Trx 促进脑缺血后海马神经再生及改善认知功能障碍的作用及机制研究

Neurogenesis, an endogenous repair process, exists in the adult brain of mammals. Persistent progenitor cell self-renew and neurogenesis following cerebral ischemia often occur in the SGZ and DG in the adult hippocampus. Newly generated neurons play important roles in cell proliferation, differentiation, maturation, migration to the injured area in the brain, and can be integrated into the brain circuits. Thus, promoting the endogenous neural regeneration following stroke could provide new strategies for neuroprotection. Thioredoxin (Trx) is a member of antioxidant protein family, which is necessary to maintain the redox state in the body. It is not only involved in the regulation of redox signals, but also in the promotion of cell proliferation, regulating inflammation and immune response and has the effects on neuroprotection and so on. Our previous studies have demonstrated that Trx could promote neurogenesis and facilitate cognitive dysfunction after cerebral ischemia in the mice. However, the underlying mechanisms were not well illustrated. Wnt/β-catenin signaling pathway is generally known to regulate neurogensis, which also participates in the process of learning and memory. Therefore, we hypothesized that the activation of Wnt/β-catenin signaling pathway is important for promoting neurogenesis after administration of Trx following cerebral ischemia by using behavioral test, morphological, electro physiological and gene regulation methods. On the basis of previous results, our current study is designed to investigate the underlying mechanisms of Wnt/β-catenin signaling pathway in the role of promotion of neurogenesis. All these works will provide new targets for amelioration of cognitive dysfunction following brain ischemia reperfusion injury.

神经再生是成年哺乳动物体内的内源性修复机制之一，脑缺血损伤后新生神经元可向缺血部位发生迁移、分化、成熟后整合入大脑回路中发挥作用，因此促进内源性神经再生将为脑保护策略提供新的干预靶点，有可能用于治疗缺血性中风。硫氧还蛋白Trx是抗氧化家族成员之一，在控制机体氧化/还原平衡、细胞增殖/生存等过程中发挥重要作用。我们前期研究证实Trx可促进脑缺血后海马神经干细胞再生，改善学习、记忆能力，但其具体作用机制不明。Wnt/β-catenin 信号通路是调控神经发生的经典通路，并参与学习、记忆形成。本课题拟在前期基础上，以Wnt/β-catenin 为切入点，明确Wnt信号分子的定位与数量变化并筛选出可能的相关Wnt亚型，探讨Wnt/β-catenin 信号通路在Trx促进脑缺血损伤后海马神经再生中的作用机制，为改善脑缺血再灌注损伤后认知功能障碍、寻找药物干预靶点提供新的思路。

神经再生是成年哺乳动物体内的内源性修复机制之一，脑缺血损伤后新生神经元可向缺血部位发生迁移、分化、成熟后整合入大脑回路中发挥作用，因此促进内源性神经再生将为脑保护策略提供新的干预靶点，有可能用于治疗缺血性中风。硫氧还蛋白 Trx 是抗氧化家族成员之一，在控制机体氧化/还原平衡、细胞增殖/生存等过程中发挥重要作用我们近期的研究发现 Trx 可以改善小鼠脑缺血再灌注损伤后的认知功能，并可促进小鼠全脑缺血后海马齿状回 NSCs 再生。但 Trx 通过哪些下游分子、如何调控 NSCs 的增殖和分化，尚属未解之谜。Wnt/β-catenin 被认为是调控神经再生的经典通路，在胚胎发育阶段对细胞的增殖、分化、迁移、极性化和凋亡均起到重要的调控作用；最近的研究也支持 Wnt/β-catenin 在成年神经再生中发挥关键调控作用。基于上述理论及预实验基础，本课题提出“Trx 通过Wnt/β-catenin 途径调控海马神经发生，改善脑缺血再灌注损伤后认知功能的假说”。本课题主要研究内容包括：1. Trx 是否通过活化 Wnt/β-catenin 通路，进而影响海马神经干细胞的增殖、分化、迁移、存活和整合；2. Trx 影响 Wnt/β-catenin 通路相关的下游信号分子有哪些，不同的靶基因产生的作用有何不同；3. Trx 通过调控 Wnt/β-catenin 通路促进海马神经发生是否可改善认知功能。本课题研究证实，外源性给予 Trx 可以促进小鼠全脑缺血后海马齿状回神经再生，改善脑缺血后小鼠空间学习和记忆能力，发挥神经保护作用。其机制可能与 Trx 促进成体神经干细胞增殖和分化作用有关，并且 MEK/ERK 信号通路参与了 Trx 的促神经再生作用，证实 Trx 促神经再生作用与 MEK/ERK 信号通路间的相互关系，为将 Trx 应用于临床治疗脑中风提供了新的理论依据，为改善脑缺血再灌注损伤后认知功能障碍、药物干预靶点提供了新的思路。