title: The selective prostaglandin EP4 agonist, APS-999 Na, induces follicular growth and maturation in the rat ovary.
abstract: OBJECTIVE
  It is known that prostaglandin E2 (PGE2) plays a crucial role in the ovulation process. PGE2 mediates its actions through four subtypes of receptors designated EP1-EP4. However, the nature of the ovulation-promoting effect of PGE2 is not well understood. We have carried out this in vivo research utilizing a new selective EP4 receptor agonist (EP4A; APS-999 Na) to investigate its role in folliculogenesis aiming at more understanding of the biological mechanism of action of PGE2.
  
  
  METHODS
  Immature, 22 day old Wistar rats were used. Animals were injected once either with placebo, 20 IU pregnant mare serum gonadotrophin (PMSG), or EP4A (10, 20 or 50 microg). In other experiments, EP4A was injected in PMSG stimulated rats. Ovarian follicle growth and development was assessed through total count and size measurement of ovulatory follicles in whole ovaries of the investigated groups. Utilizing immunohistochemistry, the spatial localization of the EP4 receptor in immature rat ovary and IL-8 pattern of expression after EP4A injection was also investigated.
  
  
  RESULTS
  Our study showed that injection of EP4A resulted in increased follicle growth and development compared with the control, in a time- and dose-dependent manner. The highest values for follicle count and size were observed 12 and 24 h after EP4A injection. EP4A induced follicle growth with morphological characteristics similar to that induced by the standard PMSG. Most dense immune staining for EP4 receptor was noticed in proliferating granulosa cells of the secondary follicles while those of the primordial and primary follicles were not stained. EP4A injection induced the expression of IL-8 in the follicles.
  
  
  CONCLUSIONS
  Our study revealed that: (i) the localization of EP4 receptor in the ovary implies a role in follicle growth, (ii) PGE2 induced ovarian follicle growth and development is mediated at least in part through the EP4 receptor, (iii) the action of EP4A is mediated through IL-8 up regulation and (iv) the new EP4A could be a promising reagent for various systems used to induce follicle maturation in clinical or agricultural fields. This knowledge may provide useful targets for manipulation of infertility.
authors.affiliation: Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, 431-3192 Hamamatsu, Shizuoka, Japan. nagwaebrahim@hotmail.com
authors.forename: Nagwa
authors.initials: N
authors.lastname: El-Nefiawy
authors.forename: Khaled
authors.initials: K
authors.lastname: Abdel-Hakim
authors.forename: Naohiro
authors.initials: N
authors.lastname: Kanayama
mesh_terms: D000818:Animals; D015232:Dinoprostone / Q000502:physiology; D005260:Female; D006064:Gonadotropins, Equine / Q000494:pharmacology; D007150:Immunohistochemistry; D016209:Interleukin-8 / Q000378:metabolism; D006080:Ovarian Follicle / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018078:Receptors, Prostaglandin E / Q000819:agonists* / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: C429966:APS-999 Na; D006064:Gonadotropins, Equine; D016209:Interleukin-8; C545652:Ptger4 protein, rat; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013438:Sulfhydryl Compounds; D013876:Thiophenes; D015232:Dinoprostone