2. Academic Validation
  3. 4-Methylesculetin attenuates inflammatory pain via inhibition of Sp1-TRPV1 and inflammation related signaling pathways

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

  • Int Immunopharmacol. 2025 Apr 16:152:114379. doi: 10.1016/j.intimp.2025.114379.
Weixin Zhao 1,  Mengyu Chen 1,  Xialin Yu 1,  Huayu Zhong 2,  Shikang Hao 3,  Shuangyu Liu 1,  Ziyu Tian 2,  Lilong Dong 4,  Shijie Dai 5,  Haiyan Liu 6,  Han Hao 7
Affiliations

Affiliations

  • 1 Department of Pharmacology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of New Drug Pharmacology and Toxicology, Center of Innovative Drug Research and Evaluation, Hebei Medical University, Shijiazhuang 050000, China.
  • 2 State Key Laboratory of Macromolecular Drugs and Large-scale Manufacturing, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
  • 3 Basic medical college, Shanxi Medical University, Taiyuan 030000, China.
  • 4 Department of Pharmaceutical Analysis, School of Pharmacy, Hebei Medical University, Shijiazhuang 050000, China.
  • 5 State Key Laboratory of Macromolecular Drugs and Large-scale Manufacturing, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China. Electronic address: daishijie_123@wmu.edu.cn.
  • 6 Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000.China. Electronic address: drliuhaiyan@163.com.
  • 7 Department of Pharmacology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of New Drug Pharmacology and Toxicology, Center of Innovative Drug Research and Evaluation, Hebei Medical University, Shijiazhuang 050000, China. Electronic address: 18800790@hebmu.edu.cn.
PMID: 40054325 DOI: 10.1016/j.intimp.2025.114379
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.

Keywords

4-Methylesculetin; DRG; Inflammatory pain; Sp1; TRPV1.

Figures
Products