title: Cardamonin, a Novel Antagonist of hTRPA1 Cation Channel, Reveals Therapeutic Mechanism of Pathological Pain.
abstract: The increasing demand for safe and effective treatments of chronic pain has promoted the investigation of novel analgesic drugs. Some herbals have been known to be able to relieve pain, while the chemical basis and target involved in this process remained to be clarified. The current study aimed to find anti-nociceptive candidates targeting transient receptor potential ankyrin 1 (TRPA1), a receptor that implicates in hyperalgesia and neurogenic inflammation. In the current study, 156 chemicals were tested for blocking HEK293/TRPA1 ion channel by calcium-influx assay. Docking study was conducted to predict the binding modes of hit compound with TRPA1 using Discovery Studio. Cytotoxicity in HEK293 was conducted by Cell Titer-Glo assay. Additionally, cardiotoxicity was assessed via xCELLigence RTCA system. We uncovered that cardamonin selectively blocked TRPA1 activation while did not interact with TRPV1 nor TRPV4 channel. A concentration-dependent inhibitory effect was observed with IC50 of 454 nM. Docking analysis of cardamonin demonstrated a compatible interaction with A-967079-binding site of TRPA1. Meanwhile, cardamonin did not significantly reduce HEK293 cell viability, nor did it impair cardiomyocyte constriction. Our data suggest that cardamonin is a selective TRPA1 antagonist, providing novel insight into the target of its anti-nociceptive activity.
authors: Key Laboratory of TCM-Information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 6 Wangjing Zhonghuan South Road, Chaoyang District, Beijing 100102, China. wangshifeng@bucm.edu.cn.
authors: Shifeng
authors: S
authors: Wang
authors: Key Laboratory of TCM-Information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 6 Wangjing Zhonghuan South Road, Chaoyang District, Beijing 100102, China. zhaichenxi1991@163.com.
authors: Chenxi
authors: C
authors: Zhai
authors: Key Laboratory of TCM-Information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 6 Wangjing Zhonghuan South Road, Chaoyang District, Beijing 100102, China. collean_zhang@163.com.
authors: Yanling
authors: Y
authors: Zhang
authors: Key Laboratory of TCM-Information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 6 Wangjing Zhonghuan South Road, Chaoyang District, Beijing 100102, China. louisyang@bucm.edu.cn.
authors: Yangyang
authors: Y
authors: Yu
authors: Key Laboratory of TCM-Information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 6 Wangjing Zhonghuan South Road, Chaoyang District, Beijing 100102, China. zhangyuxinwjzy@163.com.
authors: Yuxin
authors: Y
authors: Zhang
authors: HD Biosciences, Co., Ltd., 590 Ruiqing Road, Zhangjiang Hi-Tech Park East Campus, Pudong New Area, Shanghai 201201, China. malianghui@hdbiosciences.com.
authors: Lianghui
authors: L
authors: Ma
authors: Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, No. 1 Beichen West Road, Chaoyang District, Beijing 100101, China. lishiyou@big.ac.cn.
authors: Shiyou
authors: S
authors: Li
authors: Key Laboratory of TCM-Information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 6 Wangjing Zhonghuan South Road, Chaoyang District, Beijing 100102, China. yjqiao@bucm.edu.cn.
authors: Yanjiang
authors: Y
authors: Qiao
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D047188:Chalcones / Q000737:chemistry* / Q000494:pharmacology*; D059350:Chronic Pain / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D047188:Chalcones; D009419:Nerve Tissue Proteins; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050052:TRPC Cation Channels; D050051:Transient Receptor Potential Channels; C480976:Trpa1 protein, rat; C436747:cardamonin
keywords: Alpinia katsumadai hayata; TRPA1 antagonist; cardamonin; cardiotoxicity; hyperalgeisa