The Lipoxygenase Inhibitor, Nordihydroguaiaretic Acid, Inhibits Ovulation and Reduces Leukotriene and Prostaglandin Levels in the Rat Ovary1

Abstract

Eicosanoids, the active metabolites of arachidonic acid, are grouped into cyclooxygenase products (prostaglandins [PGs] and thromboxanes) and lipoxygenase products (leukotrienes [LTs] and lipoxins). Numerous studies suggest a role for the lipoxygenase system in ovulation. The aim of this study was to further characterize the effects of lipoxygenase inhibition and the interactions of the lipoxygenase and cyclooxygenase systems in the rat ovary during ovulation. The lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA), was administered in vivo and in the isolated perfused rat ovary to determine its effect on ovulation rate. The in vivo study confirmed the inhibitory effect of NDGA, and in the perfusion experiments, NDGA caused a dose-dependent reduction in the ovulation rate. To further define the interaction between the lipoxygenase and cyclooxygenase systems, a second set of perfusions was performed with NDGA (10 microM) and the combination of NDGA (10 microM) plus a nonselective cyclooxygenase inhibitor, indomethacin (10 microM). NDGA significantly reduced the number of ovulations compared to that in controls. The ovulation rate for the combination of NDGA+indomethacin was also significantly lower than in controls but not different from that in the NDGA-treated group. Steroidogenesis was decreased only in the NDGA+indomethacin perfusions. Ovarian tissue PGE2 and PGF2alpha levels in the NDGA-treated ovaries were significantly suppressed compared to those in controls. Almost a complete block of PGE2 and PGF2alpha was seen in the NDGA+indomethacin group. LTB4 levels in the 10-h-perfused ovarian tissues were significantly decreased by NDGA compared to those in control tissues. Furthermore, LTB4 (3 microg added twice) completely reversed the inhibitory effect of 0.1 microM NDGA on ovulation rate and partially reversed the effect of 10 microM NDGA in the perfusion model. These results demonstrate that the products of the lipoxygenase pathway, especially LTB4, are important in the process of ovulation in this cyclically ovulating species. The interconnected lipoxygenase and cyclooxygenase pathways may optimize ovulation and facilitate steroidogenesis.

A Novel Pathway Involving Progesterone Receptor, 12/15-Lipoxygenase-derived Eicosanoids, and Peroxisome Proliferator-activated Receptor γ Regulates Implantation in Mice

“…Although the HETEs and HODEs oppose inflammatory responses in certain tissues, they are also associated with proinflammatory effects such as neutrophilic and eosiniphilic chemotaxis in other tissues (13)(14)(15)(16). Arachidonic and linoleic acids are also metabolized by the cyclooxygenase family to produce prostaglandin derivatives, which are well known mediators of inflammation, coagulation, and vasodilation (25). It is well documented that prostaglandins play essential roles in female reproduction.…”

Polar phospholipids from bovine endogenously oxidized low density lipoprotein interfere with follicular thecal function

“…These effects on female reproduction seem to occur in single-ovulating species at a preovulatory stage, since the development of dominant follicles was not a limiting factor in the bovine reproductive recovery postpartum at different energy balance and dietary fat levels (Beam & Butler 1997). Such responses mimic COX-2 gene knock-out and COX-2 inhibition in vivo and in vitro (Lim et al 1997, Mikuni et al 1998, Davis et al 1999. Thus, the present observations may contribute to a better understanding of the effects of lipid on female reproductive dysfunction.…”

“…These mediators include eicosanoids and oxygen radicals that are also required for the resumption of meiosis (Behrman et al 2001). Both lipoxygenase and cyclooxygenase pathways seem to play a role in the ovulatory process and are expressed in response to the preovulatory LH surge (Mikuni et al 1998). Little information exists about bovine thecal expression of COX-2 mRNA; therefore we focused on COX-2 mRNA expression reported to be a marker of the preovulatory follicle (Sirois et al 2004).…”

“…Consistent with the porcine data (Newman et al 2004), the concentration of oxylipids in the bovine follicle fluid did not correlate with other follicle parameters. However, uptake of or exposition to circulatory reactive phospholipids, such as PAF and PAF-like phospholipids, may be a source of interference with oxylipids produced by thecal cyclooxygenase and lipoxygenase pathways (Spector et al 2004) essential for ovulatory regulation (Mikuni et al 1998, Acosta et al 2003.…”

“…They are generated by strong oxidants that arise from very reactive superoxide anions with other radicals. The LH surge appears also to induce the ovulatory process via interconnected cyclooxygenase and lipoxygenase pathways (Mikuni et al 1998). These activities can generate oxylipids, such as oxy and epoxy eicosatrienoic acids and oxidized forms of phospholipids, including platelet-activating factor (PAF)-like compounds, all present in the follicular fluid (Lopez Bernal et al 1992, Narahara et al 1996, Newman et al 2004.…”