Dysidotronic acid, a new sesquiterpenoid, inhibits cytokine production andthe expression of nitric oxide synthase

In a previous study, we reported a new bioactive sesquiterpenoid, named dys idotronic acid, to be a potent, selective human synovial phospholipase A(2) inhibitor. Dysidotronic acid is a novel, non-complex manoalide analogue la cking the pyranofuranone ring. We now investigate the effect of this compou nd on cytokine, nitric oxide and prostanoid generation on the mouse macroph age cell line RAW 264.7, where it showed a dose-dependent inhibition with i nhibitory concentration 50% Values in the micromolar range. This effect was also confirmed in the mouse air pouch injected with zymosan. Dysidotronic acid inhibited the production of tumor necrosis factor alpha and interleuki n-l beta as well as the production of nitric oxide, prostaglandin E-2 and l eukotriene B-4. Decreased nitric oxide generation was the consequence of in hibition of the expression of nitric oxide synthase, whereas PGE(2) and LTB 4, reduction was due to inhibition of arachidonic acid bioavailability thro ugh a direct inhibitory effect of dysodotronic acid on secretory phospholip ase A(2). (C) 2001 Elsevier Science B.V. All rights reserved.