Betulin Derivatives Effectively Suppress Inflammation in Vitro and in Vivo

Mirka Laavola, Raisa Haavikko, Mari Hämäläinen, Tiina Leppänen, Riina Nieminen, Sami Alakurtti, Vania M. Moreira, Jari Yli-Kauhaluoma, Eeva Moilanen (Corresponding Author)

    Research output: Contribution to journalArticleScientificpeer-review

    29 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
    JournalJournal of Natural Products
    Volume79
    Issue number2
    DOIs
    Publication statusPublished - 2016
    MoE publication typeA1 Journal article-refereed

    Fingerprint

    Anti-Inflammatory Agents
    Inflammation
    Derivatives
    Betula
    Nitric Oxide Synthase Type II
    Plant Bark
    Chemokine CCL2
    Carrageenan
    Cyclooxygenase 2
    In Vitro Techniques
    betulin
    Gene expression
    Interleukin-6
    Nitric Oxide
    Steroids
    Cytokines
    Gene Expression
    Pharmaceutical Preparations
    betulinic acid

    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
    Laavola, Mirka ; Haavikko, Raisa ; Hämäläinen, Mari ; Leppänen, Tiina ; Nieminen, Riina ; Alakurtti, Sami ; Moreira, Vania M. ; Yli-Kauhaluoma, Jari ; Moilanen, Eeva. / Betulin Derivatives Effectively Suppress Inflammation in Vitro and in Vivo. In: Journal of Natural Products. 2016 ; Vol. 79, No. 2. pp. 274-280.
    @article{e66f411f75c84244a57281119a6e1586,
    title = "Betulin Derivatives Effectively Suppress Inflammation in Vitro and in Vivo",
    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.",
    author = "Mirka Laavola and Raisa Haavikko and Mari H{\"a}m{\"a}l{\"a}inen and Tiina Lepp{\"a}nen and Riina Nieminen and Sami Alakurtti and Moreira, {Vania M.} and Jari Yli-Kauhaluoma and Eeva Moilanen",
    year = "2016",
    doi = "10.1021/acs.jnatprod.5b00709",
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    Laavola, M, Haavikko, R, Hämäläinen, M, Leppänen, T, Nieminen, R, Alakurtti, S, Moreira, VM, Yli-Kauhaluoma, J & Moilanen, E 2016, 'Betulin Derivatives Effectively Suppress Inflammation in Vitro and in Vivo', Journal of Natural Products, vol. 79, no. 2, pp. 274-280. https://doi.org/10.1021/acs.jnatprod.5b00709

    Betulin Derivatives Effectively Suppress Inflammation in Vitro and in Vivo. / Laavola, Mirka; Haavikko, Raisa; Hämäläinen, Mari; Leppänen, Tiina; Nieminen, Riina; Alakurtti, Sami; Moreira, Vania M.; Yli-Kauhaluoma, Jari; Moilanen, Eeva (Corresponding Author).

    In: Journal of Natural Products, Vol. 79, No. 2, 2016, p. 274-280.

    Research output: Contribution to journalArticleScientificpeer-review

    TY - JOUR

    T1 - Betulin Derivatives Effectively Suppress Inflammation in Vitro and in Vivo

    AU - Laavola, Mirka

    AU - Haavikko, Raisa

    AU - Hämäläinen, Mari

    AU - Leppänen, Tiina

    AU - Nieminen, Riina

    AU - Alakurtti, Sami

    AU - Moreira, Vania M.

    AU - Yli-Kauhaluoma, Jari

    AU - Moilanen, Eeva

    PY - 2016

    Y1 - 2016

    N2 - 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.

    AB - 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.

    U2 - 10.1021/acs.jnatprod.5b00709

    DO - 10.1021/acs.jnatprod.5b00709

    M3 - Article

    VL - 79

    SP - 274

    EP - 280

    JO - Journal of Natural Products

    JF - Journal of Natural Products

    SN - 0163-3864

    IS - 2

    ER -

    Laavola M, Haavikko R, Hämäläinen M, Leppänen T, Nieminen R, Alakurtti S et al. Betulin Derivatives Effectively Suppress Inflammation in Vitro and in Vivo. Journal of Natural Products. 2016;79(2):274-280. https://doi.org/10.1021/acs.jnatprod.5b00709