Antipsoriatic effects of avarol-3'-thiosalicylate are mediated by inhibition of TNF-alpha generation and NF-kappaB activation in mouse skin.
OBJECTIVE
Avarol is a marine sesquiterpenoid hydroquinone with anti-inflammatory and antipsoriatic properties. The aim of this study was to evaluate the in vitro and in vivo pharmacological behaviour of the derivative avarol-3'-thiosalicylate (TA) on some inflammatory parameters related to the pathogenesis of psoriasis.


METHODS
Human neutrophils and monocytes as well as the human keratinocyte cell line HaCaT were used to study the effect of TA on oxidative stress, the arachidonic acid pathway, tumour necrosis factor-alpha (TNF-alpha) release and nuclear factor-kappaB (NF-kappaB) activation. All these parameters were also determined in vivo using the zymosan induced mouse air pouch model and the 12-O-tetradecanoylphorbol-13-acetate (TPA) induced mouse epidermal hyperplasia model.


RESULTS
TA showed antioxidant properties in human neutrophils and in the hypoxanthine/xanthine oxidase assay. This compound reduced, in a concentration-dependent manner, leukotriene B(4), prostaglandin E(2) and TNF-alpha production in activated leukocytes. Oral and intrapouch administration of TA in the mouse air pouch model produced a dose-dependent reduction of all these inflammatory mediators. TA also inhibited secretory phospholipase A(2) activity and NF-kappaB DNA-binding in HaCaT keratinocytes. In TPA-induced mouse epidermal hyperplasia, topical administration of TA reduced oedema, leukocyte infiltration, eicosanoid levels and TNF-alpha in skin. In addition, interleukin (IL)-1beta and IL-2 production were also inhibited. Finally, TA was also capable of suppressing NF-kappaB nuclear translocation in vivo.


CONCLUSIONS
TA inhibited several key biomarkers up-regulated in the inflammatory response of psoriatic skin and this compound could be a promising antipsoriatic agent.
Amigó
M
M
Departament de Farmacologia, Facultat de Farmàcia, Universitat de València, Burjassot, Valencia, Spain.
Payá
M
M
De Rosa
S
S
Terencio
M C
MC
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000188:drug therapy / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011565:Psoriasis / Q000188:drug therapy* / Q000503:physiopathology; D012459:Salicylates / Q000008:administration & dosage / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects* / Q000378:metabolism
D000975:Antioxidants; D018836:Inflammation Mediators; D016328:NF-kappa B; D012459:Salicylates; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; C493040:avarol-3'-thiosalicylate; D016718:Arachidonic Acid