A plant-derived TRPV3 inhibitor suppresses pain and itch

  • Br J Pharmacol. 2021 Apr;178(7):1669-1683. doi: 10.1111/bph.15390.
Yalan Han  1  2 ,  Anna Luo  1  2 ,  Peter Muiruri Kamau  1  2  3 ,  Pitchayakarn Takomthong  4 ,  Jingmei Hu  5 ,  Chantana Boonyarat  4 ,  Lei Luo  1 ,  Ren Lai  1  3  6
Affiliations
  • 1. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Kunming, China.
  • 2. University of Chinese Academy of Sciences, Beijing, China.
  • 3. Sino-African Joint Research Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
  • 4. Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, Thailand.
  • 5. College of Life Sciences, Nanjing Agricultural University, Nanjing, China.
  • 6. KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Kunming Primate Research Center and National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Institute of Zoology, Kunming, China.
PMID: 33501656 DOI: 10.1111/bph.15390
Abstract

Background and purpose: Itching is the most frequent pathology in dermatology that has significant impacts on people's mental health and social life. Transient receptor potential vanilloid 3 (TRPV3) channel is a promising target for treating pruritus. However, few selecetive and potent antagonists have been reported. This study was designed to identify selective TRPV3 antagonist and elucidate its anti-pruritus pharmacology.

Experimental approach: FlexStation and calcium fluorescence imaging were conducted to track the functional compounds. Whole-cell patch clamp was used to record itch-related ion channel currents. Homologous recombination and site-directed mutagenesis were employed to construct TRPV3 channel chimeras and point mutations for exploring pharmacological mechanism. Mouse models were used for in vivo anti-pruritus assay.

Key results: An acridone alkaloid (citrusinine-II) was purified and characterized from Atalantia monophylla. It directly interacts with Y564 within S4 helix of TRPV3 to selectively inhibit the channel with a half maximal inhibitory concentration (IC50 ) of 12.43 μM. Citrusinine-II showed potential efficacy to attenuate both chronic and acute itch. Intradermal administration of citrusinine-II (143 ng/skin site) nearly completely inhibited itch behaviours. It also shows significant analgesic effects. Little side effects of the compound are observed.

Conclusion and implications: By acting as a selective and potent inhibitor of TRPV3 channel, citrusinine-II shows valuable therapeutic effects in pruritus animal models and is a promising candidate drug and/or lead molecule for the development of anti-pruritus drugs.

Keywords
Inhibition; Itch; Pain; TRPV3; citrusinine-II.
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