The Selective Prostaglandin Endoperoxide Synthase-2 Inhibitor, NS-398, Reduces Prostaglandin Production and Ovulation In Vivo and In Vitro in the Rat1

Mikuni, M; Pall, Marita; Peterson, C. Matthew; Peterson, Craig A.; Hellberg, Pår; Brännström, Mats; Richards, JoAnne S.; Hedin, Lars O.

doi:10.1095/biolreprod59.5.1077

Cited by 80 publications

(43 citation statements)

References 50 publications

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“…COX-2 catalyzes the production of prostaglandins known to be necessary for ovulation (38); mice null for COX-2 have severely impaired ovulation (39,40). COX-2 mRNA was undetectable by RT-PCR analysis in ovaries of PMSG-treated PRϩ͞Ϫ and PRKO mice but was induced rapidly by hCG in ovaries of both genotypes (Fig.…”

Section: Ovarian Expression Of Prmentioning

confidence: 95%

Progesterone-regulated genes in the ovulation process: ADAMTS-1 and cathepsin L proteases

Robker

Russell

Espey

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

484

369

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Ovulation is a precisely timed process by which a mature oocyte is released from an ovarian follicle. This process is initiated by the pituitary surge of luteinizing hormone (LH), is temporally associated with transcriptional regulation of numerous genes, and is presumed to involve the synthesis and͞or activation of specific proteases that degrade the follicle wall. The progesterone receptor (PR), a nuclear receptor transcription factor, is induced in granulosa cells of preovulatory follicles in response to the LH surge and has been shown to be essential for ovulation, because mice lacking PR fail to ovulate and are infertile. Using these mice as a model in which to elucidate PR-regulated genes in the ovulation process, we show that the matrix metalloproteinases MMP-2 and MMP-9 are not targets of PR during ovulation. In contrast, two other proteases, ADAMTS-1 (A disintegrin and metalloproteinase with thrombospondin-like motifs) and cathepsin L (a lysosomal cysteine protease), are transcriptional targets of PR action. ADAMTS-1 is induced after LH stimulation in granulosa cells of preovulatory follicles and depends on PR. Cathepsin L is induced in granulosa cells of growing follicles by follicle-stimulating hormone, but the highest levels of cathepsin L mRNA occur in preovulatory follicles in response to LH in a PR-dependent manner. The identification of two regulated proteases in the ovary, together with their abnormal expression in anovulatory PR knockout mice, suggests that each plays a critical role in follicular rupture and represents a major advance in our understanding of the proteolytic events that control ovulation.

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Section: Ovarian Expression Of Prmentioning

confidence: 95%

Progesterone-regulated genes in the ovulation process: ADAMTS-1 and cathepsin L proteases

Robker

Russell

Espey

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

484

369

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“…Accumulating evidence in multiple species including mouse (Lim et al 1997, Davis et al 1999, rat (Mikuni et al 1998, Gaytan et al 2002, sheep (Murdoch et al 1986), pig (Downey & Ainsworth 1980), monkey (Duffy & Stouffer 2002), and cattle (Peters et al 2004) indicates that intrafollicular synthesis of prostanoids in response to the LH surge is critical for the ovulatory process. The cyclooxygenase (COX)-2 enzyme, which catalyzes the rate limiting step in intrafollicular prostanoid synthesis, is induced within the granulosa layer of rat (Sirois et al 1992), equine (Sirois & Dore 1997), and bovine preovulatory follicles (Sirois 1994, Tsai et al 1996 in response to the LH surge.…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiling of bovine preovulatory follicles: gonadotropin surge and prostanoid-dependent up-regulation of genes potentially linked to the ovulatory process

Jimenez-Krassel

Ireland

et al. 2009

Reproduction

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The molecular mechanisms of ovulation and luteinization have not been well established, partially due to lack of a comprehensive understanding of functionally significant genes up-regulated in response to an ovulatory stimulus and the signaling pathways involved. In the present study, transcripts increased in bovine preovulatory follicles following a GnRH-induced LH surge were identified using microarray technology. Increased expression of 368 and 878 genes was detected at 12 (368 genes) and 20 h (878 genes) following GnRH injection. The temporal, cell specific and prostanoid-dependent regulation of selected genes (ADAM10, DBI, CD36, MTSS1, TFG, and RABGAP1) identified from microarray studies and related genes (ADAM17 and AREG) of potential significance were also investigated. Expression of mRNA for DBI and CD36 was simultaneously up-regulated in theca and granulosa cells (GC) following the LH surge, whereas temporal regulation of ADAM10, MTSS1, TFG, and RABGAP1 was distinct in the two cell compartments and increased granulosa TFG and RABGAP1 mRNA were prostanoid dependent. AREG mRNA was increased in theca and GCs at 12 and 24 h following GnRH injection. ADAM17 mRNA was increased in theca, but reduced in GCs 24 h following GnRH injection. The increased ADAM17 and AREG mRNA were prostanoid dependent. ADAM10 and ADAM17 protein were increased specifically in the apex but not the base of preovulatory follicles and the increase in ADAM17 was prostanoid dependent. Results reveal novel information on the regulation of preovulatory gene expression and suggest a potential functional role for ADAM10 and ADAM17 proteins in the region of follicle rupture.

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“…The inducible type PTGS2 and PGE 2 -EP 2 receptor signaling play crucial roles in proper follicle rupture and cumulus expansion in a murine model of induced ovulation (Hizaki et al 1999, Matsumoto et al 2001, Ochsner et al 2003, Sirois et al 2004b. Pharmacological or genetical inhibition of PTGS2 activity results in potential suppression of ovulation (Espey et al 1986, Lim et al 1997, Mikuni et al 1998a. On the other hand, the involvement of the alternative LOX pathway in ovulation process was first suggested by Reich et al (1983) who demonstrated that chemical inhibition of LOX blunted ovulatory response in gonadotropins-primed immature rats.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of ovulation by a lipoxygenase inhibitor involves reduced cyclooxygenase-2 expression and prostaglandin E2 production in gonadotropin-primed immature rats

Kurusu¹,

Jinno²,

Ehara³

et al. 2009

Reproduction

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Potential roles of cyclooxygenase (COX) pathway of arachidonic acid (AA) metabolism are established in a murine model of induced ovulation. Pharmacological inhibition of an alternative lipoxygenase (LOX) pathway has been shown to cause defective ovulation, but the mechanism is still undefined. This study investigated the effects of two LOX inhibitors and their time dependency on ovulation and COX activity in gonadotropins (eCG and human chorionic gonadotropin (hCG))-primed immature rats. Intra-ovarian bursal treatment with a general LOX inhibitor nordihydroguaiaretic acid (NDGA) at 0 h post-hCG (hCG0h) dose dependently inhibited ovulation rate. The drug was still but less effective when treated at hCG6h. A more specific inhibitor, 3,4-dihydroxyphenyl ethanol (DPE) was also inhibitory when treated at hCG0h but not at hCG6h. Interestingly, treatment with DPE at hCG0h resulted in attenuated expression of immunoreactive PTGS2 in granulosa layers and concomitant decrease in ovarian prostaglandin E 2 (PGE 2 ) content at hCG8h. NDGA treatment reduced immunoreactive PTGS2. Ovulatory impairment by both inhibitors was prevented by systemic administration of PGE 2 at hCG6h. Immunohistochemistry revealed the expression of ALOX5 and ALOX12 in both thecal and granulosa layers of preovulatory follicles and, notably, the augmented immunoreactivities during 8 h after hCG treatment. Our results indicate the probable presence of multiple LOX isoforms and that specific inhibition of LOX at an early stage of hCG-signaling led to reduced PTGS2 activity and thus defective ovulation. They reveal a probable relationship between two pathways of AA metabolism and account at least partly for the mechanism by which the LOX inhibitor causes impaired ovulation.

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The Selective Prostaglandin Endoperoxide Synthase-2 Inhibitor, NS-398, Reduces Prostaglandin Production and Ovulation In Vivo and In Vitro in the Rat1

Cited by 80 publications

References 50 publications

Progesterone-regulated genes in the ovulation process: ADAMTS-1 and cathepsin L proteases

Progesterone-regulated genes in the ovulation process: ADAMTS-1 and cathepsin L proteases

Gene expression profiling of bovine preovulatory follicles: gonadotropin surge and prostanoid-dependent up-regulation of genes potentially linked to the ovulatory process

Inhibition of ovulation by a lipoxygenase inhibitor involves reduced cyclooxygenase-2 expression and prostaglandin E2 production in gonadotropin-primed immature rats

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