Wikstroemia indica (L.) C. A. Mey. Exerts analgesic activity by inhibiting NaV1.7 channel

Keyi Zhang; Min Gao; Beiru Xue; Peter Muiruri Kamau; Ren Lai; Lei Luo

doi:10.1016/j.jep.2023.117392

Wikstroemia indica (L.) C. A. Mey. Exerts analgesic activity by inhibiting Na_V1.7 channel

J Ethnopharmacol. 2024 Feb 10:320:117392. doi: 10.1016/j.jep.2023.117392. Epub 2023 Nov 9.

Authors

Keyi Zhang¹, Min Gao², Beiru Xue³, Peter Muiruri Kamau⁴, Ren Lai⁵, Lei Luo⁶

Affiliations

¹ School of Molecular Medicine, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310000, China; Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Kunming Primate Research Center, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Sino-African Joint Research Center, and Engineering Laboratory of Peptides, Kunming Institute of Zoology, Kunming, 650107, China; Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China.
² Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Kunming Primate Research Center, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Sino-African Joint Research Center, and Engineering Laboratory of Peptides, Kunming Institute of Zoology, Kunming, 650107, China.
³ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Kunming Primate Research Center, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Sino-African Joint Research Center, and Engineering Laboratory of Peptides, Kunming Institute of Zoology, Kunming, 650107, China; Department of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, China.
⁴ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Kunming Primate Research Center, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Sino-African Joint Research Center, and Engineering Laboratory of Peptides, Kunming Institute of Zoology, Kunming, 650107, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, 100049, China.
⁵ School of Molecular Medicine, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310000, China; Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Kunming Primate Research Center, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Sino-African Joint Research Center, and Engineering Laboratory of Peptides, Kunming Institute of Zoology, Kunming, 650107, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: rlai@mail.kiz.ac.cn.
⁶ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Kunming Primate Research Center, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Sino-African Joint Research Center, and Engineering Laboratory of Peptides, Kunming Institute of Zoology, Kunming, 650107, China. Electronic address: luolei@mail.kiz.ac.cn.

PMID: 37949328
DOI: 10.1016/j.jep.2023.117392

Abstract

Ethnopharmacological relevance: Wikstroemia indica (L.) C. A. Mey. is traditionally used for the treatment of gastrointestinal disorders, respiratory illnesses, skin infections, and inflammatory conditions. Despite extensive evidence of its biological potential, including antipyretic, antimicrobial, antifungal, anti-inflammatory, and diuretic properties, there are currently no reports indicating its analgesic effects.

Aim of the study: Crude extracts from W. indica stems were examined for anti-nociceptive activity. Additionally, an in-depth investigation was conducted to uncover the molecular basis for the possible analgesic phenomenon.

Materials and methods: W. indica stems were subjected to ethanol extraction. To evaluate the in vivo analgesic activity, both chemical and physical-induced pain models were employed. Additionally, single-cell electrophysiological recordings were performed on human embryonic kidney 293T (HEK293T) cells expressing Na_V1.7 channel.

Results: Crude extracts derived from W. indica exhibited significant efficacy in mitigating the pain sensation, as evidenced by their substantial effects in both acetic acid-induced and heat-induced pain models. Further screening unveiled osthenol as a key bioactive compound responsible for mediating the analgesic properties of W. indica. Osthenol directly interacts with the pore domain of Na_V1.7 channels, leading to channel inhibition. Importantly, this interaction is independent of any changes in the channel gating modifier domain.

Conclusion: Both W. indica and osthenol demonstrate potential as effective anti-nociceptive agents in preclinical studies. Their analgesic effects are likely achieved by inhibiting the Na_V1.7 channel, which is crucial in pain initiation, transmission, and modulation. These results elucidate the molecular basis of the W. indica as a pain-relieving medication. Additionally, osthenol holds great potential in advancing the development of anti-nociceptive drugs targeting the Na_V1.7 channel.

Keywords: Anti-nociceptive activity; Lead molecule; Na(V)1.7; Osthenol; Wikstroemia indica (L.) C. A. Mey..

MeSH terms

Analgesics / pharmacology
Analgesics / therapeutic use
HEK293 Cells
Humans
Pain / drug therapy
Plant Extracts / pharmacology
Plant Extracts / therapeutic use
Wikstroemia* / chemistry

Substances

Analgesics
Plant Extracts