Protective effect of sodium ferulate against lipopolysaccharideinduced preterm delivery and intra-uterine fetal death in mice

LI Xiao-jun,MA Zhen-guo,GUO Yu,3,KOU Hao,SUN Rong-ze,JI Zheng-yu,WANG Hui,3

(1.Department of Pharmacology,School of Pharmaceutical Sciences,South Central University for Nationalities,Wuhan 430074,China;2.Department of Pharmacology,School of Basic Medical Science,Wuhan University,Wuhan 430071,China;3.Hubei Provincial Key Laboratory of Developmentally Originated Disease,Wuhan 430071,China)

·ORIGINAL ARTICLES·

Protective effect of sodium ferulate against lipopolysaccharideinduced preterm delivery and intra-uterine fetal death in mice

LI Xiao-jun1,2,MA Zhen-guo2,GUO Yu2,3,KOU Hao2,SUN Rong-ze2,JI Zheng-yu2,WANG Hui2,3

(1.Department of Pharmacology,School of Pharmaceutical Sciences,South Central University for Nationalities,Wuhan 430074,China;2.Department of Pharmacology,School of Basic Medical Science,Wuhan University,Wuhan 430071,China;3.Hubei Provincial Key Laboratory of Developmentally Originated Disease,Wuhan 430071,China)

OBJECTIVETo investigate the effect of sodium ferulate(SF)on lipopolysaccharide (LPS)-induced preterm delivery and intra-uterine fetal death(IUFD).METHODSPregnant Kunming mice were subcutaneously pretreated with SF(25 or 50 mg·kg-1)from gestational day(GD)10 to GD 15 and with the single injection of LPS(150 μg·kg-1,ip)on GD15.5.The incidence of preterm delivery and IUFD was observed.HE staining was used for uterine and placental histological evaluation.The levels of thiobarbituric acid reactive substances(TBARS)and reduced glutathione(GSH)as well as the activities of glutathione S-transferase(GST)and glutathione peroxidase(GSH-Px)were detected in the maternal liver,placenta,and fetal liver using commercial kits.Interleukin-1β(IL-1β)and tumor necrosis factor-α(TNF-α)levels in amniotic fluid were evaluated by enzyme linked immunosorbent assay.RESULTSFor LPS group,the incidence of preterm was 47.8%,delivery time was(17.5±1.3)d, and the pups′survival rate was only 42.6%.Compared with LPS-treated group,SF 50 mg·kg-1group showed a lower incidence of preterm(14.3%,P＜0.01),longer gestational days(18.4±0.5,P＜0.05), and a higher pups′survival rate(75.6%,P＜0.01).SF 50 mg·kg-1restored the LPS-induced GSH both in the maternal and fatal liver(a tendency without statistical significance),GST activity〔(163±82)kU·g-1proteinvs(95±90)kU·g-1protein,P＜0.01)〕in the placenta,TBARS content〔(2.5±0.4)μmol·g-1proteinvs(3.1±0.6)μmol·g-1protein,P＜0.01〕in the fetal liver,and TNF-α level〔(11±8)ng·L-1vs(20±8)ng·L-1,P＜0.01〕in the amniotic fluid.SF also attenuated LPS-induced placental congestion and neutrophil infiltra?tion in the uterus.CONCLUSIONSF may protect against LPS-induced preterm delivery and IUFD, and anti-oxidation as well as anti-inflammation may contribute to these effects.

sodium ferulate;lipopolysaccharide;preterm delivery;intra-uterine fetal death

Preterm delivery,defined as birth before the completion of 37 weeks of gestation,accounts for as much as 70%of the perinatal mortality and nearly half of long-term neurologic morbidity[1]. Approximately 10%of parturitions worldwide are premature[2-3].Maternal infections are believed to be major causes of preterm delivery,and infec?tions are found in 30%-40%of women who deliv?ered prematurely[2,4-5].Lipopolysaccharide(LPS)has been commonly used to induce preterm delivery in animal models[6-7].LPS exposure has been associ?ated with adverse developmental outcomes,including preterm labor,intra-uterine fetal death(IUFD), and intra-uterine growth retardation(IUGR)[7]. These adverse effects of LPS appear to be medi?ated through a cascade of inflammatory cyto?kines,and possibly with the contributions of reac?tive oxygen species(ROS),which are character?ized by lipid peroxidation and depletion of reduced glutathione(GSH)[8].Several tocolytic agents have currently been applied to the cure of preterm labor, including magnesium sulfate,indometacin,nife?dipine,and atosiban.However,these agents were found to have limited effects and/or have signifi?cant maternal and fetal adverse reactions[9].Ferulic acid(FA)is widely distributed in plants and consti?tutes a bioactive ingredient of many staple foods, such as grain bran,whole grain foods,citrus fruits,and banana[10].Sodium ferulate(SF)has been clinically used for treatment of cardiovascular and cerebrovascular diseases in China[11].Our previous studies have demonstrated a broad spec?trum of biological activities of SF,e.g.protection on IUGR induced by prenatal tobacco/alcohol expo?sure,anti-inflammatory effect against osteoarthritis, and anti-oxidation as well as hepatic protective effect on various hepatic injury models[12-16].In view of the ubiquitous presence of SF and its antiinflammation as well as anti-oxidation effect,we evaluated the protective effects of SF on LPS-induced preterm delivery and IUFD in mice,and determined the effects of SF on LPS-caused tissue oxidative injury as well as levets of inflammation factors.

1 MATERIALS AND METHODS

1.1 Reagents

SF was purchased from Hainan Shuangcheng Pharmaceuticals Inc.(Hainan,China).LPS (Escherichia coliLPS,serotype 0127:B8)was purchased from Sigma-Aldrich Chemical Co.(St. Louis,MO,USA).GSH,glutathione peroxidase (GSH-Px),glutathione S-transferase(GST)and thiobarbituric acid reactive substances(TBARS) detection kits and bicinchoninic acid(BCA)protein assay kits were obtained from Nanjing Jiancheng Bioengineering Institute(Nanjing,China).Tumor necrosis factor-α(TNF-α)and interleukin-1β(IL-1β) assay kits were provided by eBioscience(San Diego,California,US).All other chemicals were of an analytical grade.

1.2 Animals and treatments

Kunming mice(8-9 weeks old;male:28-32 g; female:26-30 g)were purchased from Experi?mental Center of the Medical Scientific Academy of Hubei(China).Animal experiments were conducted in the Center for Animal Experiment of Wuhan University(Wuhan,China),which has been accredited by Association for Assessment and Accreditation of Laboratory Animal Care International(AAALAC International).All experimental procedures were approved and performed in accordance with the Guidelines for the Care and Use of Laboratory Animals of the Chinese Animal Welfare Committee. The animals were allowed free access to food and water and maintained on a 12 h light/dark cycle in a controlled temperature(20-25)°C and humidity (50±5)%environment for one week before study. For mating purposes,two females were housed overnight with one male starting at 7:00 pm and the females were checked by 7:00 am the next morning. The presence of a vaginal plug was designated as gestational day 0(GD0).

1.3 Detection of delivery rate,gestation dura?tion,and intra-uterine fetal death

The pregnant mice were randomly assigned to four groups:normal control,LPS,LPS+SF 25 and LPS+SF 50 mg·kg-1.SF was administered subcutaneously(25 or 50 mg·kg-1)from GD9 to GD15(between 3∶00 pm to 4∶00 pm)and LPS-treated mice were given a single intraperitoneal injection of LPS(150 μg·kg-1),which was dis?solved in normal saline and administered at GD 15.5(10∶00 pm).The parturition of dams and the newborns was checked every 2 h after LPS injection.Preterm delivery was designated as thedeliveryoccurringbetweenGD15.5and GD17(12∶00 pm)while the term delivery was defined as birth on GD18-GD20.The pup survival rate was calculated by dividing the number ofsurvival pups in one group by the number of the total pups(both live and dead)in that group.SF 50 mg·kg-1was also administered subcutaneously to the normal pregnant mice,and there was no significant toxicity(data not shown).

1.4 Animal treatment

The pregnant mice were randomly assigned to three groups:normal control,LPS and LPS+SF 50 mg·kg-1.The treatment for each group was the same as described in1.3.All the dams were euthanized 6 h after LPS treatment.Uterus, amniotic fluid,maternal livers,placentas,and fetal livers were collected.Amniotic fluid,placentas and fetal livers were pooled from each dam and counted as one independent sample.

1.5 HE staining for morphological examination

The inflammatory responses to ascending infection fell into two components:the maternal and fetal inflammatory responses[17].Since placenta and uterus are very critical organs that account for the pathogenesis of preterm birth,morphological exami?nation was conducted in these three organs[17]. Placentas and uterus were fixed with 4%neutral formaldehyde.The fixed samples were processed by standard histological techniques and stained with hematoxylin and eosin(HE).The slides were observed under light microscopy,and the photo?micrographs were obtained by Photo Imaging System(Nikon,TE2000).The maternal and fetal liver histology was also checked with the above method.However,no significant changes were observed(data not shown).

1.6 Biochemical assays

For the preparation of liver homogenates, 0.1 g of the liver was homogenized in 1 mL of ice-cold homogenization buffer(mmol·L-1:Tris-HCl 50,KCl 180,ethylenediamine tetraacetic acid 10,pH 7.4).The homogenates were centri?fuged at a speed of 1000×gfor 10 min and the supernatants were collected.The contents of GSH,total protein,TBARS as well as the activi?ties of GSH-Px,GST in homogenates of the fetal liver,placenta,and maternal liver were detected by a series of commercial kits.

1.7 Determination of TNF-α and IL-1β in amni?otic fluid by ELISA

Commercial ELISA kits were used to determine levels of TNF-α and IL-1β in amniotic fluid according to the manufacturer′s protocols.

1.8 Statistical analysis

The concentrations of GSH and TBARS,and the activities of GSH-Px and GST were expressed asDifferent groups were compared by ANOVA with SPSS for Windows version 13(SPSS Science Inc,Chicago,Illinois).Preterm delivery rate and pup survival rate were compared using Fisher exact test.Statistical significance was attributed atP＜0.05.

2 RESULTS

2.1 Effects of SF on LPS-induced preterm labor rate,IUFD and gestation duration

Under normal conditions,the rate of preterm delivery in mice is 0,however,LPS induced nearly half of dams(11/23,47.8%,P＜0.01)preterm (Tab.1).Compared with LPS group,the mice treated with SF prior to LPS injection that a re?duced rate of preterm delivery，especially thedams given SF 50 mg·kg-1(4/28,P＜0.05).SF pretreatment prolonged the shortening of gesta?tion duration induced by LPS.LPS induced 57.4%(78/136)of the fetal mortality.Treatment with SF 50 mg·kg-1significantly enhanced the survival rate of fetuses exposed to LPS(150/198vs58/136,P＜0.05).

Tab.1 Effect of sodium ferulate（SF）on preterm delivery rate，gestation duration，and intra-uterine fetal death induced by lipopolysaccharide（LPS）in mice

2.2 Effects of SF on LPS-induced pathological alterations of placenta and uterus

The placental labyrinths in mice treated with LPS were congested,characterized by retained red blood cells in the labyrinths.SF 50 mg·kg-1pretreatment attenuated the pathological conges? tion induced by LPS.Accumulation of neutrophils was observed in uterine tissues from LPS-treated mice,and SF 50 mg·kg-1pretreated mice showed lower numbers of neutrophils in uterine(Fig.1).

2.3 Effects of SF on LPS-induced redox func?tions in maternal and fetal livers

AS shown in Tab 2,SF pretreatment attenu?ated LPS-induced GSH depletion in both maternal and fetal livers.The data showed a tendency of no statisticalsignificance. SF pretreatment enhanced the activity of GSH-Px in maternal and fetal livers,especially in the maternal liver when compared with LPS alone group(P＜0.01).SF50 mg·kg-1pretreatment also restored GST activity in placenta and TBARS contents in fetal liver(P＜0.01).

Fig.1 Effect of SF on placental and uterine of mice induced by LPS.See Tab.1 for the mouse treatment.Arrow indicates the neutrophil.

Tab 2.Effects of SF on activities of reduced glutathione（GSH），glutathione peroxidase（GSH-Px），glutathione S-transferase（GST）and thiobarbituric acid reactive substances（TBARS）in maternal liver，placenta，and fetal liver induced by LPS

2.4 Effects of SF on TNF-α and IL-1β in amniotic fluid induced by LPS in mice

Compared with the LPS group,SF 50 mg·kg-1significantly down-regulated the level of TNF-α in amniotic fluid(P＜0.05).However,the levels of IL-1β showed no difference between the ese groups (Tab.3).

Tab 3.Effect of SF on production of tumor necrosis factor-α（TNF-α）and interleukin-1β（IL-1β）in amniotic fluid induced by LPS in mice.

3 DISCUSSION

In the present study,LPS induced 49%of the preterm delivery and 57.4%of the fetal death.SF showed a potent protective effect that significantly reduced therates of LPS-induced premature delivery and IUFD.

So far,there has been no thoroughly clarified mechanism for LPS-induced premature delivery and IUFD.After LPS enters the abdominal cavity,it combines with Toll-like receptors on macrophages to produce inflammatory factors.Alternatively,LPS interacts with membrane lipids,resulting in formation of ROS[18].Upregulation of inflammatory factors and/or ROS can lead to contraction of uterus ultimately[19].

Levels of ROS can be regulated by endoge?nous antioxidants.It has been reported that maternal exposure to LPS resulted in GSH deple?tion and lipid peroxidation in LPS-induced terato?genesis in mice[20].It was supported by the evidence that antioxidants,such as melatonin, ascorbic acid and N-acetylcysteine,can signifi?cantly attenuate LPS-induced fetal death[8,21-22]. In our study,SF pretreatment restored TBARS contents in the fetal liver.The protective effect may be partly attributed to the anti-oxidative property of SF as evidenced by the elevation of GSH content as well as GST activity in maternal and/or fetal livers.The anti-oxidative effect of SF was consis?tent with our previous studies on hepatic,renal and placental oxidative injuries[16,23-24].

Inflammation also plays a key role in the process of LPS-induced adverse pregnant outcomes. An increased TNF-α production was found in adverse pregnant outcomes induced by LPS[25-26].It was reported that LPS injection on GD15.5 increased the concentration of TNF-α in amniotic fluid,and pentoxifylline,an inhibitor of TNF-α synthesis, significantly inhibited TNF-α production and attenu?ated LPS-induced IUFD[27].In addition,TNF-α blocker could decrease preterm delivery and IUFD in an LPS-induced preterm delivery model[28]. However,as for IL-1β,LPS elevated TNF-α level in amniotic fluid without notably altering IL-1β[29]. In our study,we also found that SF significantly down-regulated the level of TNF-α in amniotic fluid induced by LPS.SF showed no remarkable effect on IL-1β.Congestion and neutrophil infiltra?tion are indicators of inflammatory response eval?uated in the present study.We found that SF pretreat?ment reduced placental congestion and neutro?phil infiltrate in uterus induced by LPS.That effect was consistent with a recent study,which reported that SF could decrease inflammatory cell numbers in lungs from LPS-treated mice[30]. Thus,the protection of SF against LPS-induced adverse pregnant outcome is also attributed to its anti-inflammation property.

In summary,the protective effects of SF against LPS-induced preterm delivery and IUFD were observed in the present study.Taking into consideration,the low cost,ready availability,ab?sence of obvious adverse effects[13,31],and signifi?cant protection against LPS,SF has the poten?tial to be developed into a useful therapeutic drug for preventing preterm birth and/or IUFD.

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阿魏酸鈉對脂多糖引起小鼠早產(chǎn)和死胎的防治作用

李小軍1，2，馬振國2，郭 喻2，3，寇 皓2，孫榮則2，紀振宇2，汪 暉2，3

（1.中南民族大學藥學院藥理系，湖北武漢 430074；2.武漢大學基礎(chǔ)醫(yī)學院藥理系，湖北武漢 430071；3.發(fā)育源性疾病湖北省重點實驗室，湖北武漢 430071）

目的研究阿魏酸鈉（SF）對脂多糖導致早產(chǎn)和死胎的防治作用。方法昆明種孕小鼠妊娠10～15 d（GD10～GD15）每天sc給予SF 25或50 mg·kg-1，GD15.5 ip給予脂多糖（LPS）150 μg·kg-1造成早產(chǎn)及死胎模型，觀察早產(chǎn)和死胎的發(fā)生率；利用HE染色，觀察胎盤和子宮組織病理學變化；通過商用試劑盒測定母肝、胎盤和胎肝中硫代巴比妥酸反應(yīng)產(chǎn)物（TBARS）及還原型谷胱甘肽（GSH）濃度含量、谷胱甘肽巰基轉(zhuǎn)移酶（GST）及谷胱甘肽過氧化物酶（GSH-Px）活性；酶聯(lián)免疫吸附測定羊水中白細胞介素1β（IL-1β）和腫瘤壞死因子α（TNF-α）的水平。結(jié)果LPS組早產(chǎn)發(fā)生率為47.8%，妊娠天數(shù)為（17.5±1.3）d，活胎率為42.6%；與之相比，SF 50 mg·kg-1可以顯著降低LPS引起早產(chǎn)發(fā)生率（14.3%，P＜0.01），延長妊娠時間〔（18.4±0.5）d，P＜0.05〕，并提高活胎率（75.6%，P＜0.01）。與LPS組相比，SF 50 mg·kg-1具有逆轉(zhuǎn)母肝和胎肝GSH降低的趨勢；恢復胎盤GST活性〔（163±82）kU·g-1蛋白質(zhì)vs（95±90）kU·g-1蛋白質(zhì)，P＜0.01〕以及胎肝TBARS的含量水平〔（2.5±0.4）μmol·g-1蛋白質(zhì)vs（3.1±0.6）μmol·g-1蛋白質(zhì)，P＜0.01〕；降低羊水TNF-α表達水平〔（11±8）ng·L-1vs（20±8）ng·L-1，P＜0.01〕；抑制胎盤充血和子宮粒細胞浸潤。結(jié)論SF可以防治LPS導致的早產(chǎn)和死胎，其作用機制可能與抗氧化和抑制炎癥有關(guān)。

阿魏酸鈉；脂多糖；早產(chǎn)；宮內(nèi)胎兒死亡

2016-06-02接受日期：2016-10-08）

國家自然科學基金（81220108026）；國家自然科學基金（81430089）；國家教育部回國人員科研啟動基金資助（20111020）；國家大學生創(chuàng)新創(chuàng)業(yè)訓練項目（1210486080）

汪暉，Tel：（027）68758665；E-mail：wanghui19@whu.edu.cn

R99

A

1000-3002-(2017)01-0028-07

10.3867/j.issn.1000-3002.2017.01.003

（本文編輯：喬 虹）

Foundation item：The project supported by National Natural Science Foundation of China（81220108026）；National Natural Science Foundation of China（81430089）；Scientific Research Foundation for the Returned Overseas Chinese Scholars，State Ministry of Education（20111020）；and Project of Innovation and Entrepreneurship Training of National Undergraduate（1210486080）

Biography：LI Xiao-jun，male，Doctor degree，lecturer，main research field is ethnodrugs against alcoholic liver diseases. Corresponding author：WANG Hui，Tel：（027）68758665，E-mail：wanghui19@whu.edu.cn