VX-765 reduces neuroinflammation after spinal cord injury in mice

• Published in: Neural regeneration research Vol. 16; no. 9; pp. 1836 - 1847
• Main Authors: Chen, Jing, Chen, Yu-Qing, Shi, Yu-Jiao, Ding, Shu-Qin, Shen, Lin, Wang, Rui, Wang, Qi-Yi, Zha, Cheng, Ding, Hai, Hu, Jian-Guo, Lü, He-Zuo
• Format: Journal Article
• Language: English
• Published: India Wolters Kluwer India Pvt. Ltd 01.09.2021; Medknow Publications and Media Pvt. Ltd; Medknow Publications & Media Pvt. Ltd; Clinical Laboratory, the First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui Province, China; Anhui Key Laboratory of Tissue Transplantation,the First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui Province, China%Clinical Laboratory, the First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui Province, China%Anhui Key Laboratory of Tissue Transplantation,the First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui Province, China; Anhui Key Laboratory of Tissue Transplantation,the First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui Province, China; Department of Immunology, Bengbu Medical College, and Anhui Key Laboratory of Infection and Immunity at Bengbu Medical College, Bengbu, Anhui Province, China%Clinical Laboratory, the First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui Province, China; Wolters Kluwer - Medknow; Wolters Kluwer Medknow Publications
• Subjects: Cytokines; Drug therapy; Enzyme inhibitors; immune cell subsets; immune function; inflammasomes; leukocyte infiltration; macrophages; microglia; pathways; spinal cord injury; Inflammation; Neuroprotective agents; Pharmacology, Experimental; Spinal cord injuries; China; spinal cord injury; immune cell subsets; macrophages; inflammasomes; immune function; pathways; leukocyte infiltration; microglia
• ISSN: 1673-5374; 1876-7958
• DOI: 10.4103/1673-5374.306096

Inflammation is a major cause of neuronal injury after spinal cord injury. We hypothesized that inhibiting caspase-1 activation may reduce neuroinflammation after spinal cord injury, thus producing a protective effect in the injured spinal cord. A mouse model of T9 contusive spinal cord injury was established using an Infinite Horizon Impactor, and VX-765, a selective inhibitor of caspase-1, was administered for 7 successive days after spinal cord injury. The results showed that: (1) VX-765 inhibited spinal cord injury-induced caspase-1 activation and interleukin-1β and interleukin-18 secretion. (2) After spinal cord injury, an increase in M1 cells mainly came from local microglia rather than infiltrating macrophages. (3) Pro-inflammatory Th1Th17 cells were predominant in the Th subsets. VX-765 suppressed total macrophage infiltration, M1 macrophages/microglia, Th1 and Th1Th17 subset differentiation, and cytotoxic T cells activation; increased M2 microglia; and promoted Th2 and Treg differentiation. (4) VX-765 reduced the fibrotic area, promoted white matter myelination, alleviated motor neuron injury, and improved functional recovery. These findings suggest that VX-765 can reduce neuroinflammation and improve nerve function recovery after spinal cord injury by inhibiting caspase-1/interleukin-1β/interleukin-18. This may be a potential strategy for treating spinal cord injury. This study was approved by the Animal Care Ethics Committee of Bengbu Medical College (approval No. 2017-037) on February 23, 2017.