Luo Bang, Xie Yao, Kuang Wending, Wang Yuzheng, Chen Gang, Zhang Yang, Yuan Mei
Departments of Neurology.
Gastroenterology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan Province, China.
Neuroreport. 2025 Apr 2;36(6):314-326. doi: 10.1097/WNR.0000000000002152. Epub 2025 Mar 26.
Poststroke depression (PSD) affects approximately one-third of stroke survivors, contributing to poor outcomes and elevated mortality. This study aimed to investigate the therapeutic effects of hydrogen sulfide (H2S), administered as sodium hydrosulfide (NaHS), on PSD-induced inflammation, with a focus on the modulation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway and the enhancement of endoplasmic reticulum (ER) autophagy in microglial cells. An in-vivo rat model was established to evaluate the effects of NaHS on depression-like behaviors and inflammation. Mechanistic studies were conducted in vitro using BV2 microglia subjected to oxygen-glucose deprivation (OGD) and corticosterone. Key inflammatory markers, cGAS-STING pathway activity, and ER-autophagy-related proteins were analyzed using quantitative reverse transcription PCR, Western blotting, ELISA, transmission electron microscopy, and immunofluorescence staining. Depression-like behaviors in rats were assessed using the forced swimming and tail suspension tests. H2S treatment ameliorated depression-like symptoms, mitigated hippocampal damage, and reduced pro-inflammatory markers, including NOD-like receptor protein 3, interleukin-1β (IL-1β), and IL-18 by inhibiting the cGAS-STING pathway. Furthermore, H2S significantly upregulated autophagy-related proteins (LC3, Beclin-1, and FAM134B) and autophagic vesicles, indicating enhanced ER autophagy. Notably, silencing FAM134B reversed the inhibitory effects of H2S on the cGAS-STING pathway, underscoring the pivotal role of ER autophagy in H2S-mediated neuroprotection. These findings demonstrate that H2S mitigates PSD-induced microglial inflammation and depression-like behaviors by inhibiting the cGAS-STING pathway and promoting ER autophagy, suggesting its potential as a therapeutic strategy for PSD. Further investigation into H2S and autophagy-related pathways could reveal novel therapeutic avenues for neuroinflammatory conditions.
中风后抑郁（PSD）影响约三分之一的中风幸存者，导致不良预后和死亡率升高。本研究旨在探讨以硫氢化钠（NaHS）形式给予的硫化氢（H2S）对PSD诱导的炎症的治疗作用，重点关注环磷酸鸟苷-腺苷酸合成酶（cGAS）-干扰素基因刺激因子（STING）通路的调节以及小胶质细胞内质网（ER）自噬的增强。建立了体内大鼠模型以评估NaHS对抑郁样行为和炎症的影响。使用遭受氧-葡萄糖剥夺（OGD）和皮质酮处理的BV2小胶质细胞进行体外机制研究。使用定量逆转录PCR、蛋白质免疫印迹、酶联免疫吸附测定、透射电子显微镜和免疫荧光染色分析关键炎症标志物、cGAS-STING通路活性和ER自噬相关蛋白。使用强迫游泳和悬尾试验评估大鼠的抑郁样行为。H2S治疗改善了抑郁样症状，减轻了海马损伤，并通过抑制cGAS-STING通路降低了促炎标志物，包括NOD样受体蛋白3、白细胞介素-1β（IL-1β）和IL-18。此外，H2S显著上调自噬相关蛋白（LC3、Beclin-1和FAM134B）和自噬小泡，表明ER自噬增强。值得注意的是，沉默FAM134B可逆转H2S对cGAS-STING通路的抑制作用，强调了ER自噬在H2S介导的神经保护中的关键作用。这些发现表明，H2S通过抑制cGAS-STING通路和促进ER自噬减轻PSD诱导的小胶质细胞炎症和抑郁样行为，表明其作为PSD治疗策略的潜力。对H2S和自噬相关通路的进一步研究可能会揭示神经炎症性疾病的新治疗途径。
