Facilitating the Recovery of Function Following Stroke: The Efficacy of Inosine

促进中风后功能恢复：肌苷的功效

• 批准号: 8425534
• 负责人: TARA L MOORE
• 金额: $ 24.56万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8425534
• 关键词: American; Animal Model; Animals; Area; Axon; Blood Vessels; Brain; Brain Injuries; Brain Stem; Cell membrane; Clinical Research; Clinical Trials; Control Groups; Corticospinal Tracts; Data; Development; Dose; Equilibrium; Experimental Designs; FOS Protein; Funding; Future; Goals; Growth; Hand; Hand functions; Harvest; Hour; Human; Immunohistochemistry; Individual; Infarction; Injection of therapeutic agent; Injury; Inosine; Intervention; Ischemia; Ischemic Stroke; Label; Limb structure; MRI Scans; Macaca mulatta; Manganese; Maps; Methods; Modeling; Monkeys; Motor; Motor Cortex; Multiple Sclerosis; Neurodegenerative Disorders; Neurons; Operative Surgical Procedures; Oral; Oral Administration; Parkinson Disease; Patients; Pattern; Performance; Pharmacologic Substance; Play; Postoperative Period; Process; Property; Protein Kinase; Proteins; Purine Nucleosides; Recovery; Recovery of Function; Recurrence; Research; Rodent; Rodent Model; Role; Serum; Signal Pathway; Signal Transduction; Spinal; Spinal Cord; Stroke; Structure; Study models; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Tracer; Training; Urate; Uric Acid; axon growth; brain tissue; clinically relevant; disability; experience; improved; ischemic lesion; juvenile animal; middle age; motor impairment; nerve supply; neuroprotection; nonhuman primate; partial recovery; presynaptic; stroke recovery; synaptogenesis

DESCRIPTION (provided by applicant): Approximately 750,000 Americans experience a new or recurrent stroke each year, and 80% of these experience impairment of motor function of the extremities. Partial recovery of motor function occurs even without pharmacological interventions. Clinical studies and animal models suggest that this recovery results from adaptive plasticity and reorganization in intact cortical areas. At the cellular level, reorganizaton following ischemic injury has been found to correlate with dendritic remodeling, increased levels of presynaptic growth- associated proteins and synaptogenesis in peri-infarct regions. Though the precise mechanisms promoting axonal growth and synaptogenesis are unclear, the relationship between these markers of plasticity and recovery provides compelling evidence for investigating plasticity as a target for therapeutic intervention. The therapeutic agent, inosine, stimulates axonal growth and has been shown to enhance functional recovery in rodent models of stroke. Following unilateral stroke, inosine enhances the ability of neurons in the undamaged hemisphere to extend axon collaterals into brainstem and spinal cord areas that have lost normal innervation. This rewiring is accompanied by improved use of an impaired limb. Inosine is a naturally occurring purine nucleoside that crosses the cell membrane and activates Mst3b, a protein kinase that plays a central role in the cell-signaling pathway through which trophic factors stimulate axonal growth. The plasticity enhancing properties of inosine are currently being tested clinically in patients with multiple sclerosis and Parkinson's Disease (Parkinson's Disease Study Group, 2011; Markowitz et al, 2009). The goal of this proposal is to use our rhesus monkey model of cortical ischemic stroke developed with R21 AG-028680 to explore the efficacy of inosine in the recovery of motor function following cortical ischemia in a gyrencephalic animal with brain structure and fine motor dexterity highly similar to humans. ! PUBLIC HEALTH RELEVANCE: Brain damage from stroke commonly results in permanent disability.While a great deal of research has focused on limiting damage through neuroprotective strategies, it has provided limited benefits, as treatments must be administered within hours of onset. Consequently, alternative strategies to improve recovery of function in the weeks and months following stroke are needed and this proposal seeks to assess the efficacy of inosine on recovery of function and associated brain plasticity in rhesus monkeys.

描述（由申请人提供）：大约75万美国人每年经历新的或经常性的中风，其中80％的肢体运动功能受损。运动功能的部分恢复即使没有药理干预措施也会发生。临床研究和动物模型表明，这种恢复是由完整皮质区域的自适应可塑性和重组产生的。在细胞水平上，发现缺血性损伤后的重组织与树突状重塑相关，突触前生长与蛋白质的水平增加和侵略周围区域的突触发生相关。尽管促进轴突生长和突触发生的确切机制尚不清楚，但这些可塑性和恢复标志之间的关系为研究可塑性作为治疗干预的靶标提供了令人信服的证据。治疗剂肌苷刺激轴突生长，并已被证明可以增强中风模型的功能恢复。单侧中风后，肌苷增强了未损坏的半球神经元将轴突侧支延伸到脑干和脊髓造成正常神经的脊髓区域的能力。这种重新布置伴随着改善肢体受损的使用。肌苷是一种天然存在的嘌呤核苷，越过细胞膜并激活MST3B，MST3B是一种蛋白激酶，在细胞信号途径中起着核心作用，营养因子刺激轴突生长。目前，正在对多发性硬化症和帕金森氏病的患者进行临床测试肌苷的可塑性增强特性（帕金森氏病研究小组，2011年； Markowitz等，2009）。该提案的目的是使用我们的恒河猴猴子模型的皮质缺血性中风模型，它使用R21 AG-028680开发的皮质缺血性中风模型来探索肌苷在带有脑结构的gyrcephalic动物中皮质缺血后恢复运动功能的疗效，具有脑结构，具有与人类相似的精细运动性。呢 公共卫生相关性：中风造成的脑损伤通常会导致永久性残疾。虽然大量研究集中在通过神经保护策略限制损害，但它提供了有限的益处，因为必须在发作数小时内进行治疗。因此，需要在中风后数周和几个月内提高功能恢复的替代策略，该提案旨在评估肌苷在恒河猴中恢复功能和相关的大脑可塑性的疗效。