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 journalArticlepeer-review

44 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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