Effects of ginkgetin from Ginkgo biloba leaves on cyclooxygenases and in vivo skin inflammation

Ginkgetin, a biflavone from Ginkgo biloba leaves, was previously reported to be a phospholipase A, inhibitor and this compound showed the potent antiarthritic activity in rat adjuvant-induced arthritis as well as analgesic activity. This investigation was carried out to find effects on cyclooxygenase (COX)-1 and -2 including an in vivo effect. Ginkgetin (1 - 10 MM) and the biflavonoid mixture (10 - 50 pg/ml), mainly a 1:1 mixture of ginkgetin and isoginkgetin, from G. biloba leaves, inhibited production of prostaglandin E-2 from lipopolysaccharide-induced RAW 264.7 cells. This inhibition was mediated, at least in part, by down-regulation of COX-2 expression, but not by direct inhibition of COX-1 or COX-2 activity. Down-regulation of COX-2 by ginkgetin was also proved in the dorsal skin of ICR mouse treated by 12-O-tet- radecanoylphorbol 13-acetate (TPA). At total doses of 1,000 mug/site on the dorsal skin (15 mm X 15 mm), ginkgetin inhibited prostaglandin E-2 production by 65.6% along with a marked suppression of COX-2 induction, in addition, ginkgetin and the biflavonoid mixture (100 - 1,000 mug/ear) dose-dependently inhibited skin inflammation of croton oil induced ear edema in mice by topical application. The present study suggests that ginkgetin from G. biloba leaves down-regulates COX-2 induction in vivo and this down-regulating potential is associated with an anti-inflammatory activity against skin inflammatory responses.