Mechanisms underlying the inhibitory actions of the pentacyclic triterpene alpha-amyrin in the mouse skin inflammation induced by phorbol ester 12-O-tetradecanoylphorbol-13-acetate
Otuki, Michel F.
Avellar, Maria Christina W.
Calixto, Joao B.
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The present study evaluated some of the mechanisms through which alpha-amyrin, a pentacyclic triterpene isolated from Protium Kleinii and other plants, exerts its effects against 12-O-tetradecanoylphorbol-acetate (TPA)-induced skin inflammation in mice. Topical application of a-amyrin (0.1-1 mg/ear) dose-dependently inhibited TPA-induced increase of prostaglandin E-2 (PGE(2)) levels. in contrast with the selective cyclooxygenase (COX)-1 SC560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole] or COX-2 rofecoxib inhibitors, alpha-amyfin failed to alter either COX-1 or COX-2 activities in vitro. Western blot analysis revealed that a-amyrin dose-dependently inhibited TPA-induced COX-2 expression in the mouse skin. the evaluation of nuclear factor-kappa B (NF-kappa B) pathway revealed that topical treatment with alpha-amyrin is able to prevent I kappa B alpha degradation, p65/RelA phosphorylation and NF-kappa B activation. Moreover, alpha-amyrin given topically dose-dependently inhibited the activation of upstream protein kinases, namely extracellular signal-regulated protein kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and protein kinase C (PKC)alpha, following topical TPA treatment. Collectively, present results suggest that topical skin application of alpha-amyrin exerts a strong and rapid onset inhibition of TPA-induced inflammation. These effects seem to be associated with the suppression of skin PGE(2) levels by mechanisms involving the suppression of COX-2 expression, via inhibition of upstream protein kinases - namely ERK, p38 MAPK and PKC alpha - and blocking of NF-kappa B activation. These results indicate that a-amyrin-derivative could be potentially relevant for the development of a topical agent for the management of inflammatory diseases. (c) 2006 Elsevier B.V. All rights reserved.
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