Obeticholic acid prevents cyclophosphamide-induced placental injury via SIRT1 and TLR4/NF-κB pathways.

Abstract

Background: The aim of the current study is to identify the possible protective effect of obeticholic acid (OCA) on placental injury caused by cyclophosphamide (CP). OCA was administered in the presence and absence of CP.

Methods: Thirty-two pregnant female rats were randomly assigned to four groups: control group, OCA group: received OCA (10 mg/kg /day, orally), CP group: received CP 20 mg/kg intraperitoneally at 12th day, OCA + CP group. Placental weight and placental growth factor (PlGF) were measured. Placental oxidative stress parameters (malondialdahide (MDA) and total antioxidant capacity (TAC)), besides Sirtuin type 1 (SIRT1), nuclear factor erythroid 2-related factor 2 (Nrf2), myeloid differentiation factor 88 (Myd88) and caspase-3 biomarkers, were evaluated. Nuclear factor-kappa B (NF-κB) and tumor necrosis factor-alpha (TNF-α) gene expression were also measured. Placental histopathological examination, toll- like receptor4 (TLR4) and forkhead-box transcription factor1 (FOXO1) immunohistochemical study were performed.

Results: CP significantly decreased PlGF, placental weight, TAC, SIRT1 and Nrf2 with increased placental MDA, Myd88, caspase-3, NF-κB and TNF-α. Histopathological findings of placental damage and high TLR4, FOXO1 immunoexpressions were detected. OCA significantly increased PlGF level, placental weight and normalized the distributed oxidative stress, inflammatory, and apoptotic biomarkers with a prompt improvement in the histopathological picture and decrease TLR4 and FOXO1 immunoexpressions.

Conclusion: Accordingly, these findings suggest that OCA protects CP-induced placental injury by modulating TLR4/Myd88/NF-κB; SIRT1-dependant signaling pathways.