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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.
Eur J Pharmacol. 2007 Mar 22; 559(2-3):227-35.EJ

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.

Authors+Show Affiliations

Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17258194

Citation

Medeiros, Rodrigo, et al. "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." European Journal of Pharmacology, vol. 559, no. 2-3, 2007, pp. 227-35.
Medeiros R, Otuki MF, Avellar MC, et al. 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. Eur J Pharmacol. 2007;559(2-3):227-35.
Medeiros, R., Otuki, M. F., Avellar, M. C., & Calixto, J. B. (2007). 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. European Journal of Pharmacology, 559(2-3), 227-35.
Medeiros R, et al. 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. Eur J Pharmacol. 2007 Mar 22;559(2-3):227-35. PubMed PMID: 17258194.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Medeiros,Rodrigo, AU - Otuki,Michel F, AU - Avellar,Maria Christina W, AU - Calixto,João B, Y1 - 2006/12/29/ PY - 2006/05/04/received PY - 2006/12/05/revised PY - 2006/12/08/accepted PY - 2007/1/30/pubmed PY - 2007/5/10/medline PY - 2007/1/30/entrez SP - 227 EP - 35 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 559 IS - 2-3 N2 - 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. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/17258194/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_ DB - PRIME DP - Unbound Medicine ER -