Betulin derivatives effectively suppress inflammation in vitro and in vivo

Mirka Laavola, Raisa Haavikko, Mari Hämäläinen, Tiina Leppänen, Riina Nieminen, Sami Alakurtti, Vânia M. Moreira, Jari Yli-Kauhaluoma, Eeva Moilanen

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Betulin is a pharmacologically active triterpenoid found in the bark of the birch tree (Betula sp. L.). Betulin and betulinic acid are structurally related to anti-inflammatory steroids, but little is known about their potential anti-inflammatory properties. In the present study, the inflammatory gene expression and the anti-inflammatory properties of betulin, betulinic acid, and 16 semisynthetic betulin derivatives were investigated. Betulin derivatives 3, 4, and 5 selectively inhibited the expression of the inducible nitric oxide synthase (iNOS) in a post-transcriptional manner. They also inhibited nitric oxide (NO) production but had no effect on the other inflammatory factors studied. More interestingly, a new anti-inflammatory betulin derivative 9 with a wide-spectrum anti-inflammatory activity was discovered. Compound 9 was found to suppress the expression of cytokines interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1), as well as that of prostaglandin synthase-2 (COX-2) in addition to iNOS. The in vivo anti-inflammatory effect of compound 9 was indicated via significant suppression of the carrageenan-induced paw inflammation in mice. The results show, for the first time, that the pyrazole-fused betulin derivative (9) and related compounds have anti-inflammatory properties that could be utilized in drug development.

Original languageEnglish
Pages (from-to)274-280
Number of pages7
JournalJournal of Natural Products
Volume79
Issue number2
Early online date14 Jan 2016
DOIs
Publication statusPublished - 26 Feb 2016

Keywords

  • animals
  • anti-inflammatory agents
  • betula
  • carrageenan
  • chemokine CCL2
  • cyclooxygenase 2
  • cytokines
  • dinoprostone
  • inflammation
  • interleukin-6
  • lipopolysaccharides
  • macrophages
  • male
  • mice
  • molecular structure
  • NF-kappa B
  • nitric oxide
  • nitric oxide synthase type II
  • triterpenes

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  • Cite this

    Laavola, M., Haavikko, R., Hämäläinen, M., Leppänen, T., Nieminen, R., Alakurtti, S., ... Moilanen, E. (2016). Betulin derivatives effectively suppress inflammation in vitro and in vivo. Journal of Natural Products, 79(2), 274-280. https://doi.org/10.1021/acs.jnatprod.5b00709