Hydrogen sulfide ameliorates lipopolysaccharide-induced anxiety-like behavior by inhibiting checkpoint kinase 1 activation in the hippocampus of mice

• Published in: Experimental neurology 2024-01, Vol.371, p.114586-114586, Article 114586
• Main Authors: Shentu, Yangping, Chen, Mengfan, Wang, Hui, Du, Xiaotong, Zhang, Wenjing, Xie, Guizhen, Zhou, Shaoyan, Ding, Lu, Zhu, Yun, Zhu, Min, Zhang, Nan, Du, Congkuo, Ma, Jianshe, Chen, Ran, Yang, Jinge, Fan, Xiaofang, Gong, Yongsheng, Zhang, Hongyu, Fan, Junming
• Format: Article
• Language: English
• Subjects: Animals; Anxiety - chemically induced; Anxiety - drug therapy; Checkpoint Kinase 1 - metabolism; Hippocampus - metabolism; Hydrogen Sulfide - metabolism; Hydrogen Sulfide - pharmacology; Hydrogen Sulfide - therapeutic use; Inflammasomes - metabolism; Lipopolysaccharides - toxicity; Mice; Neuroinflammatory Diseases
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2023.114586

Hydrogen sulfide (H S), an endogenous gasotransmitter, exhibits the anxiolytic roles through its anti-inflammatory effects, although its underlying mechanisms remain largely elusive. Emerging evidence has documented that cell cycle checkpoint kinase 1 (Chk1)-regulated DNA damage plays an important role in the neurodegenerative diseases; however, there are few relevant reports on the research of Chk1 in neuropsychiatric diseases. Here, we aimed to investigate the regulatory role of H S on Chk1 in lipopolysaccharide (LPS)-induced anxiety-like behavior focusing on inflammasome activation in the hippocampus. Cystathionine γ-lyase (CSE, a H S-producing enzyme) knockout (CSE ) mice displayed anxiety-like behavior and activation of inflammasome-mediated inflammatory responses, manifesting by the increase levels of interleukin-1β (IL-1β), IL-6, and ionized calcium-binding adaptor molecule-1 (Iba-1, microglia marker) expression in the hippocampus. Importantly, expression of p-Chk1 and γ-H2AX (DNA damage marker) levels were also increased in the hippocampus of CSE mice. LPS treatment decreased the expression of CSE and CBS while increased p-Chk1 and γ-H2AX levels and inflammasome-activated neuroinflammation in the hippocampus of mice. Moreover, p-Chk1 and γ-H2AX protein levels and cellular immunoactivity were significantly increased while CSE and CBS were markedly decreased in cultured BV2 cells followed by LPS treatment. Treatment of mice with GYY4137, a donor of H S, inhibited LPS-induced increased in p-Chk1 and γ-H2AX levels, mitigated inflammasome activation and inflammatory responses as well as amelioration of anxiety-like behavior. Notably, SB-218078, a selective Chk1 inhibitor treatment attenuated the effect of LPS on inflammasome activation and inflammatory responses and the induction of anxiety-like behavior. Finally, STAT3 knockdown with AAV-STAT3 shRNA alleviated LPS-induced anxiety-like behavior and inhibited inflammasome activation in the hippocampus, and blockade of NLRP3 with MCC950 attenuated neuroinflammation induction and ameliorated LPS-induced anxiety-like behavior. Overall, this study indicates that downregulation of Chk1 activity by H S activation may be considered as a valid strategy for preventing the progression of LPS-induced anxiety-like behavior.