Critical role of checkpoint kinase 1 in spinal cord injury-induced motor dysfunction in mice.

Autor: Fan J; School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Cixi People's Hospital, Institute of Cixi Biomedical Research, Wenzhou Medical University, Cixi, Ningbo, Zhejiang 315302, China., Du X; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China., Chen M; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China., Xu Y; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China., Xu J; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China., Lu L; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Emergency, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China., Zhou S; School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China., Kong X; School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China., Xu K; Cixi People's Hospital, Institute of Cixi Biomedical Research, Wenzhou Medical University, Cixi, Ningbo, Zhejiang 315302, China. Electronic address: godxu1987@163.com., Zhang H; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Cixi People's Hospital, Institute of Cixi Biomedical Research, Wenzhou Medical University, Cixi, Ningbo, Zhejiang 315302, China. Electronic address: st.hyz@126.com.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2024 Sep 10; Vol. 138, pp. 112521. Date of Electronic Publication: 2024 Jun 24.
DOI: 10.1016/j.intimp.2024.112521
Abstrakt: Spinal cord injury (SCI) is a devastating neurotraumatic condition characterized by severe motor dysfunction and paralysis. Accumulating evidence suggests that DNA damage is involved in SCI pathology. However, the underlying mechanisms remain elusive. Although checkpoint kinase 1 (Chk1)-regulated DNA damage is involved in critical cellular processes, its role in SCI regulation remains unclear. This study aimed to explore the role and potential mechanism of Chk1 in SCI-induced motor dysfunction. Adult female C57BL/6J mice subjected to T9-T10 spinal cord contusions were used as models of SCI. Western blotting, immunoprecipitation, histomorphology, and Chk1 knockdown or overexpression achieved by adeno-associated virus were performed to explore the underlying mechanisms. Levels of p-Chk1 and γ-H2AX (a cellular DNA damage marker) were upregulated, while ferroptosis-related protein levels, including glutathione peroxidase 4 (GPX4) and x-CT were downregulated, in the spinal cord and hippocampal tissues of SCI mice. Functional experiments revealed increased Basso Mouse Scale (BMS) scores, indicating that Chk1 downregulation promoted motor function recovery after SCI, whereas Chk1 overexpression aggravated SCI-induced motor dysfunction. In addition, Chk1 downregulation reversed the SCI-increased levels of GPX4 and x-CT expression in the spinal cord and hippocampus, while immunoprecipitation assays revealed strengthened interactions between p-Chk1 and GPX4 in the spinal cord after SCI. Finally, Chk1 downregulation promoted while Chk1 overexpression inhibited NeuN cellular immunoactivity in the spinal cord after SCI, respectively. Collectively, these preliminary results imply that Chk1 is a novel regulator of SCI-induced motor dysfunction, and that interventions targeting Chk1 may represent promising therapeutic targets for neurotraumatic diseases such as SCI.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: