Hydrogen attenuates postoperative pain through Trx1/ASK1/MMP9 signaling pathway

Jinhui Jia, Juan Li, Li Wan, Li Zhang, Liang Hu, Man-Lin Duan, Pan Yu, Peng Teng, Qian Li, Qilin Peng, Rumeng Jia, Shirong Ruan, Wen-Tao Liu, Xing Yang, Ya-Dan Shi, Yinbing Pan

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DOI: 10.1186/s12974-022-02670-0 DOI is the universal ID for this study.

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Background: Postoperative pain is a serious clinical problem with a poorly understood mechanism, and lacks effective treatment. Hydrogen (H2) can reduce neuroinflammation; therefore, we hypothesize that H2 may alleviate postoperative pain, and aimed to investigate the underlying mechanism.

Methods: Mice were used to establish a postoperative pain model using plantar incision surgery. Mechanical allodynia was measured using the von Frey test. Cell signaling was assayed using gelatin zymography, western blotting, immunohistochemistry, and immunofluorescence staining. Animals or BV-2 cells were received with/without ASK1 and Trx1 inhibitors to investigate the effects of H2 on microglia.

Results: Plantar incision surgery increased MMP-9 activity and ASK1 phosphorylation in the spinal cord of mice. MMP-9 knockout and the ASK1 inhibitor, NQDI-1, attenuated postoperative pain. H2 increased the expression of Trx1 in the spinal cord and in BV-2 cells. H2 treatment mimicked NQDI1 in decreasing the phosphorylation of ASK1, p38 and JNK. It also reduced MMP-9 activity, downregulated pro-IL-1β maturation and IBA-1 expression in the spinal cord of mice, and ameliorated postoperative pain. The protective effects of H2 were abolished by the Trx1 inhibitor, PX12. In vitro, in BV-2 cells, H2 also mimicked NQDI1 in inhibiting the phosphorylation of ASK1, p38, and JNK, and also reduced MMP-9 activity and decreased IBA-1 expression induced by LPS. The Trx1 inhibitor, PX12, abolished the protective effects of H2 in BV-2 cells. Conclusions: For the first time, the results of our study confirm that H2 can be used as a therapeutic agent to alleviate postoperative pain through the Trx1/ASK1/MMP9 signaling pathway. MMP-9 and ASK1 may be the target molecules for relieving postoperative pain.

Publish Year 2023
Country China
Rank Positive
Journal Journal of Neuroinflammation
Primary Topic Spine
Secondary TopicSurgery/Transplantation
Model Mouse
Tertiary TopicPostoperative Pain
Vehicle Saline (Dissolved)
pH Neutral
Application Injection