Combination Therapy for Chronic Stroke-Induced Impairment

描述(申请人提供)：拟议实验的目的是确定是否可以通过两种增强可塑性的治疗方法的组合来改善老年动物的慢性中风引起的损伤：暴露在环境丰富的环境中和使用软骨素酶ABC(CABC)治疗，这已被证明可以促进脊髓损伤后的轴突生长。这项提议寻求在三个勘探不足的地区开辟新的天地。首先，CABC促进卒中后轴突可塑性的潜力尚未被研究。其次，CABC和环境丰富的结合还没有在任何神经疾病模型中尝试过。第三，尽管中风在老年人中普遍存在，而且老年人中枢神经系统固有的特殊考虑因素，但很少有研究涉及老年系统中的中风损伤。因此，我们建议对老年大鼠进行检查，并在慢性损伤阶段解决与中风相关的运动障碍。这一目标符合NINDS的使命，即通过实现基础研究成果的翻译潜力来减轻神经疾病的负担。应用血管收缩因子内皮素-1(ET-1)对老龄大鼠造成局灶性脑缺血损伤。随后，动物将在标准的社会住房中停留一个月，以建立人类慢性、未经治疗的损伤模型。然后，动物将被转移到丰富的住所，并接受CABC治疗。行为测试将再持续三个月，以确定丰富的住房和CABC的组合是否可以改善慢性中风引起的损害。最后，动物将被宰杀，并对脑组织进行处理，以寻找轴突生长的标志。 我们预计，仅有丰富的环境不足以产生可测量的行为改善，但丰富的住房和CABC的结合将减少损伤并增强轴突可塑性。这一应用与公共卫生相关，因为中风幸存者在我们社会的老年人中很普遍。这项拟议的实验将测试一种潜在的治疗老年大脑中风相关慢性损伤的方法。

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.