Chronic cerebral hypoperfusion (CCH) been well characterized as a common pathological status contributing to neurodegenerative diseases such as Alzheimer’s disease and vascular dementia. CCH is an important factor that leads to cognitive impairment, but the underlying neurobiological mechanism is poorly understood and no effective treatment is available. Recently, transient receptor potential melastatin 4 (TRPM4) cation channel has been identified as an important molecular element in focal cerebral ischemia. Over activation of the channel is a major molecular mechanism of oncotic cell death. However, the role of TRPM4 in CCH that propagates global brain hypoxia have not been explored. Therefore, the present study is designed to investigate the effect of TRPM4 inhibition on the cognitive functions of the rats following CCH via permanent bilateral occlusion of common carotid arteries (PBOCCA) model. In this model, treatment with siRNA suppressed TRPM4 expression at both the mRNA and protein levels and improved cognitive deficits of the CCH rats without affecting their motor function. Furthermore, treatment with siRNA rescued the LTP impairment in CCH-induced rats. Consistent with the restored of LTP, western blot analysis revealed that siRNA treatment prevented the reduction of synaptic proteins, including calcium/calmodulin-dependent kinase II alpha (CaMKIIα) and brain-derived neurotrophic factor (BDNF) in brain regions of CCH rats. The present findings provide a novel role of TRPM4 in restricting cognitive functions in CCH and suggest inhibiting TRPM4 may represent a promising therapeutic strategy in targeting ion channels to prevent the progression of cognitive deficits induced by ischemia.

慢性脑灌注不足 (CCH) 被公认为是导致神经退行性疾病（如阿尔茨海默病和血管性痴呆）的常见病理状态。CCH是导致认知障碍的重要因素，但其潜在的神经生物学机制知之甚少，也没有有效的治疗方法。最近，瞬时受体电位 melastatin 4 (TRPM4) 阳离子通道已被确定为局灶性脑缺血的重要分子元素。通道的过度激活是渗透性细胞死亡的主要分子机制。然而，尚未探索 TRPM4 在传播全球脑缺氧的 CCH 中的作用。所以，本研究旨在通过永久双侧颈总动脉闭塞 (PBOCCA) 模型研究 TRPM4 抑制对 CCH 后大鼠认知功能的影响。在该模型中，siRNA 治疗在 mRNA 和蛋白质水平抑制 TRPM4 表达，并改善 CCH 大鼠的认知缺陷，而不影响其运动功能。此外，siRNA 治疗挽救了 CCH 诱导大鼠的 LTP 损伤。与 LTP 的恢复一致，蛋白质印迹分析显示，siRNA 治疗阻止了 CCH 大鼠脑区突触蛋白的减少，包括钙/钙调蛋白依赖性激酶 II α (CaMKIIα) 和脑源性神经营养因子 (BDNF)。