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
  • 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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