D-serine在慢性脑低灌注致认知障碍中的作用研究

Prevalence for vascular cognitive impairment (VCI) is increasing with aging of the world population，which leads to heave burden of society and families. However, the pathogenesis of the VCI remains unclear and there are no specific therapeutic measures for it. Therefore, it is an important medical subject to detect pathological changes and mechanism and design new drugs for treatment of VCI. VCI caused by chronic cerebral hypoperfusion involve in neuronal degeneration and white matter damage. Growing evidence has shown that N-methyl-D-aspartate (NMDA) receptors are involved in the neurological diseases or various insults which results in neuronal death. The D-serine molecule has been shown to be involved in the exitotoxicity as a major endogenous co-agonist of the NMDA receptors. Therefore, we hypothesize that D-serine signaling may also be involved in the pathogenesis, excitotoxicity, neuronal damage and cognitive impairment development of chronic cerebral hypoperfusion possibly by inducing NMDA receptor over-activation. Our previous research has shown that a large number of degenating neurons and D-serine-positive cells were found after chronic hypoperfusion. Therefore, in the present study we intend to investigate brain damage, related pathogenesis and role of D-serine in neuronal damage and cognitive impairment by chronic cerebral hypoperfusion model and oxygen-glucose deprivation model of hippocampus neurons in vitro. Our findings might provide important evidence for understanding the pathogenesis of VCI and new target point for the treatment of clinical cognitive impairment and brain protection.

随着世界人口老龄化进程加快、程度加深，血管性认知功能障碍的发生率也相应增高，给社会和家庭带来沉重负担，但其发病机制尚不十分清楚，也无特效疗法。已证实，慢性脑低灌注所致认知障碍涉及神经元变性和白质损害，而NMDA受体的过度激活参与各种急慢性病理事件，D-serine作为NMDA受体的重要内源性协同激动剂参与兴奋毒性过程。因此，我们推测，D-serine信号也许会通过NMDA受体的过度激活参与慢性脑低灌注过程的兴奋毒性、神经元损害和认知障碍。我们的前期研究显示慢性脑低灌注模型中不仅出现神经元变性，而且相应区域的D-serine表达异常。基于此，本项目拟采用慢性脑低灌注模型和体外海马神经元低氧低糖培养模型，探讨慢性脑低灌注所致的脑损害特征、相关机制及D-serine在神经元损害和认知功能障碍中的作用，这将为血管性认知障碍发生机制的认识和治疗药物的研发提供新的实验依据及新的作用靶点。

随着世界人口老龄化进程的加快、老龄化程度的加深，血管性认知功能障碍的发生率也相应增高，但其发病机制尚不十分清楚，也无特效疗法，这给社会和家庭带来沉重的负担。因此，探讨其发病机理、研发新的治疗方案，是医学领域研究的重要课题。慢性脑低灌注所致的认知障碍涉及神经元变性和白质损害。动物双侧颈总动脉持久结扎会导致脑血流显著下降，因此，可作为慢性脑低灌注的有用模型，此动物模型表现为学习记忆障碍和神经元变性。已证实，NMDA受体在中枢神经系统的神经元存活、兴奋性传递及突触可塑性方面起关键作用，其过度激活涉及各种急慢性病理事件，造成神经元死亡。D-serine为一种右旋氨基酸，在CNS神经元的NMDA信号调节方面起重要作用。D-serine结合到NMDA受体的甘氨酸位点上，作为NMDA受体的重要内源性协同激动剂参与兴奋毒性。因此，我们推测，D-serine信号也许通过NMDA受体的过度激活参与慢性脑低灌注的发病、兴奋毒性、神经元损害和和认知障碍的发展。本课题旨在研究慢性脑低灌注造成的神经元损害特征及涉及的损害机制，探讨D-serine在神经元损害和认知功能障碍中的作用，这将为血管性认知障碍发生机制的认识和治疗药物的研发提供新的实验依据及新的作用靶点。本课题显示慢性脑低灌注导致明显的记忆障碍及神经元变性，这包括表现为逃逸潜伏期长、目标象限游泳时间短的空间学习记忆缺陷和大脑皮质和海马CA1区神经元大量丢失和核固缩。D-serine的数量上调也提示D-serine参与的兴奋毒性机制可能在慢性脑低灌注所致的神经元变性方面起重要作用。结合变性细胞中凋亡信号分子的出现，这项研究不仅有利于更好地理解慢性脑低灌注后所发生的中枢神经系统病理变化及导致认知障碍的可能机制，而且从治疗干预的可能性角度考虑，有助于探测神经保护措施以预防或减轻认知障碍，提高生活质量。