Archives of Gynecology and Obstetrics

, Volume 298, Issue 3, pp 631–638 | Cite as

Magnesium sulphate can alleviate oxidative stress and reduce inflammatory cytokines in rat placenta of intrahepatic cholestasis of pregnancy model

  • Fei Han
  • Linhao Xu
  • Yaqing Huang
  • Tianqi Chen
  • Tiancheng Zhou
  • Liwei YangEmail author
General Gynecology



In our study, we try to investigate whether magnesium sulphate (MgSO4) could provide protection against oxidative damage and inflammatory response in rat placenta of intrahepatic cholestasis of pregnancy (ICP) model.


The rat model of ICP was established by injecting s.c. 17α-ethinyl estradiol (EE) daily for 5 days. MgSO4, as an therapeutic drug for ICP, was injected i.p. daily for 3 days. Age-matched pregnant rats served as controls. The level of serum total bile acid (TBA) was measured. The data including the number and weight of offsprings on day 20 of pregnancy were collected. We observed ultrastructural changes of mitochondria and endoplasmic reticulum (ER) in placenta by transmission electron microscope. The antioxidant proteins peroxiredoxin-6 (Prdx6) and nuclear factor erythroid 2-related factor-2 (Nrf2) were analyzed by Western Blot. The inflammatory cytokines including IL-1β, TNF-α and IFN-γ were investigated by real-time PCR (RT-PCR) and enzyme-linked immune-sorbent assay (ELISA).


The weight of offsprings on day 20 of pregnancy increased in ICP rats treated with MgSO4 (ICP + MG group) compared with that in ICP rats (ICP group). However, the level of TBA was not reduced. The damage of mitochondria and ER was observed in placenta, which was much more slighter in ICP + MgSO4 group as compared with that in ICP group. Prdx6 and Nrf2 were increased, while the inflammatory cytokines including IL-1β, TNF-α and IFN-γ were decreased in ICP + MgSO4 group compared with that in ICP group.


MgSO4 had beneficial effect on improving growth of offsprings in rat model of ICP. The protective effect of MgSO4 on alleviating oxidative damage and inflammatory response in placenta may play an important role in the process. MgSO4 may improve the function of placenta.


Intrahepatic cholestasis of pregnancy Magnesium sulphate Placenta Oxidative stress Inflammatory cytokines 



We thanked Zhejiang Provincial People’s Hospital and Zhejiang Chinese Medical University for providing assists for our research. We thanked the Department of Health of Zhejiang Province for providing fund for our research.

Author contributions

FH: data collection and analysis, manuscript writing. LHX: data analysis, manuscript revision. YQH: data collection and analysis. TQC: literature collection, data collection. TCZ: data collection. LWY: protocol development, manuscript revision.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest with the contents of this article

Ethical approval

This study protocol was approved by the Animal Care Committee of Zhejiang Chinese Medical University. All the experiments were performed according to the approved National Institutional Guidelines for the Care and Use of Laboratory Animals.


  1. 1.
    Ozkan S, Ceylan Y, Ozkan OV, Yildirim S (2015) Review of a challenging clinical issue: intrahepatic cholestasis of pregnancy. World J Gastroenterol 21(23):7134–7141. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Joshi D, James A, Quaglia A, Westbrook RH, Heneghan MA (2010) Liver disease in pregnancy. Lancet 375(9714):594–605. CrossRefPubMedGoogle Scholar
  3. 3.
    Larson SP, Kovilam O, Agrawal DK (2016) Immunological basis in the pathogenesis of intrahepatic cholestasis of pregnancy. Exp Rev Clin Immunol 12(1):39–48. CrossRefGoogle Scholar
  4. 4.
    Wu WB, Xu YY, Cheng WW, Wang YX, Liu Y, Huang D, Zhang HJ (2015) Agonist of farnesoid X receptor protects against bile acid induced damage and oxidative stress in mouse placenta—a study on maternal cholestasis model. Placenta 36(5):545–551. CrossRefPubMedGoogle Scholar
  5. 5.
    Ignacio Barrasa J, Olmo N, Perez-Ramos P, Santiago-Gomez A, Lecona E, Turnay J, Antonia Lizarbe M (2011) Deoxycholic and chenodeoxycholic bile acids induce apoptosis via oxidative stress in human colon adenocarcinoma cells. Apoptosis 16(10):1054–1067. CrossRefPubMedGoogle Scholar
  6. 6.
    Duchen MR (2004) Mitochondria in health and disease: perspectives on a new mitochondrial biology. Mol Aspects Med 25(4):365–451. CrossRefPubMedGoogle Scholar
  7. 7.
    Scheuner D, Kaufman RJ (2008) The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetes. Endocr Rev 29(3):317–333. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Qu K, Shen NY, Xu XS, Su HB, Wei JC, Tai MH, Meng FD, Zhou L, Zhang YL, Liu C (2013) Emodin induces human T cell apoptosis in vitro by ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction. Acta Pharmacol Sin 34(9):1217–1228. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Singh SP, Chhunchha B, Fatma N, Kubo E, Singh SP, Singh DP (2016) Delivery of a protein transduction domain-mediated Prdx6 protein ameliorates oxidative stress-induced injury in human and mouse neuronal cells. Am J Physiol Cell Physiol 310(1):C1–16. CrossRefPubMedGoogle Scholar
  10. 10.
    Ma Q (2010) Transcriptional responses to oxidative stress: pathological and toxicological implications. Pharmacol Ther 125(3):376–393. CrossRefPubMedGoogle Scholar
  11. 11.
    Sykiotis GP, Bohmann D (2010) Stress-activated cap ‘n’ collar transcription factors in aging and human disease. Sci Signal 3(112):3. CrossRefGoogle Scholar
  12. 12.
    Zhang Y, Hu L, Cui Y, Qi Z, Huang X, Cai L, Zhang T, Yin Y, Lu Z, Xiang J (2014) Roles of PPARgamma/NF-kappaB signaling pathway in the pathogenesis of intrahepatic cholestasis of pregnancy. PLoS ONE 9(1):e87343. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Agarwal R, Iezhitsa IN, Agarwal P, Spasov AA (2013) Mechanisms of cataractogenesis in the presence of magnesium deficiency. Magnes Res 26(1):2–8. PubMedCrossRefGoogle Scholar
  14. 14.
    Turner DL, Ford WR, Kidd EJ, Broadley KJ, Powell C (2017) Effects of nebulised magnesium sulphate on inflammation and function of the guinea-pig airway. Eur J Pharmacol 801:79–85. CrossRefPubMedGoogle Scholar
  15. 15.
    Lee PY, Yang CH, Kao MC, Su NY, Tsai PS, Huang CJ (2015) Phosphoinositide 3-kinase beta, phosphoinositide 3-kinase delta, and phosphoinositide 3-kinase gamma mediate the anti-inflammatory effects of magnesium sulfate. J Surg Res 197(2):390–397. CrossRefPubMedGoogle Scholar
  16. 16.
    Bain ES, Middleton PF, Crowther CA (2013) Maternal adverse effects of different antenatal magnesium sulphate regimens for improving maternal and infant outcomes: a systematic review. BMC Pregnancy childbirth 13:195. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ozler A, Ucmak D, Evsen MS, Kaplan I, Elbey B, Arica M, Kaya M (2014) Immune mechanisms and the role of oxidative stress in intrahepatic cholestasis of pregnancy. Central Eur J Immunol 39(2):198–202. CrossRefGoogle Scholar
  18. 18.
    Perez MJ, Macias RI, Marin JJ (2006) Maternal cholestasis induces placental oxidative stress and apoptosis. Protective effect of ursodeoxycholic acid. Placenta 27(1):34–41. CrossRefPubMedGoogle Scholar
  19. 19.
    Zhang Y, Pan Y, Lin C, Zheng Y, Sun H, Zhang H, Wang J, Yuan M, Duan T, Du Q, Chen J (2016) Bile acids evoke placental inflammation by activating Gpbar1/NF-kappaB pathway in intrahepatic cholestasis of pregnancy. J Mol Cell Biol 8(6):530–541. CrossRefPubMedGoogle Scholar
  20. 20.
    Shi Q, Wang J, Yan S, Zhao J, Li H (2014) Expression of neuropeptide Y and pro-opiomelanocortin in hypothalamic arcuate nucleus in 17alpha-ethinyl estradiol-induced intrahepatic cholestasis pregnant rat offspring. J Obstet Gynaecol Res 40(2):445–452. CrossRefPubMedGoogle Scholar
  21. 21.
    Bhat AH, Dar KB, Anees S, Zargar MA, Masood A, Sofi MA, Ganie SA (2015) Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomed Pharmacother 74:101–110. CrossRefPubMedGoogle Scholar
  22. 22.
    Chen Y, Lv L, Jiang Z, Yang H, Li S, Jiang Y (2013) Mitofusin 2 protects hepatocyte mitochondrial function from damage induced by GCDCA. PLoS ONE 8(6):e65455. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Yang X, Shao H, Liu W, Gu W, Shu X, Mo Y, Chen X, Zhang Q, Jiang M (2015) Endoplasmic reticulum stress and oxidative stress are involved in ZnO nanoparticle-induced hepatotoxicity. Toxicol Lett 234(1):40–49. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Yu S, Zhao J, Wang X, Lei S, Wu X, Chen Y, Wu J, Zhao Y (2013) 4-Hydroxybenzyl alcohol confers neuroprotection through up-regulation of antioxidant protein expression. Neurochem Res 38(7):1501–1516. CrossRefPubMedGoogle Scholar
  25. 25.
    Shao Y, Chen J, Zheng J, Liu CR (2017) Effect of histone deacetylase HDAC3 on cytokines IL-18, IL-12 and TNF-alpha in patients with intrahepatic cholestasis of pregnancy. Cell Physiol biochem 42(4):1294–1302. CrossRefPubMedGoogle Scholar
  26. 26.
    Acar N, Soylu H, Edizer I, Ozbey O, Er H, Akkoyunlu G, Gemici B, Ustunel I (2014) Expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and peroxiredoxin 6 (Prdx6) proteins in healthy and pathologic placentas of human and rat. Acta Histochem 116(8):1289–1300. CrossRefPubMedGoogle Scholar
  27. 27.
    Witkin SS, Linhares IM, Bongiovanni AM, Herway C, Skupski D (2011) Unique alterations in infection-induced immune activation during pregnancy. BJOG 118(2):145–153. CrossRefPubMedGoogle Scholar
  28. 28.
    Durackova Z (2010) Some current insights into oxidative stress. Physiol Res 59(4):459–469PubMedGoogle Scholar
  29. 29.
    Rani V, Deep G, Singh RK, Palle K, Yadav UC (2016) Oxidative stress and metabolic disorders: pathogenesis and therapeutic strategies. Life Sci 148:183–193. CrossRefPubMedGoogle Scholar
  30. 30.
    Gurung V, Middleton P, Milan SJ, Hague W, Thornton JG (2013) Interventions for treating cholestasis in pregnancy. Cochrane Database Syst Rev 6:CD000493. CrossRefGoogle Scholar
  31. 31.
    Nguyen TM, Crowther CA, Wilkinson D, Bain E (2013) Magnesium sulphate for women at term for neuroprotection of the fetus. Cochrane Database Syst Rev 2:CD009395. CrossRefGoogle Scholar
  32. 32.
    Johnson AC, Tremble SM, Chan SL, Moseley J, LaMarca B, Nagle KJ, Cipolla MJ (2014) Magnesium sulfate treatment reverses seizure susceptibility and decreases neuroinflammation in a rat model of severe preeclampsia. PLoS ONE 9(11):e113670. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Fomin VP, Gibbs SG, Vanam R, Morimiya A, Hurd WW (2006) Effect of magnesium sulfate on contractile force and intracellular calcium concentration in pregnant human myometrium. Am J Obstet Gynecol 194(5):1384–1390. CrossRefPubMedGoogle Scholar
  34. 34.
    Euser AG, Cipolla MJ (2009) Magnesium sulfate for the treatment of eclampsia: a brief review. Stroke 40(4):1169–1175. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Zhejiang Chinese Medical UniversityHangzhouChina
  2. 2.Hangzhou Medical CollegeHangzhouChina
  3. 3.Zhejiang Provincial People’s HospitalHangzhouChina
  4. 4.People’s Hospital of Shaoxing CityShaoxingChina

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