Melatonin enhances antioxidant molecules in the placenta, reduces secretion of soluble fms-like tyrosine kinase 1 (sFLT) from primary trophoblast but does not rescue endothelial dysfunction: An evaluation of its potential to treat preeclampsia

Preeclampsia is one of the most serious complications of pregnancy. Currently there are no medical treatments. Given placental oxidative stress may be an early trigger in the pathogenesis of preeclampsia, therapies that enhance antioxidant pathways have been proposed as treatments. Melatonin is a direct free-radical scavenger and indirect antioxidant. We performed in vitro assays to assess whether melatonin 1) enhances the antioxidant response element genes (heme-oxygenase 1, (HO-1), glutamate-cysteine ligase (GCLC), NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), thioredoxin (TXN)) or 2) alters secretion of the anti-angiogenic factors soluble fms-like tyrosine kinase-1 (sFLT) or soluble endoglin (sENG) from human primary trophoblasts, placental explants and human umbilical vein endothelial cells (HUVECs) and 3) can rescue TNF-α induced endothelial dysfunction. In primary trophoblast melatonin treatment increased expression of the antioxidant enzyme TXN. Expression of TXN, GCLC and NQO1 was upregulated in placental tissue with melatonin treatment. HUVECs treated with melatonin showed an increase in both TXN and GCLC. Melatonin did not increase HO-1 expression in any of the tissues examined. Melatonin reduced sFLT secretion from primary trophoblasts, but had no effect on sFLT or sENG secretion from placental explants or HUVECs. Melatonin did not rescue TNF-α induced VCAM-1 and ET-1 expression in endothelial cells. Our findings suggest that melatonin induces antioxidant pathways in placenta and endothelial cells. Furthermore, it may have effects in reducing sFLT secretion from trophoblast, but does not reduce endothelial dysfunction. Given it is likely to be safe in pregnancy, it may have potential as a therapeutic agent to treat or prevent preeclampsia.

子痫前期（Preeclampsia）是妊娠期最严重的并发症之一，目前尚无特效临床治疗手段。鉴于胎盘氧化应激可能是子痫前期发病的早期触发因素，增强抗氧化通路的治疗策略已被提出作为潜在疗法。褪黑素（Melatonin）是一种直接的自由基清除剂，同时具备间接抗氧化活性。本研究通过体外实验评估褪黑素的三项潜在作用：1）是否可上调抗氧化反应元件相关基因的表达，包括血红素氧合酶1（heme-oxygenase 1, HO-1）、谷氨酸-半胱氨酸连接酶（glutamate-cysteine ligase, GCLC）、NAD(P)H:醌受体氧化还原酶1（NAD(P)H:quinone acceptor oxidoreductase 1, NQO1）以及硫氧还蛋白（thioredoxin, TXN）；2）是否会改变人原代滋养层细胞、胎盘组织外植体及人脐静脉内皮细胞（human umbilical vein endothelial cells, HUVECs）分泌的抗血管生成因子可溶性fms样酪氨酸激酶-1（soluble fms-like tyrosine kinase-1, sFLT）与可溶性内皮因子（soluble endoglin, sENG）的水平；3）能否挽救肿瘤坏死因子-α（TNF-α）诱导的内皮功能障碍。实验结果显示：在原代滋养层细胞中，褪黑素处理可提升抗氧化酶TXN的表达水平；在经褪黑素处理的胎盘组织中，TXN、GCLC与NQO1的表达均被上调；经褪黑素处理的HUVECs中，TXN与GCLC的表达量均有所升高。但在所有检测的组织样本中，褪黑素均未上调HO-1的表达。褪黑素可降低原代滋养层细胞的sFLT分泌量，但对胎盘组织外植体或HUVECs的sFLT及sENG分泌无显著影响。此外，褪黑素未能挽救TNF-α诱导的内皮细胞VCAM-1与ET-1表达异常。本研究结果表明，褪黑素可在胎盘组织与内皮细胞中激活抗氧化通路；其或可降低滋养层细胞的sFLT分泌，但无法改善内皮功能障碍。鉴于褪黑素在妊娠期使用安全性良好，其有望成为治疗或预防子痫前期的潜在治疗药物。