Department of Toxicology, Anhui Medical University, Hefei, China.
J Pineal Res. 2011 May;50(4):418-26. doi: 10.1111/j.1600-079X.2011.00860.x. Epub 2011 Mar 1.
Melatonin protects mice from lipopolysaccharide (LPS)-induced fetal death and intra-uterine growth retardation. Nevertheless, its molecular mechanism remains obscure. In the present study, we investigated the effects of melatonin on LPS-induced cellular stress in placenta. Pregnant mice were given with melatonin [5.0 mg/kg, intraperitoneal (i.p.)] 30 min before and 150 min after LPS (300 μg/kg, i.p.) on gestational day 15. Oxidative stress, endoplasmic reticulum (ER) stress, hypoxic stress, and heat stress in placenta were analyzed at 4 hr after LPS. As expected, maternal LPS administration resulted in placental glutathione (GSH) depletion and up-regulated the expression of placental antioxidative enzymes. In addition, LPS significantly increased the level of inducible nitric oxide synthase (iNOS) and enhanced the intensity of placental 3-nitrotyrosine residues. An ER stress, as determined by a decreased GRP78 expression, an obvious eIF2α and JNK phosphorylation, and an increased CHOP expression, were observed in placenta of pregnant mice injected with LPS. In addition, LPS significantly increased mRNA level of placental HIF-1α, VEGF, and ET-1, the markers of hypoxic stress. Heme oxygenase (HO)-1, a marker of heat stress, was also up-regulated in placenta of LPS-treated pregnant mice. Interestingly, LPS-induced placental oxidative stress, hypoxic stress, and ER stress were significantly alleviated when pregnant mice were given with melatonin, whereas melatonin had little effect on LPS-evoked placental HO-1 expression. In conclusion, maternally administered melatonin alleviates LPS-induced cellular stress in the placenta. Melatonin may be useful as pharmacological agents to protect the fetuses against LPS-induced intra-uterine fetal death and intra-uterine growth restriction.
褪黑素可保护小鼠免于脂多糖（LPS）诱导的胎儿死亡和宫内生长受限。然而，其分子机制尚不清楚。本研究探讨了褪黑素对 LPS 诱导胎盘细胞应激的影响。妊娠 15 天的小鼠，于 LPS（300μg/kg，腹腔内）前 30 分钟和后 150 分钟给予褪黑素[5.0mg/kg，腹腔内]。LPS 后 4 小时分析胎盘的氧化应激、内质网（ER）应激、缺氧应激和热应激。如预期的那样，母体 LPS 给药导致胎盘谷胱甘肽（GSH）耗竭，并上调胎盘抗氧化酶的表达。此外，LPS 还显著增加诱导型一氧化氮合酶（iNOS）的水平，并增强胎盘 3-硝基酪氨酸残基的强度。LPS 注射的妊娠小鼠胎盘中观察到 ER 应激，表现为 GRP78 表达降低、eIF2α 和 JNK 磷酸化明显以及 CHOP 表达增加。此外，LPS 还显著增加了胎盘缺氧诱导因子 1α（HIF-1α）、血管内皮生长因子（VEGF）和内皮素 1（ET-1）的 mRNA 水平，这些都是缺氧应激的标志物。热应激标志物血红素加氧酶（HO）-1也在 LPS 处理的妊娠小鼠胎盘内上调。有趣的是，当给妊娠小鼠给予褪黑素时，LPS 诱导的胎盘氧化应激、缺氧应激和 ER 应激明显减轻，而褪黑素对 LPS 诱导的胎盘 HO-1 表达几乎没有影响。总之，母体给予褪黑素可减轻 LPS 诱导的胎盘细胞应激。褪黑素可用作药理学制剂，以保护胎儿免受 LPS 诱导的宫内胎儿死亡和宫内生长受限。
