554: Melatonin for prevention of placental malperfusion and fetal compromise associated with intrauterine inflammation-induced oxidative stress

Oxidative stress induces vasoconstriction, hypercoagulation and pathologic vascular remodeling. We hypothesized that maternally-administered melatonin may reduce oxidative stress, hypercoagulability and structural injury in placenta, and prevent fetal sequelae in a mouse model of intrauterine inflammation(IUI)-induced oxidative stress. CD1 pregnant dams were randomized to intrauterine injections of either lipopolysaccharide (LPS; a model of IUI) or phosphate-buffered saline (PBS) at E17 as follows: (1) control (C); (2) Melatonin (M); (3) LPS (L); (4) LPS with Melatonin group (LM). Doppler ultrasonography was utilized to obtain fetal and maternal hemodynamic measurements in utero. Proinflammatory mediators (NFkB, TNFα, and IL1β), oxidative stress markers (4-HNE) and antioxidant mediators (Nrf2, HO1) were analyzed in the placenta by real-time RT-qPCR and western blots. Confirmatory histochemistry (PTAH, H&E, Nissl staining) and immunohistochemical analyses (Vimentin & CD31, a vascular endothelial cell marker; and Iba1, a marker of microglial activation) were performed. The systolic/diastolic (S/D) ratio, resistance index (RI) and pulsatility index (PI) in uterine artery (UtA) and umbilical artery (UA) were significantly increased in L compared to C, M, or ML groups. The rate of early diastolic notch in the UtA and the rate of absent end-diastolic flow (AEDF) in UA were significantly higher in L than C, M, or ML. Tei indices were significantly increased in L compared to C, M, or ML. The rate of abnormal Tei indices (>0.44) was significantly higher in L compared to C, M, or ML. The expression of SIRT1, Nrf2 and HO1 in the placenta were significantly decreased in L comparing to C or ML. The expression of NFkB, TNFα, and IL1β were significantly increased in L comparing to C, and ML. 4-HNE was increased in L comparing to C, M and ML. The area of vimentin in the placenta was decreased in L than C or M. PTAH staining in the placenta showed increased deposit of fibrin in L comparing to C, M, or ML. Iba1 expression was increased in fetal brains in L compared to C, M, and ML. Maternal pretreatment with melatonin appears to modulate maternal placental malperfusion, fetal cardiovascular compromise and fetal neuroinflammation induced by intrauterine oxidative stress. Current results suggest that melatonin could serve as a new preventive and/or therapeutic agent to prevent fetal injury from IUI-induced oxidative stress.View Large Image Figure ViewerDownload Hi-res image Download (PPT)