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Prostaglandin-Independent Anovulatory Mechanism of Indomethacin Action: Inhibition of Tumor Necrosis Factor -Induced Sheep Ovarian Cell Apoptosis¹

^a Department of Animal Science, University of Wyoming, Laramie, Wyoming 82071

Indomethacin, a nonsteroidal anti-inflammatory agent, is a potent inhibitor of ovulation in vertebrates. The presumptive obligate anovulatory mode of indomethacin action is via suppression of ovarian prostaglandin production. We report that a very high systemic dose of indomethacin (800 mg i.m.) is required to block ovulation in gonadotropin-treated anestrous ewes. A lower dose of indomethacin (200 mg), which negated the preovulatory rise in follicular prostaglandin (PGF₂) biosynthesis, did not prevent ovulation. Endothelial secretion of tumor necrosis factor (TNF)- within the apical follicular wall (prospective site of rupture) was not altered by indomethacin; notwithstanding, the apoptosis (DNA-fragmentation)-inducing effect of TNF- (a determinant of ovulatory stigma formation) was attenuated by 800 (but not 200) mg indomethacin. A suprapharmacological concentration of indomethacin also was necessary to protect ovarian surface epithelial cells from a (prostaglandin-independent) cytotoxic effect of TNF- in vitro. It is concluded that indomethacin inhibits ovulation by anti-apoptotic mechanisms that can be dissociated from the paradigm of prostanoid down-regulation.

¹ Supported by USDA-NRI grant 95–37203–2131.

² Correspondence: W.J. Murdoch, Department of Animal Science, P.O. Box 3684, University of Wyoming, Laramie, WY 82071. FAX: 307 766 2355; wmurdoch{at}uwyo.edu

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