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

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

  • Exp Neurol. 2023 Oct 26:114586. doi: 10.1016/j.expneurol.2023.114586.
Yangping Shentu 1,  Mengfan Chen 2,  Hui Wang 3,  Xiaotong Du 4,  Wenjing Zhang 5,  Guizhen Xie 3,  Shaoyan Zhou 3,  Lu Ding 3,  Yun Zhu 1,  Min Zhu 3,  Nan Zhang 3,  Congkuo Du 3,  Jianshe Ma 3,  Ran Chen 3,  Jinge Yang 6,  Xiaofang Fan 3,  Yongsheng Gong 7,  Hongyu Zhang 8,  Junming Fan 9
Affiliations

Affiliations

  • 1 Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
  • 2 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 3 Institute of Hypoxia Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 4 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Institute of Cixi Biomedical Research, Wenzhou Medical University, Cixi, Zhejiang 315302, China.
  • 5 Renji College, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 6 Department of Medical Technology, Jiangxi Medical College, Shangrao, Jiangxi 334709, China.
  • 7 Institute of Hypoxia Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: [email protected].
  • 8 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Institute of Cixi Biomedical Research, Wenzhou Medical University, Cixi, Zhejiang 315302, China. Electronic address: [email protected].
  • 9 Institute of Hypoxia Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Institute of Cixi Biomedical Research, Wenzhou Medical University, Cixi, Zhejiang 315302, China. Electronic address: [email protected].
PMID: 37898396 DOI: 10.1016/j.expneurol.2023.114586
Abstract

Hydrogen sulfide (H2S), 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 H2S on Chk1 in lipopolysaccharide (LPS)-induced anxiety-like behavior focusing on inflammasome activation in the hippocampus. Cystathionine γ-lyase (CSE, a H2S-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 H2S, 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 H2S activation may be considered as a valid strategy for preventing the progression of LPS-induced anxiety-like behavior.

Keywords

Anxiety-like behavior; CSE; Chk1; H(2)S; Hippocampus; Inflammasome.

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