4-Methylesculetin attenuates inflammatory pain via inhibition of Sp1-TRPV1 and inflammation related signaling pathways

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-03-06 DOI:10.1016/j.intimp.2025.114379

Weixin Zhao , Mengyu Chen , Xialin Yu , Huayu Zhong , Shikang Hao , Shuangyu Liu , Ziyu Tian , Lilong Dong , Shijie Dai , Haiyan Liu , Han Hao

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Abstract

Background

Discovering lead compounds with anti-inflammatory and analgesic activities from natural products with minimal toxic side effects has been a long-term goal for researchers. 4-Methylesculetin (4-ME), a natural coumarin derivative, has been reported to have anti-inflammatory and antioxidant properties, but its analgesic effect has not yet been studied. This research investigates the analgesic effect and underlying mechanism of 4-ME in peripheral inflammatory pain.

Methods

Acute or chronic inflammatory pain model was established by injecting formalin or Complete Freund's Adjuvant (CFA) into the right hindpaw of rat, respectively. The mechanical and thermal thresholds were detected by using Von Frey and thermal radiation instrument. Patch-clamp recording was performed to study the electrophysiological properties of ion channel. RT-qPCR, western blot, and immunofluorescence were used to analyze mRNA and protein expressions of relevant signaling pathway molecules.

Results

Intraperitoneal injection of 4-ME could significantly alleviate mechanical and thermal hyperalgesia induced by CFA injection, as well as spontaneous pain induced by formalin injection. In the CFA-induced chronic pain model, 4-ME reduced the levels of IL-6, TNF-α, IL-1β, and inhibited ERK, NF-κB, NLRP3 pathways in dorsal root ganglia (DRG). It downregulated abnormally high expression of TRPV1 caused by CFA injection in DRG, without altering the electrophysiological properties of TRPV1 channel. Further mechanistic studies demonstrated that 4-ME regulated the expression of TRPV1 by inhibiting the transcription factor Sp1. Compared to other coumarin derivatives, 4-ME exhibited a better analgesic effect at low dosage.

Conclusion

Our study reveals for the first time that 4-ME could alleviate peripheral inflammatory pain by inhibiting Sp1-TRPV1 pathway, suggests 4-ME as a potential analgesic, and provides a theoretical basis for 4-ME translation into clinical application.

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.