A plant‐derived TRPV3 inhibitor suppresses pain and itch

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 (IC 50) 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 Abbreviations: 2-APB, 2-aminoethoxydiphenyl borate; ASIC3, acid-sensing (proton-gated) ion channel 3; CCK8, cell counting kit-8; Nav, voltage-gated sodium channel; TRP, transient receptor potential; TRPA1, transient receptor potential ankyrin 1; TRPM8, transient receptor potential melastatin 8; TRPV1, transient receptor potential vanilloid 1; TRPV2, transient receptor potential vanilloid 2; TRPV3, transient receptor potential vanilloid 3; TRPV4, transient receptor potential vanilloid 4.

Abnormal Somatosensory Behaviors Associated With a Gain-of-Function Mutation in TRPV3 Channels

“…Contrastingly, Yoshioka et al (2009) found that a transgenic Trpv3 G 573 S mutant on either C57BL or DS background shows increased scratching, but whether the mutants are raised in the SPF or conventional conditions is not specified. Additionally, TRPV3 antagonists such as forsythoside B and citrusinine-II are shown to attenuate acute and chronic itch and pain; however, these compounds have known ( Jiang et al, 2012 ; Liu et al, 2019 ), or could have unknown off-targets that might result in suppression of itch ( Zhang et al, 2019 ; Han et al, 2021 ). Also, no conclusive evidence is available that can indicate how an overactive TRPV3 channel can collaborate with genetic, environmental, and/or inflammatory triggers to induce itch in the patients harboring gain-of-function mutations in the Trpv3 gene.…”

“…These findings suggest that itch sensitization in DS- Nh mice or patients with Olmsted syndrome might not be directly caused by the hyperactivation of TRPV3 channels. Recent studies focus on the function of TRPV3 channels in acute chemical itch transmission ( Sun et al, 2020 ; Zhao et al, 2020 ; Han et al, 2021 ). However, none of the studies have provided conclusive evidence of how TRPV3 is involved in itch sensation.…”

Inhibition of temperature-sensitive TRPV3 channel by two natural isochlorogenic acid isomers for alleviation of dermatitis and chronic pruritus

“…Recently our group reported that pharmacological inhibition of TRPV3 by a relative specific natural compound forsythoside B can rescue cell death caused by excessive activation TRPV3 and also attenuate pruritus 27 . The therapeutic potential of TRPV3 inhibitors in itch and pain is also recently reported by two independent laboratories 28 , 29 . However, all of these inhibitors are either nonselective or less potent 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , and it is imperative to identify selective and potent TRPV3 inhibitors that can be used either to further understand the channel pharmacology or lead to development potential for novel therapy of dermatitis and chronic pruritus.…”

Acridone Derivatives from Atalantia monophyla Inhibited Cancer Cell Proliferation through ERK Pathway

“…Acridone alkaloids are naturally occurring phytochemicals containing the acridin-9(10H)-one. Acridone is a unique alkaloid known to possess several biological functions, such as anti-viral [11], anti-microbial [12], anti-pruritic [13], and anti-Alzheimer's disease [14,15] activities. Moreover, some acridone derivatives have been shown ability to combat cancer cells [16,17].…”