Administration of melatonin for prevention of preterm birth and fetal brain injury associated with premature birth in a mouse model

Abstract

ProblemMaternal inflammation leads to preterm birth and perinatal brain injury. Melatonin, through its anti‐inflammatory effects, has been shown to be protective against inflammation‐induced perinatal adverse effects. However, the immunomodulatory effects of melatonin on preterm birth and prematurity‐related morbidity remain unknown. We wanted to investigate the effects of maternally administered melatonin on preterm birth and perinatal brain injury in a mouse model of maternal inflammation.Method of studyA model of maternal inflammation employing lipopolysaccharide (LPS) was used to mimic the most common clinical scenario of preterm birth, that of maternal inflammation. Mice were randomly divided into the following groups: control, LPS, and LPS with melatonin pre‐treatment. Doppler ultrasonography was used to obtain fetal and maternal hemodynamic measurements in utero. Placenta and fetal brains were harvested and analyzed for proinflammatory markers and signs of perinatal brain injury, respectively. Surviving offspring were assessed for neuromotor outcomes.ResultsMelatonin pre‐treatment lowered the level of proinflammatory cytokines in the uterus and the placenta, significantly improved LPS‐induced acute fetal neuroinflammation and perinatal brain injury, as well as significantly upregulated the SIRT1/Nrf2 signaling pathway to reduce LPS‐induced inflammation. Melatonin also prevented adverse neuromotor outcomes in offspring exposed to maternal inflammation.ConclusionMaternally administered melatonin modulated immune responses to maternal inflammation and decreased preterm birth and perinatal brain injury. These results suggest that melatonin, a safe treatment during pregnancy, may be used as an experimental therapeutic in clinical trials.

Melatonin for prevention of placental malperfusion and fetal compromise associated with intrauterine inflammation‐induced oxidative stress in a mouse model

“…25 Our group recently demonstrated that melatonin pretreatment in LPS-treated mice resulted in reduced levels of pro-inflammatory cytokines in the uterus and the placenta. 26 We also showed that melatonin may prevent adverse neuromotor outcomes in offspring exposed to maternal inflammation. 26 Despite the vast research on the overall anti-inflammatory qualities of melatonin, there have only been few reports on the antioxidative effects of melatonin on pathologic vascular changes of placenta and fetal sequelae as a result of IUIinduced oxidative stress.…”

“…26 We also showed that melatonin may prevent adverse neuromotor outcomes in offspring exposed to maternal inflammation. 26 Despite the vast research on the overall anti-inflammatory qualities of melatonin, there have only been few reports on the antioxidative effects of melatonin on pathologic vascular changes of placenta and fetal sequelae as a result of IUIinduced oxidative stress. 24,25,[27][28][29] Based on the antioxidant features of melatonin, we hypothesized that maternally administered melatonin may reduce oxidative stress, pathologic vascular changes of the placenta, and fetal complications caused by IUI-induced oxidative stress.…”

“…In preeclampsia, melatonin therapy was assessed to be a safe and effective adjuvant therapy by improving endothelial function and prolonging pregnancy although no significant results could be seen with its antioxidative effects against the excessive placental oxidative stress in preeclampsia . Our group recently demonstrated that melatonin pretreatment in LPS‐treated mice resulted in reduced levels of pro‐inflammatory cytokines in the uterus and the placenta . We also showed that melatonin may prevent adverse neuromotor outcomes in offspring exposed to maternal inflammation …”

“…Our group recently demonstrated that melatonin pretreatment in LPS‐treated mice resulted in reduced levels of pro‐inflammatory cytokines in the uterus and the placenta . We also showed that melatonin may prevent adverse neuromotor outcomes in offspring exposed to maternal inflammation …”

Melatonin Promotes Uterine and Placental Health: Potential Molecular Mechanisms

“…Melatonin (10 mg/kg), when injected intraperitoneally 30 min before lipopolysaccharide (LPS) administration, prevented insufficiency of uterine and umbilical artery, placental hypercoagulation, pro-inflammatory and oxidative processes, in addition to protecting against ventricular dysfunctions in fetuses exposed to LPS-induced oxidative stress. Moreover, melatonin protected uterine and placental tissues from LPS-induced maternal inflammation with a decreased incidence in preterm birth; this effect may be attributed to the downregulation of TNF-α, IL-1β, IL-6, and COX-2 in the uterus possibly via upregulating the SIRT/Nrf2 signaling pathway [83]. There is similar evidence with pregnant women displaying low levels of melatonin and placental insufficiency (PI)-associated inflammation.…”