SDF-1α/CXCR4轴在重复经颅磁刺激改善脑卒中后认知功能障碍中作用机制的研究

Stroke is the second most common cause of cognitive impairment, while still no unequivocally efficacious drug treatment. Clinical reports have shown that rTMS may significantly improve cognitive impairment in stroke patients. However, the concrete mechanisms have not been investigated. Emerging evidences indicate that neurogenesis is relevant for the post-stroke cognitive impairment(PSCI). Our previous studies verified that rTMS can stimulate the proliferation of NSCs after cerebral ischemia. However, NSCs should migrate to dentate gyrus and mature into neurons to exert functions, which were affected by several factors. SDF-1α and its receptor CXCR4 play key roles in neurogenesis after cerebral ischemia. Activated endogenous NSCs give rise to new neurons and integrate into the preexisting hippocampal circuitry would have therapeutic effect on PSCI. From this point, we explore the impacts of rTMS on SDF-1α/CXCR4 axis expressions and neurogenesis in the hippocampus following cerebral ischemia. The present study is designed to detect the cognitive functions from neurobehavioral test, and the proliferation, migration and differentiation of NSCs from cellular level in both vivo and vitro. We proposed that rTMS treatment after ischemic stroke could improve cognitive impairment by enhancing neurogenesis in hippocampus which might be mediated by SDF-1α/CXCR4 axis. These findings would provide strong theoretical basis for future clinical application of rTMS.

PSCI已成为引起认知功能障碍的第二位原因，然而尚未有明确有效的药物。研究表明脑缺血后海马的神经再生有利于PSCI的恢复。我们前期证实rTMS可以促进脑缺血后NSCs的增殖，但NSCs能否迁移至靶位分化为神经元以产生修复作用对改善PSCI至关重要。SDF-1α/CXCR4轴在脑缺血后NSCs增殖、迁移、神经元形成中发挥关键作用。本项目拟从在体和离体实验两方面探索rTMS对脑缺血后SDF-1α/CXCR4轴的表达和神经再生的影响。运用SDF-1α/CXCR4轴抑制剂，从补充缺血半暗带丢失的细胞，重建神经传导环路的角度出发，在行为学水平观察PSCI功能恢复, 在细胞水平观察在体和离体缺血模型中NSCs的增殖、迁移、分化，证实rTMS通过调控脑缺血后海马SDF-1α/CXCR4轴促进海马神经再生进而改善PSCI的假说，为rTMS在PSCI的临床应用提供有力依据。

PSCI已成为引起认知功能障碍的第二位原因，然而尚未有明确有效的药物。研究表明脑缺血后海马的神经再生有利于PSCI的恢复。SDF-1α/CXCR4轴在脑缺血后NSCs增殖、迁移、神经元形成中发挥关键作用。我们前期证实rTMS可以促进脑缺血后NSCs的增殖，但NSCs能否迁移至靶位分化为神经元以产生修复作用对改善PSCI至关重要。本项目探索了rTMS对脑缺血后SDF-1α/CXCR4轴的表达和神经再生的影响。本研究通过SDF-1α/CXCR4轴抑制剂，从补充缺血半暗带丢失的细胞，重建神经传导环路的角度出发，研究结果发现脑缺血后大鼠的学习记忆能力下降，但rTMS能改善脑缺血大鼠学习记忆功能的恢复，rTMS还能有效的促进脑缺血后大鼠内源性NSCs的增殖和分化，而这些作用与SDF-1α/CXCR4轴相关蛋白的表达有关。本研究结果证实了rTMS可以通过调控脑缺血后海马SDF-1α/CXCR4轴促进海马神经再生进而改善PSCI，为rTMS在PSCI的临床应用提供了有力依据。