title: Cilostazol administered to female mice induces ovulation of immature oocytes: a contraceptive animal model.
abstract: OBJECTIVE
  Both Cilostamide and Org 9935 are phosphodiesterase 3A (PDE3A) inhibitors that were evaluated in rodents and monkeys for their non-steroidal contraceptive properties. Although both compounds inhibited oocyte maturation, an adverse effect on heart rate was observed. Cilostazol (CLZ, Pletal) is a safe PDE3A inhibitor that was recently reported to block pregnancy in naturally cycling mice. In this study, the dose, frequency, time of administration, and reversibility effects of CLZ on oocyte maturation were defined using superovulated mice.
  
  
  METHODS
  Superovulated mice were gavaged once or twice with 0, 7.5, or 15 mg CLZ at various times around the ovulatory stimulus. Ovulated oocytes were then evaluated for maturational stages.
  
  
  RESULTS
  CLZ resulted in mice ovulating significant numbers of immature oocytes when administered anytime between 9h before the ovulatory stimulus and 2 h after the stimulus. This inhibitory effect was greater when CLZ dose was increased, administered twice or closer to the time of the ovulatory stimulus. Conversely, ovulated immature oocytes resumed maturation in oviducts when CLZ dose was reduced, administered once and away from the time of the stimulus.
  
  
  CONCLUSIONS
  Controlling CLZ dose, frequency, and time of administration produced mice ovulating immature oocytes at different stages, which may be an advantage over the conventional collection of immature oocytes from ovaries. More importantly, the capability of a clinically approved PDE3A inhibitor, with a reasonable margin of safety, to arrest oocyte maturation over a wide range of administration times and at doses extrapolated from human therapeutic doses demonstrates the contraceptive capacity of CLZ.
authors.affiliation: College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, United States; Barz Center for Embryo Research and Infertility Treatment, 40 Koyah Street, Erbil, Iraq. Electronic address: amtaiyeb@aggienetwork.com.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Taiyeb
authors.affiliation: Barz Center for Embryo Research and Infertility Treatment, 40 Koyah Street, Erbil, Iraq.
authors.forename: Mundhir T
authors.initials: MT
authors.lastname: Ridha
authors.affiliation: Center for Aerosol & Nanomaterials Engineering, RTI International, NC 27709, United States.
authors.forename: Christie M
authors.initials: CM
authors.lastname: Sayes
authors.affiliation: College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, United States.
authors.forename: William L
authors.initials: WL
authors.lastname: Dees
authors.affiliation: College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, United States.
authors.forename: Duane C
authors.initials: DC
authors.lastname: Kraemer
mesh_terms: D000818:Animals; D000077407:Cilostazol; D005260:Female; D006736:Horses; D006801:Humans; D051379:Mice; D023421:Models, Animal; D009865:Oocytes / Q000187:drug effects* / Q000254:growth & development*; D013480:Superovulation / Q000187:drug effects* / Q000502:physiology; D013777:Tetrazoles / Q000008:administration & dosage*
chemical_list: D013777:Tetrazoles; D000077407:Cilostazol
keywords: Cilostazol; Contraceptives; Fertility; Immature oocytes; Ovulation; Superovulation