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

描述（由申请人提供）：每年约有750，000名美国人经历新发或复发性中风，其中80%的人经历四肢运动功能障碍。即使没有药物干预，运动功能也会部分恢复。临床研究和动物模型表明，这种恢复是由完整皮层区域的适应性可塑性和重组引起的。在细胞水平上，已经发现缺血性损伤后的重组与树突重塑、突触前生长相关蛋白水平的增加和梗塞周围区域中的突触发生相关。虽然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物之间的关系为研究可塑性作为治疗干预的靶点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啮齿动物模型的功能恢复。单侧中风后，肌苷增强了未受损半球神经元将轴突侧支延伸到失去正常神经支配的脑干和脊髓区域的能力。这种重新布线伴随着受损肢体的使用改善。肌苷是一种天然存在的嘌呤核苷，其穿过细胞膜并激活Mst 3b，Mst 3b是一种蛋白激酶，在营养因子刺激轴突生长的细胞信号传导途径中起核心作用。肌苷的可塑性增强特性目前正在多发性硬化症和帕金森病患者中进行临床测试（帕金森病研究组，2011; Markowitz等人，2009）。本提案的目标是使用我们用R21 AG-028680开发的恒河猴皮质缺血性中风模型，探索肌苷在具有大脑结构和精细运动灵巧性的脑回动物皮质缺血后运动功能恢复中的功效。与人类高度相似。!

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. !