Department of Pharmacology, College of Medicine, Jiaxing University, Jiaxing, 314001, PR China.
Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, PR China.
Metab Brain Dis. 2023 Dec;38(8):2751-2763. doi: 10.1007/s11011-023-01306-3. Epub 2023 Oct 20.
Stroke is the second leading cause of death globally. Cognitive dysfunction is a common complication of stroke, which seriously affects the patient's quality of life. Previous studies have shown that the expression of hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel is closely related to ischemia-reperfusion (IR) injury and subsequent cognitive impairment. We also found that ZD7288, a specific inhibitor of the HCN channel, attenuated IR injury during short-term reperfusion. Since apoptosis can induce cell necrosis and aggravate cognitive impairment after IR, the purpose of this study is to define whether ZD7288 could improve cognitive impairment after prolonged cerebral reperfusion in rats by regulating apoptotic pathways. Our data indicated that ZD7288 can ameliorate spatial cognitive behavior and synaptic plasticity, protect the morphology of hippocampal neurons, and alleviate hippocampal apoptotic cells in IR rats. This effect may be related to down-regulating the expressions of pro-apoptotic proteins such as AIF, p53, Bax, and Caspase-3, and increasing the ratio of Bcl-2/Bax. Taken together, it suggested that inhibition of the HCN channel improves cognitive impairment after IR correlated with its regulation of apoptotic pathways.
中风是全球范围内的第二大致死原因。认知功能障碍是中风的常见并发症，严重影响患者的生活质量。先前的研究表明，超极化激活环核苷酸门控阳离子 (HCN) 通道的表达与缺血再灌注 (IR) 损伤和随后的认知障碍密切相关。我们还发现 HCN 通道的特异性抑制剂 ZD7288 可减轻短期再灌注期间的 IR 损伤。由于细胞凋亡可诱导细胞坏死并加重 IR 后的认知障碍，因此本研究旨在确定 ZD7288 是否可以通过调节凋亡途径来改善大鼠长时间脑再灌注后的认知障碍。我们的数据表明，ZD7288 可以改善空间认知行为和突触可塑性，保护海马神经元的形态，并减轻 IR 大鼠海马中的凋亡细胞。这种作用可能与下调凋亡蛋白如 AIF、p53、Bax 和 Caspase-3 的表达，以及增加 Bcl-2/Bax 的比值有关。总之，这表明抑制 HCN 通道可以改善与凋亡途径调节相关的 IR 后认知障碍。
