Zhou Mei, Tao Xiaoqin, Lin Kuan, Leng Changlong, Yang Youhua, Gui Yuran, Sun Yaojian, Zhou Meiling, Sun Binlian, Xia Yiyuan, Shu Xiji, Liu Wei
Hubei Key Laboratory of Cognitive and Affective Disorder Jianghan University Wuhan China.
Institute of Biomedical Sciences, School of Medicine, Jianghan University Wuhan China.
J Am Heart Assoc. 2025 Apr 15;14(8):e038263. doi: 10.1161/JAHA.124.038263. Epub 2025 Apr 10.
Post-stroke depression (PSD) is a prevalent neuropsychiatric complication of stroke. However, the mechanisms underlying PSD are still unclear. Here, we aimed to investigate the role of HCN1 (hyperpolarization-activated cyclic nucleotide-gated cation channel 1) in the pathogenesis of PSD and its underlying mechanisms.
The PSD mice model was established by middle cerebral artery occlusion in vivo. Four weeks after middle cerebral artery occlusion, anxiety- and depression-like behaviors of mice were evaluated by various behavioral tests. HCN channels were downregulated by pharmacological inhibitor or neuron-specific adeno-associated virus. The oxygen-glucose deprivation/reoxygenation model in SY5Y cells was used to study the pathogenesis of PSD in vitro.
Mice exhibited anxiety- and depression-like behavior 4 weeks after middle cerebral artery occlusion, along with a significant increase in HCN1 protein expression in the ischemic hippocampus. Furthermore, the I current on neurons in the hippocampus was notably enhanced, whereas neuronal excitability was decreased in PSD mice. Treatment with HCN channel selective inhibitor ZD7288 protected SY5Y cells against oxygen-glucose deprivation/reoxygenation injury by suppressing K efflux. Additionally, we observed a significant increase in protein expressions of NLRP3 (nucleotide-binding domain-like receptor protein 3) inflammasome pathway-related molecules in the ischemic hippocampus of PSD mice. Knockdown of HCN1 channels via virus injection into the hippocampus resulted in decreased protein expressions of NLRP3 inflammasome-related molecules and improvement in anxiety- and depression-like behaviors in PSD mice.
Downregulation of HCN1 channels has a beneficial effect on PSD by suppressing the NLRP3 inflammasome pathway, thus offering promise as a strategy for preventing and treating PSD.
中风后抑郁（PSD）是中风常见的神经精神并发症。然而，PSD的潜在机制仍不清楚。在此，我们旨在研究超极化激活环核苷酸门控阳离子通道1（HCN1）在PSD发病机制中的作用及其潜在机制。
通过体内大脑中动脉闭塞建立PSD小鼠模型。大脑中动脉闭塞4周后，通过各种行为测试评估小鼠的焦虑和抑郁样行为。采用药理学抑制剂或神经元特异性腺相关病毒下调HCN通道。利用SY5Y细胞中的氧糖剥夺/复氧模型在体外研究PSD的发病机制。
大脑中动脉闭塞4周后，小鼠表现出焦虑和抑郁样行为，同时缺血海马区HCN1蛋白表达显著增加。此外，PSD小鼠海马神经元的I电流明显增强，而神经元兴奋性降低。用HCN通道选择性抑制剂ZD7288处理可通过抑制钾外流保护SY5Y细胞免受氧糖剥夺/复氧损伤。此外，我们观察到PSD小鼠缺血海马区NLRP3（核苷酸结合寡聚化结构域样受体蛋白3）炎性小体途径相关分子的蛋白表达显著增加。通过向海马注射病毒敲低HCN1通道可导致PSD小鼠中NLRP3炎性小体相关分子的蛋白表达降低，并改善其焦虑和抑郁样行为。
下调HCN1通道通过抑制NLRP3炎性小体途径对PSD具有有益作用，因此有望成为预防和治疗PSD的一种策略。
