Prostaglandin-independent anovulatory mechanism of indomethacin action: inhibition of tumor necrosis factor alpha-induced sheep ovarian cell apoptosis.
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 (PGF(2alpha)) biosynthesis, did not prevent ovulation. Endothelial secretion of tumor necrosis factor (TNF)-alpha within the apical follicular wall (prospective site of rupture) was not altered by indomethacin; notwithstanding, the apoptosis (DNA-fragmentation)-inducing effect of TNF-alpha (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-alpha in vitro. It is concluded that indomethacin inhibits ovulation by anti-apoptotic mechanisms that can be dissociated from the paradigm of prostanoid down-regulation.
Murdoch
W J
WJ
Department of Animal Science, University of Wyoming, Laramie, Wyoming 82071, USA. wmurdoch@uwyo.edu
Lund
S A
SA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053938:DNA Fragmentation; D015237:Dinoprost / Q000096:biosynthesis; D004847:Epithelial Cells / Q000502:physiology; D005260:Female; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology*; D006080:Ovarian Follicle / Q000187:drug effects / Q000378:metabolism; D010053:Ovary / Q000166:cytology*; D010060:Ovulation / Q000187:drug effects*; D012756:Sheep / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D014409:Tumor Necrosis Factor-alpha; D015237:Dinoprost; D007213:Indomethacin