BIOLOGY OF THE FEMALE REPRODUCTIVE TRACT
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(550) INHIBITION OF UTERINE PROSTAGLANDIN PRODUCTION MAY CONTRIBUTE TO IMPROVED FECUNDITY IN MICE CAUSED BY PAF ANTAGONISTS.
Siegel, Todd1, Kamicker, Barbara1, Lee, Yung1, Westbrook, Simon2, Mills, Brian2, Ricketts, Anthony1, 1 Pfizer Global Research and Development, Groton, CT2 Pfizer Global Research and Development, Sandwich, GB
ABSTRACT- The best known role for platelet activating factor (PAF) in pregnancy is its trophic effect on the early embryo. However blocking PAF later in pregnancy increases numbers of offspring in mice indicating a different role. In humans (domestic animals) PAF stimulates (PAF receptor antagonist inhibits) uterine production of luteolytic prostaglandin (PG). We investigated mechanistic links between PAF antagonist inhibition of PG production and enhanced fecundity in the mouse. Our objectives were to establish that: 1) PAF antagonist modipafant (MOD) inhibits uterine PG production in endometrial cells, 2) this activity is expressed in an in vivo PAF challenge model, 3) MOD enhances corpus luteum (CL) function, & 4) there is a fecundity benefit for a PAF antagonist in an embryo loss model. In the BEND endometrial cell line PAF stimulated PGE2 & PGF2 production by 9- & 2.5-fold respectively with a 3-fold increase in COX2 mRNA. PAF-stimulated PG was inhibited by MOD with IC50 = 100 nM and by structurally distinct PAF antagonists ginkolide B & CV3988. In addition plasma concentrations of 13,14-dihydro-15-keto-PGF2 (PGFM) were stimulated (P= 0.0014) in mice challenged with 167 g/kg PAF at D4 of pseudopregnancy (PSP). MOD given at 1 mg/kg twice daily from D1 of PSP reduced PGFM plasma concentrations of mice challenged with PAF on D5 of PSP to those of control mice (P= 0.0209). There was no significant inhibition of PGFM by MOD when mice were challenged with PAF on D1 of PSP. In several species peak levels of uterine PAF receptors occur around D5 post-estrus & trough levels occur close to estrus; hence our results are consistent with a uterine origin for the PAF-stimulated PGFM. We also observed increased plasma progesterone in mice treated with MOD from D1 to D6 of PSP (7.76 to 11.47 ng/ml). We then showed that the duration of PSP was extended (15 vs 10 days; P = 0.024) in mice given 1 mg/kg MOD which could indicate a greater lifespan for the CL. In the CBAxDBA embryo loss model ginkolide B improved embryo survival from 55 to 72%. Our results are consistent with antagonism of PAF reducing luteolytic PGs from the uterus & increasing progesterone from and prolonging lifespan of the CL and hence enhancing embryo survival. Further work is needed to extend these findings to humans or livestock species.
KEY WORDS: PAF, prostaglandin, pseudopregnancy, mouse