Avarol inhibits TNF-α generation and NF-κB activation in human cells and in animal models

• DOI: 10.1016/j.lfs.2007.11.017
• Publication Date: 2007-12-06T16:36:44Z
• Authors: Maria Amigó; Miguel Payá; Aitana Braza-Boïls; Salvatore De Rosa; Maria Carmen Tere...
• Keywords: Inflammation; Keratinocytes; 0301 basic medicine; Hyperplasia; Dose-Response Relationship, Drug; Anti-Inflammatory Agents; NF-kappa B p50 Subunit; Antineoplastic Agents; Monocytes; Cell Line; 3. Good health; Disease Models, Animal; Mice; 03 medical and health sciences; Animals; Humans; Psoriasis; Tetradecanoylphorbol Acetate; Female; Epidermis; Inflammation Mediators; Sesquiterpenes; Peroxidase

Avarol is a marine sesquiterpenoid hydroquinone with interesting pharmacological properties including anti-inflammatory and antipsoriatic effects. In the present study we evaluated the pharmacological effect of avarol on some inflammatory parameters related to the pathogenesis of psoriasis. Avarol inhibited tumor necrosis factor-alpha (TNF-alpha) generation in stimulated human monocytes (IC(50) 1 microM) and TNF-alpha-induced activation of nuclear factor-kappaB (NF-kappaB)-DNA binding in keratinocytes. In the mouse air pouch model, administration of avarol produced a dose-dependent reduction of TNF-alpha generation (ED(50) 9.2 nmol/pouch) as well as of interleukin (IL)-1beta, prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) levels in pouch exudates. In the psoriasis-like model of 12-O-tetradecanoylphorbol-acetate-induced mouse epidermal hyperplasia, topical administration of avarol (0.6-1.2 micromol/site) reduced edema, myeloperoxidase activity, IL-1beta, IL-2 and eicosanoid levels in skin. Histopathological study confirmed the inhibition of epidermal hyperplasia as well as leukocyte infiltration. The reduction of cutaneous TNF-alpha by avarol was also detected by immunohistochemical analysis. Avarol was also capable of suppressing in vivo NF-kappaB nuclear translocation, determined in mouse skin. Our results suggested that antipsoriatic properties of avarol previously described could be mediated in part by the downregulation of several inflammatory biomarkers, such as TNF-alpha and NF-kappaB in psoriatic skin.