Combination Therapy for Chronic Stroke-Induced Impairment

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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.