Pyrazine-fused triterpenoids block the TRPA1 ion channel in vitro and inhibit TRPA1-mediated acute inflammation in vivo

Ilari Mäki-Opas, Mari Hämäläinen, Lauri J. Moilainen, Raisa Haavikko, Tiina J. Ahonen, Sami Alakurtti, Vânia M. Moreira, Katsuhiko Muraki, Jari Yli-Kauhaluoma, Eeva Moilainen

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)2848-2857
Number of pages10
JournalACS Chemical Neuroscience
Volume10
Issue number6
Early online date29 Apr 2019
DOIs
Publication statusPublished - 19 Jun 2019

Fingerprint

Pyrazines
Ion Channels
Inflammation
Betula
Nociceptors
Clamping devices
Biological Products
Cations
Screening
Anti-Inflammatory Agents
Theoretical Models
Pain
Sensors
Electric potential
In Vitro Techniques
betulin
Fluo-3

Keywords

  • transient receptor potential channels
  • TRPA1
  • inflammation
  • pain
  • natural compounds
  • triterpenoids

Cite this

Mäki-Opas, I., Hämäläinen, M., Moilainen, L. J., Haavikko, R., Ahonen, T. J., Alakurtti, S., ... Moilainen, E. (2019). Pyrazine-fused triterpenoids block the TRPA1 ion channel in vitro and inhibit TRPA1-mediated acute inflammation in vivo. ACS Chemical Neuroscience, 10(6), 2848-2857. https://doi.org/10.1021/acschemneuro.9b00083
Mäki-Opas, Ilari ; Hämäläinen, Mari ; Moilainen, Lauri J. ; Haavikko, Raisa ; Ahonen, Tiina J. ; Alakurtti, Sami ; Moreira, Vânia M. ; Muraki, Katsuhiko ; Yli-Kauhaluoma, Jari ; Moilainen, Eeva. / Pyrazine-fused triterpenoids block the TRPA1 ion channel in vitro and inhibit TRPA1-mediated acute inflammation in vivo. In: ACS Chemical Neuroscience. 2019 ; Vol. 10, No. 6. pp. 2848-2857.
@article{f5bd9a1a9207475291a1916bffd48c21,
title = "Pyrazine-fused triterpenoids block the TRPA1 ion channel in vitro and inhibit TRPA1-mediated acute inflammation in vivo",
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.",
keywords = "transient receptor potential channels, TRPA1, inflammation, pain, natural compounds, triterpenoids",
author = "Ilari M{\"a}ki-Opas and Mari H{\"a}m{\"a}l{\"a}inen and Moilainen, {Lauri J.} and Raisa Haavikko and Ahonen, {Tiina J.} and Sami Alakurtti and Moreira, {V{\^a}nia M.} and Katsuhiko Muraki and Jari Yli-Kauhaluoma and Eeva Moilainen",
note = "This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Chemical Neuroscience, copyright {\circledC} 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.",
year = "2019",
month = "6",
day = "19",
doi = "10.1021/acschemneuro.9b00083",
language = "English",
volume = "10",
pages = "2848--2857",
journal = "ACS Chemical Neuroscience",
issn = "1948-7193",
publisher = "American Chemical Society",
number = "6",

}

Mäki-Opas, I, Hämäläinen, M, Moilainen, LJ, Haavikko, R, Ahonen, TJ, Alakurtti, S, Moreira, VM, Muraki, K, Yli-Kauhaluoma, J & Moilainen, E 2019, 'Pyrazine-fused triterpenoids block the TRPA1 ion channel in vitro and inhibit TRPA1-mediated acute inflammation in vivo', ACS Chemical Neuroscience, vol. 10, no. 6, pp. 2848-2857. https://doi.org/10.1021/acschemneuro.9b00083

Pyrazine-fused triterpenoids block the TRPA1 ion channel in vitro and inhibit TRPA1-mediated acute inflammation in vivo. / Mäki-Opas, Ilari; Hämäläinen, Mari; Moilainen, Lauri J.; Haavikko, Raisa; Ahonen, Tiina J.; Alakurtti, Sami; Moreira, Vânia M.; Muraki, Katsuhiko; Yli-Kauhaluoma, Jari; Moilainen, Eeva.

In: ACS Chemical Neuroscience, Vol. 10, No. 6, 19.06.2019, p. 2848-2857.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pyrazine-fused triterpenoids block the TRPA1 ion channel in vitro and inhibit TRPA1-mediated acute inflammation in vivo

AU - Mäki-Opas, Ilari

AU - Hämäläinen, Mari

AU - Moilainen, Lauri J.

AU - Haavikko, Raisa

AU - Ahonen, Tiina J.

AU - Alakurtti, Sami

AU - Moreira, Vânia M.

AU - Muraki, Katsuhiko

AU - Yli-Kauhaluoma, Jari

AU - Moilainen, Eeva

N1 - 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.

PY - 2019/6/19

Y1 - 2019/6/19

N2 - 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.

AB - 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.

KW - transient receptor potential channels

KW - TRPA1

KW - inflammation

KW - pain

KW - natural compounds

KW - triterpenoids

UR - https://pubs.acs.org/journal/acncdm

U2 - 10.1021/acschemneuro.9b00083

DO - 10.1021/acschemneuro.9b00083

M3 - Article

VL - 10

SP - 2848

EP - 2857

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

SN - 1948-7193

IS - 6

ER -