. We anticipate that enriched environment alone will be insufficient to produce a measurable behavioral improvement, but that the combination of enriched housing and cABC will reduce impairment and enhance axonal plasticity. This application is relevant to public health because stroke survivors are prevalent among the elderly in our society. The proposed experiment will test a potential treatment for chronic stroke-related impairment in the aged brain.

描述（由申请人提供）：拟议的实验的目的是确定是否可以通过两种增强塑性的治疗方法来改善慢性中风引起的老年动物损伤；暴露于环境富集和软骨素酶ABC（CABC），以前已证明可以增强脊髓损伤后轴突的生长。该提案旨在在三个未经探索的地区打破新的地面。首先，尚未研究CABC在中风后促进轴突可塑性的潜力。其次，在任何神经系统疾病模型中尚未尝试使用CABC和环境富集的组合。第三，尽管老年人的中风普遍存在以及老化的中枢神经系统固有的特殊考虑，但很少有研究解决了老年系统中的中风损伤。因此，我们建议在慢性损伤阶段检查年龄大鼠并解决与中风相关的运动障碍。这个目标符合Ninds通过实现基础研究发现的翻译潜力来减轻神经系统疾病负担的使命。局灶性脑缺血性病变将在老年大鼠中使用血管收缩素内皮素-1（ET-1）产生。随后，为了对人类的慢性，未经治疗的损害进行建模，动物将在标准社会住房中保留一个月。然后将动物转移到富含住房并用CABC处理。行为测试将持续三个月，以确定富集住房和CABC的组合是否可以改善慢性中风引起的损害。最后，将牺牲动物，并为轴突生长的标志物处理脑组织。 我们预计，仅富集的环境将不足以产生可测量的行为改善，但是富集住房和CABC的组合将减少损害并增强轴突可塑性。该应用与公共卫生有关，因为中风幸存者在我们社会的老年人中普遍存在。提出的实验将测试老年大脑中与慢性中风相关的损害的潜在治疗方法。