Abstract
Prostaglandin E2 (PGE2), the most relevant eicosanoid promoting inflammation and tumorigenesis, is formed by cyclooxygenases (COXs) and PGE2 synthases from free arachidonic acid. Preparations of the leaves of Salvia officinalis are commonly used in folk medicine as an effective antiseptic and anti-inflammatory remedy and possess anticancer activity. Here, we demonstrate that a standard ethyl acetate extract of S. officinalis efficiently suppresses the formation of PGE2 in a cell-free assay by direct interference with microsomal PGE2 synthase (mPGES)-1. Bioactivity-guided fractionation of the extract yielded closely related fractions that potently suppressed mPGES-1 with IC50 values between 1.9 and 3.5 μg/ml. Component analysis of these fractions revealed the diterpenes carnosol and carnosic acid as potential bioactive principles inhibiting mPGES-1 activity with IC50 values of 5.0 μM. Using a human whole-blood assay as a robust cell-based model, carnosic acid, but not carnosol, blocked PGE2 generation upon stimulation with lipopolysaccharide (IC50 = 9.3 μM). Carnosic acid neither inhibited the concomitant biosynthesis of other prostanoids [6-keto PGF1α, 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid, and thromboxane B2] in human whole blood nor affected the activities of COX-1/2 in a cell-free assay. Together, S. officinalis extracts and its ingredients carnosol and carnosic acid inhibit PGE2 formation by selectively targeting mPGES-1. We conclude that the inhibitory effect of carnosic acid on PGE2 formation, observed in the physiologically relevant whole-blood model, may critically contribute to the anti-inflammatory and anticarcinogenic properties of S. officinalis.
Footnotes
This work was supported by the Standortagentur Tirol and the Austrian Science Fund [Grant DNTI S10703].
Parts of this work were described previously: Koeberle A (2009) Identification and characterization of microsomal prostaglandin E2 synthase-1 inhibitors. Ph.D. thesis, Pharmaceutical Institute, University of Tuebingen, Tuebingen, Germany.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- COX
- cyclooxygenase
- 12-HHT
- 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid
- LPS
- lipopolysaccharide
- PG
- prostaglandin
- mPGES
- microsomal PGE2 synthase
- PBS
- phosphate-buffered saline
- HPLC
- high-performance liquid chromatography
- DMSO
- dimethyl sulfoxide
- ANOVA
- analysis of variance
- ELISA
- enzyme-linked immunosorbent assay
- HSD
- honestly significant difference
- LOQ
- limit of quantification
- CV4151
- (E)-7-phenyl-7-(3-pyridyl)-6-heptenoic acid
- MD52
- 2-(2-chlorophenyl)-1H-phenanthro[9,10-d]-imidazole
- MK-886
- 3-[1-(4-chlorobenzyl)-3-t-butylthio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid.
- Received February 29, 2012.
- Accepted April 13, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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