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. 2007 Mar 22;559(2-3):227-35.
doi: 10.1016/j.ejphar.2006.12.005. Epub 2006 Dec 29.

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

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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

Rodrigo Medeiros et al. Eur J Pharmacol. .

Abstract

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 alpha-amyrin (0.1-1 mg/ear) dose-dependently inhibited TPA-induced increase of prostaglandin E2 (PGE2) levels. In contrast with the selective cyclooxygenase (COX)-1 SC560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole] or COX-2 rofecoxib inhibitors, alpha-amyrin failed to alter either COX-1 or COX-2 activities in vitro. Western blot analysis revealed that alpha-amyrin dose-dependently inhibited TPA-induced COX-2 expression in the mouse skin. The evaluation of nuclear factor-kappaB (NF-kappaB) pathway revealed that topical treatment with alpha-amyrin is able to prevent IkappaB alpha degradation, p65/RelA phosphorylation and NF-kappaB 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 PGE2 levels by mechanisms involving the suppression of COX-2 expression, via inhibition of upstream protein kinases--namely ERK, p38 MAPK and PKCalpha--and blocking of NF-kappaB activation. These results indicate that alpha-amyrin-derivative could be potentially relevant for the development of a topical agent for the management of inflammatory diseases.

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