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. Moilanen, Raisa Haavikko, Tiina J. Ahonen, Sami Alakurtti, Vânia M. Moreira, Katsuhiko Muraki, Jari Yli-Kauhaluoma, Eeva Moilanen (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

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
DOIs
Publication statusPublished - 19 Jun 2019
MoE publication typeA1 Journal article-refereed

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

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

Cite this

Mäki-Opas, I., Hämäläinen, M., Moilanen, L. J., Haavikko, R., Ahonen, T. J., Alakurtti, S., ... Moilanen, 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 ; Moilanen, Lauri J. ; Haavikko, Raisa ; Ahonen, Tiina J. ; Alakurtti, Sami ; Moreira, Vânia M. ; Muraki, Katsuhiko ; Yli-Kauhaluoma, Jari ; Moilanen, 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.
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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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Mäki-Opas, I, Hämäläinen, M, Moilanen, LJ, Haavikko, R, Ahonen, TJ, Alakurtti, S, Moreira, VM, Muraki, K, Yli-Kauhaluoma, J & Moilanen, 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; Moilanen, Lauri J.; Haavikko, Raisa; Ahonen, Tiina J.; Alakurtti, Sami; Moreira, Vânia M.; Muraki, Katsuhiko; Yli-Kauhaluoma, Jari; Moilanen, Eeva (Corresponding Author).

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

Research output: Contribution to journalArticleScientificpeer-review

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AU - Mäki-Opas, Ilari

AU - Hämäläinen, Mari

AU - Moilanen, Lauri J.

AU - Haavikko, Raisa

AU - Ahonen, Tiina J.

AU - Alakurtti, Sami

AU - Moreira, Vânia M.

AU - Muraki, Katsuhiko

AU - Yli-Kauhaluoma, Jari

AU - Moilanen, Eeva

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