1. Cyclo(L-Pro-L-Trp) from Chilobrachys jingzhao alleviates formalin-induced inflammatory pain by suppressing the inflammatory response and inhibiting TRAF6-mediated MAPK and NF-κB signaling pathways.
- Author
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Liu XY, Huang JC, Zhang T, Wang HR, Xu QH, Xia YG, Xu AJ, Yang ZY, Sun L, Zhao WJ, Zhao J, Qian F, and Hou AJ
- Subjects
- Animals, Mice, Male, RAW 264.7 Cells, Peptides, Cyclic pharmacology, Peptides, Cyclic therapeutic use, Pain drug therapy, Pain chemically induced, Analgesics therapeutic use, Analgesics pharmacology, Humans, Edema drug therapy, Edema chemically induced, Edema immunology, Mitogen-Activated Protein Kinases metabolism, Macrophages drug effects, Macrophages immunology, NF-kappa B metabolism, TNF Receptor-Associated Factor 6 metabolism, Anti-Inflammatory Agents therapeutic use, Anti-Inflammatory Agents pharmacology, Signal Transduction drug effects, Formaldehyde, Inflammation drug therapy
- Abstract
Chronic pain has emerged as a significant public health issue, seriously affecting patients' quality of life and psychological well-being, with a lack of effective pharmacological treatments. Numerous studies have indicated that macrophages play a crucial role in inflammatory pain, and targeting neuro-immune interactions for drug development may represent a promising direction for pain management. Chilobrachys jingzhao (C. jingzhao) is used as a folk medicine of the Li nationality with the efficacy of eliminating swelling, detoxicating, and relieving pain, and the related products are widely used in the market. However, the chemical constituents of C. jingzhao have not been reported, and the pharmacodynamic substance and the precise functional mechanism are unrevealed. Here we isolated a cyclic dipeptide, cyclo(L-Pro-L-Trp) (CPT) from C. jingzhao for the first time. CPT remarkably alleviated formalin-induced inflammatory pain and significantly inhibited inflammatory responses. In vivo, CPT attenuated neutrophil infiltration and plantar tissue edema and suppressed the mRNA expression of pro-inflammatory molecules. In vitro, CPT suppressed inflammation triggered by lipopolysaccharide (LPS) in both RAW 264.7 and iBMDM cells, reducing expressions of inducible nitric oxide synthase (iNOS), superoxide, and pro-inflammatory molecules. A mechanistic study revealed that CPT exerted an anti-inflammatory activity by blocking the mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways, as well as alleviating the ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6). Our results elucidated the pharmacodynamic material basis of C. jingzhao, and CPT can be a promising lead for alleviating inflammation and inflammatory pain., 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.)
- Published
- 2024
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