Pyrazine-fused triterpenoids block the TRPA1 ion channel in vitro and inhibit TRPA1-mediated acute inflammation in vivo
Mäki-Opas, Ilari and Hämäläinen, Mari and Moilainen, Lauri J. and Haavikko, Raisa and Ahonen, Tiina J. and Alakurtti, Sami and Moreira, Vânia M. and Muraki, Katsuhiko and Yli-Kauhaluoma, Jari and Moilainen, Eeva (2019) Pyrazine-fused triterpenoids block the TRPA1 ion channel in vitro and inhibit TRPA1-mediated acute inflammation in vivo. ACS Chemical Neuroscience, 10 (6). pp. 2848-2857. ISSN 1948-7193 (https://doi.org/10.1021/acschemneuro.9b00083)
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Abstract
TRPA1 is a nonselective cation channel, most famously expressed in nonmyelinated nociceptors. In addition to being an important chemical and mechanical pain sensor, TRPA1 has more recently appeared to have a role also in inflammation. Triterpenoids are natural products with anti-inflammatory and anticancer effects in experimental models. In this paper, 13 novel triterpenoids were created by synthetically modifying betulin, an abundant triterpenoid of the genus Betula L., and their TRPA1-modulating properties were examined. The Fluo 3-AM protocol was used in the initial screening, in which six of the 14 tested triterpenoids inhibited TRPA1 in a statistically significant manner. In subsequent whole-cell patch clamp recordings, the two most effective compounds (pyrazine-fused triterpenoids 8 and 9) displayed a reversible and dose- and voltage-dependent effect to block the TRPA1 ion channel at submicromolar concentrations. Interestingly, the TRPA1 blocking action was also evident in vivo, as compounds 8 and 9 both alleviated TRPA1 agonist-induced acute paw inflammation in mice. The results introduce betulin-derived pyrazine-fused triterpenoids as promising novel antagonists of TRPA1 that are potentially useful in treating diseases with a TRPA1-mediated adverse component.
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Item type: Article ID code: 67816 Dates: DateEvent19 June 2019Published29 April 2019Published Online29 April 2019AcceptedNotes: This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Chemical Neuroscience, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acschemneuro.9b00083. Subjects: Medicine > Therapeutics. Pharmacology
Medicine > Internal medicine > Neuroscience. Biological psychiatry. NeuropsychiatryDepartment: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences Depositing user: Pure Administrator Date deposited: 14 May 2019 11:56 Last modified: 27 Aug 2024 04:53 Related URLs: URI: https://strathprints.strath.ac.uk/id/eprint/67816