Pharmacological inhibition of cGAS ameliorates postoperative cognitive dysfunction by suppressing caspase-3/GSDME-dependent pyroptosis

IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Neurochemistry international Pub Date : 2024-06-04 DOI:10.1016/j.neuint.2024.105788
Xueshan Bu , Ping Gong , Lei Zhang , Wenqin Song , Jiabao Hou , Qingwen Li , Wei Wang , Zhongyuan Xia
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Abstract

Neuroinflammation is a major driver of postoperative cognitive dysfunction (POCD). The cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS–STING) signaling is a prominent alarming device for aberrant double-stranded DNA (dsDNA) that has emerged as a key mediator of neuroinflammation in cognitive-related diseases. However, the role of the cGAS–STING pathway in the pathogenesis of POCD remains unclear. A POCD model was developed in male C57BL/6J mice by laparotomy under isoflurane (Iso) anesthesia. The cGAS inhibitor RU.521 and caspase-3 agonist Raptinal were delivered by intraperitoneal administration. BV2 cells were exposed to Iso and lipopolysaccharide (LPS) in the absence or presence of RU.521, and then cocultured with HT22 cells in the absence or presence of Raptinal. Cognitive function was assessed using the Morris water maze test and novel object recognition test. Immunofluorescence assays were used to observe the colocalization of dsDNA and cGAS. The downstream proteins and pro-inflammatory cytokines were detected using the Western blot and enzyme-linked immunosorbent assay (ELISA). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was used to assess the degree of cell death in the hippocampus following anesthesia/surgery treatment. Isoflurane/laparotomy and Iso + LPS significantly augmented the levels of cGAS in the hippocampus and BV2 cells, accompanied by mislocalized dsDNA accumulation in the cytoplasm. RU.521 alleviated cognitive impairment, diminished the levels of 2′3′-cGAMP, cGAS, STING, phosphorylated NF-κB p65 and NF-κB-pertinent pro-inflammatory cytokines (TNFα and IL-6), and repressed pyroptosis-associated elements containing cleaved caspase-3, N-GSDME, IL-1β and IL-18. These phenotypes could be rescued by Raptinal in vivo and in vitro. These findings suggest that pharmacological inhibition of cGAS mitigates neuroinflammatory burden of POCD by dampening caspase-3/GSDME-dependent pyroptosis, providing a potential therapeutic strategy for POCD.

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抑制 cGAS 的药理作用可通过抑制 caspase-3/GSDME 依赖性裂解来改善术后认知功能障碍
神经炎症是术后认知功能障碍(POCD)的主要驱动因素。环GMP-AMP合成酶-干扰素基因刺激器(cGAS-STING)信号传导是异常双链DNA(dsDNA)的显著报警装置,已成为认知相关疾病中神经炎症的关键介质。然而,cGAS-STING通路在POCD发病机制中的作用仍不清楚。研究人员在异氟醚(Iso)麻醉下对雄性 C57BL/6J 小鼠进行开腹手术,建立了 POCD 模型。腹腔注射 cGAS 抑制剂 RU.521 和 caspase-3 激动剂 Raptinal。在无RU.521或有RU.521的情况下,将BV2细胞暴露于Iso和脂多糖(LPS),然后在无Raptinal或有Raptinal的情况下与HT22细胞共培养。认知功能通过莫里斯水迷宫测试和新物体识别测试进行评估。免疫荧光试验用于观察dsDNA和cGAS的共定位。使用 Western 印迹和酶联免疫吸附试验(ELISA)检测下游蛋白和促炎细胞因子。末端脱氧核苷酸转移酶dUTP缺口标记(TUNEL)染色用于评估麻醉/手术治疗后海马细胞的死亡程度。异氟醚/扁桃体切除术和异体+LPS显著增加了海马和BV2细胞中cGAS的水平,并伴随着胞质中dsDNA的错位聚集。RU.521 可减轻认知障碍,降低 2′3′-cGAMP、cGAS、STING、磷酸化 NF-κB p65 和 NF-κB 相关促炎细胞因子(TNFα 和 IL-6)的水平,并抑制含有裂解的 caspase-3、N-GSDME、IL-1β 和 IL-18 的嗜热相关元素。这些表型在体内和体外均可被雷普替尼尔所挽救。这些研究结果表明,药理抑制cGAS可以通过抑制依赖于caspase-3/GSDME的热凋亡减轻POCD的神经炎症负担,为POCD提供了一种潜在的治疗策略。
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来源期刊
Neurochemistry international
Neurochemistry international 医学-神经科学
CiteScore
8.40
自引率
2.40%
发文量
128
审稿时长
37 days
期刊介绍: Neurochemistry International is devoted to the rapid publication of outstanding original articles and timely reviews in neurochemistry. Manuscripts on a broad range of topics will be considered, including molecular and cellular neurochemistry, neuropharmacology and genetic aspects of CNS function, neuroimmunology, metabolism as well as the neurochemistry of neurological and psychiatric disorders of the CNS.
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