TLR4/NF-κB/TNFα and cAMP/SIRT1 signaling cascade involved in mediating the dose-dependent effect of cilostazol in ovarian ischemia reperfusion-induced injury.

Background: One of the most dangerous gynecological emergencies is ovarian ischemia that commonly occurs during surgical manipulation or presence of ovarian masses.

Objectives: finding new therapies to prevent the associated harmful effects of ischemia/reperfusion-induced damage is still a critical need. For the first time, we aimed to evaluate the possible role of phosphodiesterase (PDE) 3 A inhibitor (PDEI), cilostazol (CLZ) in the treatment of ovarian ischemia reperfusion induced damage (OIR).

Methods: Rats were divided into five groups; sham, OIR group; CLZ (5, 10, 20 mg/kg) was given orally with induced OIR. Different biochemical parameters were detected such as total anti-oxidant capacity (TAC), reduced glutathione (GSH), malondialdehyde (MDA), cyclic adenosine monophosphate (cAMP), sirtuin1 (SIRT1), toll like receptor 4 (TLR4), nuclear factor kappa b (NF-κB) and tumor necrosis factor alpha (TNFα). In addition, histopathological features, ovarian weight changes and casapse3 immunoexpression were detected.

Results: Data revealed significant increase in ovarian weight changes, MDA, TLR4, TNFα, NF-κB and caspase 3 expressions in OIR induced group. Moreover, OIR group had histopathological features of ovarian damage with depletion of cAMP, SIRT1, TAC and GSH.

Conclusion: CLZ could ameliorate OIR-induced damage due to PDE inhibition, anti-oxidant, anti-inflammatory and anti-apoptotic properties with modulation of TLR4/NF-κB/TNFα and cAMP/SIRT1 signaling pathways.