Anti-inflammatory activity of 21(α, β)-methylmelianodiols, novel compounds from Poncirus trifoliata Rafinesque

The fruits of Poncirus trifoliata (L.) are widely used in Oriental medicine as a remedy for allergic inflammation. As a part of our program to screen medicinal plants for potential anti-inflammatory compounds, 21 alpha-methylmelianodiol (21 alpha-MMD) and 21 beta-methylmelianodiol (21 beta-MMD), which are two isomers of 21-methylmelianodiol isolated from the fruits of P. trifoliata for the first time, were found to inhibit nitric oxide (NO)production in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. 21 alpha-MMDand 21 beta-MMD attenuated LPS-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 protein expressions as well as the mRNA levels of iNOS, COX-2, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta). To investigate the mechanism involved, we examined the effect of 21 alpha-MMD and 21 beta-MMD on LPS-induced nuclear factor-kappa B (NF-kappa B) activation. Both 21 alpha-MMD and 21 beta-MMD significantly inhibited LPS-induced NF-kappa B transcriptional activity in RAW 264.7 macrophages. Moreover, the in vivo anti-inflammatory effect of 21 alpha-MMD was examined in two mouse models of acute inflammation. In the carrageenan-induced paw edema model, administration of 21 alpha-MMD (20 and 100 mg/kg, i.p.) dose-dependently reduced paw swelling. In addition, 21 alpha-MMD significantly inhibited the dye leakage in an acetic acid-induced vascular permeability assay. Taken together, our data indicate that 21-methylmelianodiol is an important constituent of the fruit of P. trifoliata, and that the inhibition of iNOS and COX-2 expression by 21 alpha-MMD and 21 beta-MMD might be one of the mechanisms responsible for their anti-inflammatory effects. (c) 2007 Elsevier B.V. All rights reserved.