Inhibition of Prostaglandin Production by a Structurally-Optimized Flavonoid Derivative, 2′,4′,7-Trimethoxyflavone and Cellular Action Mechanism

Flavonoids possess anti-inflammatory activity in vitro and in vivo. In order to find the anti-inflammatory flavone derivatives having optimum chemical structures, various flavones were previously synthesized and evaluated for their inhibitory activity of prostaglandin E2 (PGE2) production from lipopolysaccharide (LPS)-treated mouse macrophage cell line, RAW 264.7 cells. Through this screening procedure, 2′,4′,7-trimethoxyflavone (TMF) was selected for further pharmacological study. From the present investigation, it was found that TMF potently inhibited PGE2 production from LPS-treated RAW cells with an IC50 of 0.48 μM, compared to the IC50 values of 0.07 and 1.09 μM for NS-398 and wogonin. TMF, however, did not inhibit cyclooxygenase-2 (COX-2) activity or COX-2 expression level. Instead, TMF was proved to be a phospholipase A2 (PLA2) inhibitor. The IC50 values of TMF against secretory PLA2-IIA (sPLA2-IIA) and cytosolic PLA2 (cPLA2) were 70.5 and 70.4 μM, respectively. At doses of 10—250 μg/ear, TMF also showed in vivo anti-inflammatory activity by topical application against mouse croton oil-induced ear edema assay, suggesting a potential for new anti-inflammatory agent.