title: Sildenafil (Viagra®) blocks inflammatory injury in LPS-induced mouse abortion: A potential prophylactic treatment against acute pregnancy loss?
abstract: BACKGROUND
  Recurrent pregnancy losses (RPL) are common women's health issues. Inflammatory and thrombotic events have been associated with RPL including excessive production of cytokines, in particular TNF-α. However, mechanisms behind gestational losses are not yet fully understood. Sildenafil inhibits phosphodiesterase Type-5 (PDE5). This drug increases intracellular cyclic guanosine monophosphate, having vasodilatory and, more recently described, anti-inflammatory properties. PDE5 is present in murine and human uterus and placenta. Sildenafil is already used clinically for treatment of human fetal growth restriction (FGR). Our objective was to determine if Sildenafil alone or in combination with Heparin had protective effects in pregnant Swiss albino challenged to abort by lipopolysaccharide (LPS).
  
  
  METHODS
  Treatments (Sildenafil (50 mg/kg/day), Heparin (500 IU/Kg/day) or Sildenafil + Heparin at the same doses) were initiated the morning of copulation plug detection (gestational day (gd0)). On the 15th day of pregnancy, an intra-peritoneal injection of LPS (100 μg/kg) was administered. Untreated, pregnant mice challenged by LPS served as controls.
  
  
  RESULTS
  Assessments at 48 h after LPS revealed that Sildenafil + Heparin prevented fetal loss. Early assessments at 2 h after LPS indicated that the pretreatments prevented induction of inflammatory cytokine production (TNF-α, IL-1β/NF-κβ) and preserved placental histopathology.
  
  
  CONCLUSIONS
  Combined Sildenafil + Heparin therapy was superior to either treatment alone in most analyses. The known safety of Sildenafil and Heparin in human pregnancy suggests that usage of these combined agents may be of value for treatment of patients with impending pregnancy loss or prophylactically in women with a history of recurrent miscarriages.
authors: Ultrastructure Laboratory, Aggeu Magalhães Research Center, FIOCRUZ, Brazil; Department of Biomedical and Molecular Sciences, Queen's University, Canada. Electronic address: rayanalaluna@gmail.com.
authors: R L
authors: RL
authors: Luna
authors: Ultrastructure Laboratory, Aggeu Magalhães Research Center, FIOCRUZ, Brazil.
authors: A K S
authors: AK
authors: Nunes
authors: Ultrastructure Laboratory, Aggeu Magalhães Research Center, FIOCRUZ, Brazil.
authors: A G V
authors: AG
authors: Oliveira
authors: Ultrastructure Laboratory, Aggeu Magalhães Research Center, FIOCRUZ, Brazil.
authors: S M R
authors: SM
authors: Araujo
authors: Federal Rural University of Pernambuco, UFRPE, Brazil.
authors: A J J M
authors: AJ
authors: Lemos
authors: Ultrastructure Laboratory, Aggeu Magalhães Research Center, FIOCRUZ, Brazil.
authors: S W S
authors: SW
authors: Rocha
authors: Department of Biomedical and Molecular Sciences, Queen's University, Canada.
authors: B A
authors: BA
authors: Croy
authors: Ultrastructure Laboratory, Aggeu Magalhães Research Center, FIOCRUZ, Brazil.
authors: C A
authors: CA
authors: Peixoto
mesh_terms: D000026:Abortion, Habitual / Q000188:drug therapy; D000022:Abortion, Spontaneous / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010920:Placenta / Q000187:drug effects / Q000648:ultrastructure; D011247:Pregnancy; D000068677:Sildenafil Citrate / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D008070:Lipopolysaccharides; D058986:Phosphodiesterase 5 Inhibitors; D000068677:Sildenafil Citrate
keywords: Heparin; Miscarriage; Phosphodiesterase-5 inhibitor; Placenta; Ultrastructure