Kinetics of radical-scavenging activity of hesperetin and hesperidin and their inhibitory activity on COX-2 expression.

The radical-scavenging activities of the flavanones hesperetin and hesperidin were investigated by differential scanning calorimetry (DSC) monitoring of the polymerization of methyl methacrylate initiated by 2,2'-azobisisobutyronitrile (AIBN, an R* radical) or benzoylperoxide (BPO, a PhCOO* radical) at 70 degrees C under nearly anaerobic conditions. Their stoichiometric factor (number of free radicals trapped by one mole of antioxidant moiety (n)) and the ratio of the rate constant of inhibition to that of propagation (k(inh)/k(p)) were determined and compared with that for trolox The n value declined in the order trolox (2.0) > hesperetin (0.8) > hesperidin (0.2) in the AIBN system, whereas it declined in the order hesperetin (0.9) > trolox (0.1) > hesperidin (0.0) in the BPO system. The k(inh)/k(p) value declined in the order hesperidin (195) > hesperetin (33) > trolox (12) in the AIBN system, whereas it declined in the order hesperidin (362) > trolox (127) > hesperetin (18) in the BPO system. The n value of about 1 for hesperetin with a relatively small k(inh)/k(p) value suggests the formation of dimers, as a result of the coupling reaction of phenolic monomers. In contrast, n values << 1 for hesperidin and trolox in the BPO system resulted in very high values for k(inh)/k(p). Hesperidin was also much more able to suppress the growth of methyl methacrylate radicals, although its n value was small, suggesting that this compound may also suppress polyunsaturated fatty acid radicals. In the concentration range 250-500 microM, hesperetin and hesperidin showed potent inhibition of LPS-induced expression of the COX-2 gene in RAW 264.7 cells, suggesting the anti-inflammatory activity of these compounds. The ability of hesperetin and hesperidin to suppress COX-2 gene expression may be a consequence of their antioxidant activity.

Ferulic acid dimer inhibits lipopolysaccharide-stimulated cyclooxygenase-2 expression in macrophages.

Phenylpropanoids may act as nonsteroidal anti-inflammatory drug (NSAID)-like compounds. 4-cis, 8-cis-Bis (4-hydroxy-3-methoxyphenyl)-3, 7-dioxabicyclo-[3.3.0]octane-2,6-dione (bis-FA, compound 2), a dimer of ferulic acid, was synthesized from ferulic acid (1), and its effect on lipopolysaccharide (LPS)-stimulated cyclooxygenase-2 (COX-2) expression in RAW 264.7 cells was compared with those of the parent ferulic acid (1) and of iso-ferulic acid (3-hydroxy-4-methoxycinnamic acid) (3). LPS-induced gene expression of COX-2 was markedly inhibited by compound 2 at a concentration of 10 microM and by compound 3 at 100 microM, but was not inhibited by compound 1 at 100 microM. This observation suggests that compound 2 may possess potent anti-inflammatory activity. These ferulic acid-related compounds were able to scavenge the stable 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radical. The 50% inhibitory concentration for DPPH radicals declined in the order 3 (40.20 mM) > 2 (3.16 mM) > 1 (0.145 mM). Compound 1 possessed potent anti-radical activity, but no COX-2 inhibitory activity, which may be a result of enhancement of its conjugate properties by abstraction of an H atom from the phenolic OH group, causing loss of phenolic function. In contrast, inhibition of COX-2 expression by compounds 2 and 3 could be caused by their increased phenolic function, which is associated with decreased anti-radical activity. Compounds 2 and 3, particularly 2, may have potential as NSAID-like compounds.