HCN通道功能改变介导的神经元兴奋性紊乱在蛛网膜下腔出血后早期脑损伤中的作用研究

Neuronal excitability disorder plays an important role in the process of early brain injury after subarachnoid hemorrhage (SAH). It can directly lead to neuronal damage, and on the other hand, further exacerbating the energy consumption under the certain pathological conditions of SAH, thus ultimately contributes to the occurrence of secondary neurological damage after SAH. "Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel" is called the "brake" in steady-state regulation of neural circuits, which plays an important role in the regulation of neuronal excitability. The results from our early research have demonstrated the reduced HCN channel function after SAH is an important factor leading to the occurrence of neuronal excitability disorders, which may directly aggravate the early brain injury after SAH. Based on the the early study foundation, this project was designed to further evaluate the effect of HCN channels-mediated neuronal excitability disorders on early brain injury after subarachnoid hemorrhage, and deeply explore the therapeutic effects on early brain injury after SAH with interventions targeting HCN channels. This project will provide theoretical and experimental data for the development of new strategies and new drugs for the future HCN channels-targeted treatment in early brain injury after SAH, thereby changing the current clinical situation that there are no effective treatments on the secondary brain injury after SAH.

神经元兴奋性紊乱在蛛网膜下腔出血(SAH)后早期脑损伤过程中扮演重要角色，其一方面可以直接导致神经元的损伤，而另一方面又进一步加重了SAH特定病理条件下的能量消耗，并最终导致SAH后继发性神经功能损害的发生。"超极化激活-环核苷酸门控的阳离子(HCN)通道"被称为神经环路稳态调控中的"制动器"，其在神经元兴奋性调节中发挥重要作用。前期研究成果显示SAH后HCN通道功能下调是导致神经元兴奋性紊乱发生的重要环节，进而可能直接加重了SAH后早期脑损伤。本项目拟在前期研究基础上，进一步评估HCN通道功能变化所介导的神经元兴奋性紊乱在SAH后早期脑损伤发生中的作用，并深入探讨以HCN通道为靶点的干预手段在SAH后早期脑损伤中的治疗作用，旨在为将来以HCN通道为核心的、特异性的SAH后早期脑损伤治疗新策略和新药物的开发提供理论依据和实验数据，从而改变目前临床SAH继发性脑损伤治疗缺乏有效手段的现状。

神经元兴奋性紊乱在蛛网膜下腔出血(SAH)后早期脑损伤过程中扮演重要角色，其一方面可以直接导致神经元的损伤，而另一方面又进一步加重了SAH特定病理条件下的能量消耗，并最终导致SAH后继发性神经功能损害的发生。“超极化激活-环核苷酸门控的阳离子(HCN)通道”被称为神经环路稳态调控中的“制动器”，其在神经元兴奋性调节中发挥重要作用。前期研究成果显示SAH后HCN通道功能下调是导致神经元兴奋性紊乱发生的重要环节，进而可能直接加重了SAH后早期脑损伤。本项目拟在前期研究基础上，目前已顺利实现了如下目标：①阐明了模型动物SAH后早期脑内HCN通道表达变化情况；②探讨了SAH后脑内HCN通道功能改变机制；③明确了干预HCN通道功能变化后模型动物SAH后早期脑损伤的变化情况；④观察到了Hb条件下NO对大鼠海马CA1区锥体神经元兴奋性和HCN通道功能的影响；⑤明确了模型大鼠SAH后脑皮层相关关键蛋白（NMDAR1、2A、2B及Glu1、2）的表达变化情况；⑥揭示出了内源性NO在HCN通道功能调节与神经元兴奋性调节中的作用。课题部分研究结果已发表在《Crit Care Med》及《中华神经外科疾病研究杂志》等杂志上。本研究首次揭示了HCN通道功能变化所介导的神经元兴奋性紊乱在SAH后早期脑损伤发生中的重要作用，旨在为将来以HCN通道为核心的、特异性的SAH后早期脑损伤治疗新策略和新药物的开发提供理论依据和实验数据，从而改变目前临床SAH继发性脑损伤治疗缺乏有效手段的现状。