Cell and Organ Transplantology. 2020; 8(2):in press.
DOI: 10.22494/cot.v8i2.113
Plasma levels of melatonin, certain cytokines and placental growth factor at non-pharmacological correction of pineal function in pregnant women with intrauterine growth restriction
Berbets A.
- Bukovinian State Medical University, Chernivtsi, Ukraine
Abstract
The pineal gland produces the important hormone melatonin, the level of which in the blood of pregnant women decreases in case of placental insufficiency. The effect of pineal dysfunction on the immune system of pregnant women and the angiogenic activity of the placenta during pregnancy remains insufficiently studied.
Objective: to study the effect of our method of non-drug correction of pineal function on the state of the cytokine part of the immune system and the synthesis of placental growth factor (PlGF) in pregnant women with placental insufficiency manifested as fetal intrauterine growth restriction (IUGR).
Material and methods. 46 pregnant women with IUGR at 30-36 weeks of gestation were examined. The group was divided into two subgroups: with non-drug correction of the pineal function (n = 25) and without correction (n = 21). The method of correction included a set of measures to follow the lighting regimen, activity and sleep for 14 days. The control group consisted of 20 women with uncomplicated pregnancy. Levels of melatonin, PlGF, TNF-α, IL-1β, IL-6, IL-4, IL-10 were determined in the venous blood by enzyme-linked immunosorbent assay.
Results. It was established that the concentration of melatonin in the blood of pregnant women with IUGR was significantly reduced, as well as the concentration of PlGF (p < 0.01). Significant changes were also found in pregnant women with placental insufficiency, namely, increased concentrations of proinflammatory cytokines, such as TNF-α (p < 0.05), IL-1-β (p < 0.001) and IL-6 (p < 0.05), comparing to healthy pregnant women. Also, in the group of pregnant women with IUGR, the levels of anti-inflammatory cytokines IL-4 (p <0.001) and IL-10 (p < 0.001) were elevated in comparison to the control group.
After application of the developed complex of non-drug correction of pineal function, the concentration of melatonin in the blood of pregnant women in the subgroup of correction increased significantly, comparing to the subgroup without correction (p < 0.001), as well as the level of PlGF (p < 0.05). Also, significantly lower levels of proinflammatory cytokines TNF-α, IL-1-β and IL-6 were observed in pregnant women in the subgroup of correction (p < 0.01). Regarding anti-inflammatory cytokines, there was a decrease in the level of IL-4 and an increase in the level of IL-10 (p < 0.01) under the influence of the non-drug correction.
Conclusions. When the measures, aimed at non-drug correction of the pineal function, are applied in pregnant women with placental insufficiency, manifested as IUGR, the following changes are observed: increased plasma levels of melatonin and placental growth factor, decreased levels of proinflammatory cytokines. We suggest that the pineal gland exerts its effect on the immune system through melatonin, which moderates the activity of pro- and anti-inflammatory cytokines. Therefore the influence of inflammation on placental tissue reduces and results in the increase in the concentrations of placental growth factor in the blood of pregnant women.
Key words: melatonin; placenta; cytokines; placental growth factor; fetal growth restriction
| 1. Grishchenko VI. The role of the pineal gland in the physiology and pathology of the female reproductive system. Kharkiv, 1979. 248 p. | ||||
| 2. Abe M, Kawaguchi H, Miura N, Akioka K, Ushikai M, Oi S, Yukawa A, Yoshikawa T, Izumi H, Horiuchi M. Diurnal Variation of Melatonin Concentration in the Cerebrospinal Fluid of Unanesthetized Microminipig. In Vivo. 2018 May-Jun;32(3):583-590. doi: 10.21873/invivo.11279. PMID: 29695564; PMCID: PMC6000775. https://doi.org/10.21873/invivo.11279 |
||||
| 3. Zisapel N. New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation. Br J Pharmacol. 2018 Aug;175(16):3190-3199. doi: 10.1111/bph.14116. Epub 2018 Jan 15. PMID: 29318587; PMCID: PMC6057895. https://doi.org/10.1111/bph.14116 PMid:29318587 PMCid:PMC6057895 |
||||
| 4. Claustrat B, Leston J. Melatonin: Physiological effects in humans. Neurochirurgie. 2015 Apr-Jun;61(2-3):77-84. doi: 10.1016/j.neuchi.2015.03.002. Epub 2015 Apr 20. PMID: 25908646. https://doi.org/10.1016/j.neuchi.2015.03.002 PMid:25908646 |
||||
| 5. Tarocco A, Caroccia N, Morciano G, Wieckowski MR, Ancora G, Garani G, Pinton P. Melatonin as a master regulator of cell death and inflammation: molecular mechanisms and clinical implications for newborn care. Cell Death Dis. 2019 Apr 8;10(4):317. doi: 10.1038/s41419-019-1556-7. PMID: 30962427; PMCID: PMC6453953. https://doi.org/10.1038/s41419-019-1556-7 PMid:30962427 PMCid:PMC6453953 |
||||
| 6. Yi WJ, Kim TS. Melatonin protects mice against stress-induced inflammation through enhancement of M2 macrophage polarization. Int Immunopharmacol. 2017 Jul;48:146-158. doi: 10.1016/j.intimp.2017.05.006. Epub 2017 May 12. PMID: 28505494. https://doi.org/10.1016/j.intimp.2017.05.006 PMid:28505494 |
||||
| 7. Mayo JC, Sainz RM, Tan DX, Hardeland R, Leon J, Rodriguez C, Reiter RJ. Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages. J Neuroimmunol. 2005 Aug;165(1-2):139-49. doi: 10.1016/j.jneuroim.2005.05.002. PMID: 15975667. https://doi.org/10.1016/j.jneuroim.2005.05.002 PMid:15975667 |
||||
| 8. Najafi M, Shirazi A, Motevaseli E, Rezaeyan AH, Salajegheh A, Rezapoor S. Melatonin as an anti-inflammatory agent in radiotherapy. Inflammopharmacology. 2017 Aug;25(4):403-413. doi: 10.1007/s10787-017-0332-5. Epub 2017 Mar 2. PMID: 28255737. https://doi.org/10.1007/s10787-017-0332-5 PMid:28255737 |
||||
| 9. Ersoy ÖF, Özkan N, Özsoy Z, Kayaoğlu HA, Yenidoğan E, Çelik A, Özuğurlu AF, Arabacı Çakır E, Lortlar N. Effects of melatonin on cytokine release and healing of colonic anastomoses in an experimental sepsis model. Ulus Travma Acil Cerrahi Derg. 2016 Jul;22(4):315-21. doi: 10.5505/tjtes.2015.49465. PMID: 27598601. https://doi.org/10.5505/tjtes.2015.49465 PMid:27598601 |
||||
| 10. Skwarlo-Sonta K, Majewski P, Markowska M, Oblap R, Olszanska B. Bidirectional communication between the pineal gland and the immune system. Can J Physiol Pharmacol. 2003 Apr;81(4):342-9. doi: 10.1139/y03-026. PMID: 12769226. https://doi.org/10.1139/y03-026 PMid:12769226 |
||||
| 11. Haddadi GH, Fardid R. Oral administration of melatonin modulates the expression of tumor necrosis factor-α (TNF-α) gene in irradiated rat cervical spinal cord. Rep Pract Oncol Radiother. 2015 Feb 21;20(2):123-7. doi: 10.1016/j.rpor.2014.11.003. PMID: 25859403; PMCID: PMC4338217. https://doi.org/10.1016/j.rpor.2014.11.003 PMid:25859403 PMCid:PMC4338217 |
||||
| 12. Herman AP, Krawczyńska A, Bochenek J, Dobek E, Herman A, Tomaszewska-Zaremba D. LPS-induced inflammation potentiates the IL-1β-mediated reduction of LH secretion from the anterior pituitary explants. Clin Dev Immunol. 2013;2013:926937. doi: 10.1155/2013/926937. Epub 2013 Jul 17. PMID: 23956762; PMCID: PMC3730224. https://doi.org/10.1155/2013/926937 PMid:23956762 PMCid:PMC3730224 |
||||
| 13. Meng X, Li Y, Li S, Zhou Y, Gan RY, Xu DP, Li HB. Dietary Sources and Bioactivities of Melatonin. Nutrients. 2017 Apr 7;9(4):367. doi: 10.3390/nu9040367. PMID: 28387721; PMCID: PMC5409706. https://doi.org/10.3390/nu9040367 PMid:28387721 PMCid:PMC5409706 |
||||
| 14. Zhang M, Wang T, Chen HM, Chen YQ, Deng YC, Li YT. Serum levels of interleukin-1 beta, interleukin-6 and melatonin over summer and winter in kidney deficiency syndrome in Bizheng rats. Chin Med Sci J. 2014 Jun;29(2):107-11. doi: 10.1016/s1001-9294(14)60037-7. PMID: 24998233. https://doi.org/10.1016/S1001-9294(14)60037-7 |
||||
| 15. Herman AP, Bochenek J, Skipor J, Król K, Krawczyńska A, Antushevich H, Pawlina B, Marciniak E, Tomaszewska-Zaremba D. Interleukin-1 β Modulates Melatonin Secretion in Ovine Pineal Gland: Ex Vivo Study. Biomed Res Int. 2015;2015:526464. doi: 10.1155/2015/526464. Epub 2015 Aug 3. PMID: 26339621; PMCID: PMC4538322. https://doi.org/10.1155/2015/526464 PMid:26339621 PMCid:PMC4538322 |
||||
| 16. Burton GJ, Jauniaux E. Pathophysiology of placental-derived fetal growth restriction. Am J Obstet Gynecol. 2018 Feb;218(2S):S745-S761. doi: 10.1016/j.ajog.2017.11.577. PMID: 29422210. https://doi.org/10.1016/j.ajog.2017.11.577 PMid:29422210 |
||||
| 17. Dubocovich ML, Delagrange P, Krause DN, Sugden D, Cardinali DP, Olcese J. International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors. Pharmacol Rev. 2010 Sep;62(3):343-80. doi: 10.1124/pr.110.002832. Epub 2010 Jul 6. PMID: 20605968; PMCID: PMC2964901. https://doi.org/10.1124/pr.110.002832 PMid:20605968 PMCid:PMC2964901 |
||||
| 18. Richter HG, Hansell JA, Raut S, Giussani DA. Melatonin improves placental efficiency and birth weight and increases the placental expression of antioxidant enzymes in undernourished pregnancy. J Pineal Res. 2009 May;46(4):357-64. doi: 10.1111/j.1600-079X.2009.00671.x. Epub 2009 Mar 25. PMID: 19552758. https://doi.org/10.1111/j.1600-079X.2009.00671.x PMid:19552758 |
||||
| 19. Berbets AM, Davydenko IS, Barbe AM, Konkov DH, Albota OM, Yuzko OM. Melatonin 1A and 1B Receptors’ Expression Decreases in the Placenta of Women with Fetal Growth Restriction. Reprod Sci. 2021 Jan;28(1):197-206. doi: 10.1007/s43032-020-00285-5. Epub 2020 Aug 17. PMID: 32804352. https://doi.org/10.1007/s43032-020-00285-5 PMid:32804352 |
||||
| 20. Soliman A, Lacasse AA, Lanoix D, Sagrillo-Fagundes L, Boulard V, Vaillancourt C. Placental melatonin system is present throughout pregnancy and regulates villous trophoblast differentiation. J Pineal Res. 2015 Aug;59(1):38-46. doi: 10.1111/jpi.12236. Epub 2015 Apr 20. PMID: 25833399. https://doi.org/10.1111/jpi.12236 PMid:25833399 |
||||
| 21. Teixeira AA, Simoes MJ, Wanderley Teixeira V, et al. Evaluation of the implantation in pinealectomized and/or submitted to the constant illumination rats. Int J Morphol. 2004;22(3):189-194. https://doi.org/10.4067/S0717-95022004000300003 |
||||
| 22. Richter HG, Hansell JA, Raut S, Giussani DA. Melatonin improves placental efficiency and birth weight and increases the placental expression of antioxidant enzymes in undernourished pregnancy. J Pineal Res. 2009 May;46(4):357-64. doi: 10.1111/j.1600-079X.2009.00671.x. Epub 2009 Mar 25. PMID: 19552758. https://doi.org/10.1111/j.1600-079X.2009.00671.x PMid:19552758 |
||||
| 23. Reiter RJ, Tan DX, Korkmaz A, Rosales-Corral SA. Melatonin and stable circadian rhythms optimize maternal, placental and fetal physiology. Hum Reprod Update. 2014 Mar-Apr;20(2):293-307. doi: 10.1093/humupd/dmt054. Epub 2013 Oct 16. PMID: 24132226. https://doi.org/10.1093/humupd/dmt054 PMid:24132226 |
||||
| 24. Marseglia L, D’Angelo G, Manti S, Reiter RJ, Gitto E. Potential Utility of Melatonin in Preeclampsia, Intrauterine Fetal Growth Retardation, and Perinatal Asphyxia. Reprod Sci. 2016 Aug;23(8):970-7. doi: 10.1177/1933719115612132. Epub 2015 Nov 12. PMID: 26566856. https://doi.org/10.1177/1933719115612132 PMid:26566856 |
||||
| 25. Takayama H, Nakamura Y, Tamura H, Yamagata Y, Harada A, Nakata M, Sugino N, Kato H. Pineal gland (melatonin) affects the parturition time, but not luteal function and fetal growth, in pregnant rats. Endocr J. 2003 Feb;50(1):37-43. doi: 10.1507/endocrj.50.37. PMID: 12733707. https://doi.org/10.1507/endocrj.50.37 PMid:12733707 |
||||
| 26. Reznikov AG, Pishak VP, Nosenko ND [etc.] Prenatal stress and neuroendocrine pathology. Chernivtsi, 2004. 351 p. | ||||
| 27. Thorburn GD, Challis JR. Endocrine control of parturition. Physiol Rev. 1979 Oct;59(4):863-918. doi: 10.1152/physrev.1979.59.4.863. PMID: 115023. https://doi.org/10.1152/physrev.1979.59.4.863 PMid:115023 |
||||
| 28. Davis FC, Mannion J. Entrainment of hamster pup circadian rhythms by prenatal melatonin injections to the mother. Am J Physiol. 1988 Sep;255(3 Pt 2):R439-48. doi: 10.1152/ajpregu.1988.255.3.R439. PMID: 3414839. https://doi.org/10.1152/ajpregu.1988.255.3.R439 PMid:3414839 |
||||
| 29. Chan WY, Ng TB. Development of pre-implantation mouse embryos under the influence of pineal indoles. J Neural Transm Gen Sect. 1994;96(1):19-29. doi: 10.1007/BF01277925. PMID: 7531981. https://doi.org/10.1007/BF01277925 PMid:7531981 |
||||
| 30. Leach CM, Thorburn GD. A comparison of the inhibitory effects of melatonin and indomethacin on platelet aggregation and thromboxane release. Prostaglandins. 1980 Jul;20(1):51-6. doi: 10.1016/0090-6980(80)90005-2. PMID: 7403573. https://doi.org/10.1016/0090-6980(80)90005-2 |
||||
| 31. Ma Q, Reiter RJ, Chen Y. Role of melatonin in controlling angiogenesis under physiological and pathological conditions. Angiogenesis. 2020 May;23(2):91-104. doi: 10.1007/s10456-019-09689-7. Epub 2019 Oct 24. PMID: 31650428. https://doi.org/10.1007/s10456-019-09689-7 PMid:31650428 |
||||
| 32. Umapathy A, Chamley LW, James JL. Reconciling the distinct roles of angiogenic/anti-angiogenic factors in the placenta and maternal circulation of normal and pathological pregnancies. Angiogenesis. 2020 May;23(2):105-117. doi: 10.1007/s10456-019-09694-w. Epub 2019 Nov 9. PMID: 31707538. https://doi.org/10.1007/s10456-019-09694-w PMid:31707538 |
||||
| 33. Ribatti D. The discovery of the placental growth factor and its role in angiogenesis: a historical review. Angiogenesis. 2008;11(3):215-21. doi: 10.1007/s10456-008-9114-4. Epub 2008 Jun 21. PMID: 18568405. https://doi.org/10.1007/s10456-008-9114-4 PMid:18568405 |
||||
| 34. Nejabati HR, Latifi Z, Ghasemnejad T, Fattahi A, Nouri M. Placental growth factor (PlGF) as an angiogenic/inflammatory switcher: lesson from early pregnancy losses. Gynecol Endocrinol. 2017 Sep;33(9):668-674. doi: 10.1080/09513590.2017.1318375. Epub 2017 Apr 27. PMID: 28447504. https://doi.org/10.1080/09513590.2017.1318375 PMid:28447504 |
||||
| 35. Herraiz I, Llurba E, Verlohren S, Galindo A; Spanish Group for the Study of Angiogenic Markers in Preeclampsia. Update on the Diagnosis and Prognosis of Preeclampsia with the Aid of the sFlt-1/ PlGF Ratio in Singleton Pregnancies. Fetal Diagn Ther. 2018;43(2):81-89. doi: 10.1159/000477903. Epub 2017 Jul 19. PMID: 28719896. https://doi.org/10.1159/000477903 PMid:28719896 |
||||
| 36. Vrachnis N, Kalampokas E, Sifakis S, Vitoratos N, Kalampokas T, Botsis D, Iliodromiti Z. Placental growth factor (PlGF): a key to optimizing fetal growth. J Matern Fetal Neonatal Med. 2013 Jul;26(10):995-1002. doi: 10.3109/14767058.2013.766694. Epub 2013 Feb 14. PMID: 23330778. https://doi.org/10.3109/14767058.2013.766694 PMid:23330778 |
||||
| 37. Berbets AM, Barbe AM, Andriiets OA, Andriiets AV, Yuzko OM. Melatonin Levels Decrease in the Umbilical Cord in Case of Intrauterine Growth Restriction. J Med Life. 2020 Oct-Dec;13(4):548-553. doi: 10.25122/jml-2020-0128. PMID: 33456605; PMCID: PMC7803309. | ||||
| 38. Heo JS, Pyo S, Lim JY, Yoon DW, Kim BY, Kim JH, Kim GJ, Lee SG, Kim J. Biological effects of melatonin on human adipose‑derived mesenchymal stem cells. Int J Mol Med. 2019 Dec;44(6):2234-2244. doi: 10.3892/ijmm.2019.4356. Epub 2019 Sep 27. PMID: 31573052; PMCID: PMC6844604. | ||||
| 39. Li H, Zhang Y, Liu S, Li F, Wang B, Wang J, Cao L, Xia T, Yao Q, Chen H, Zhang Y, Zhu X, Li Y, Li G, Wang J, Li X, Ni S. Melatonin Enhances Proliferation and Modulates Differentiation of Neural Stem Cells Via Autophagy in Hyperglycemia. Stem Cells. 2019 Apr;37(4):504-515. doi: 10.1002/stem.2968. Epub 2019 Jan 14. PMID: 30644149. https://doi.org/10.1002/stem.2968 PMid:30644149 |
||||
| 40. Wang X, Liang T, Qiu J, Qiu X, Gao B, Gao W, Lian C, Chen T, Zhu Y, Liang A, Su P, Peng Y, Huang D. Melatonin Reverses the Loss of Stemness Induced by TNF-α in Human Bone Marrow Mesenchymal Stem Cells through Upregulation of YAP Expression. Stem Cells Int. 2019 Dec 30;2019:6568394. doi: 10.1155/2019/6568394. PMID: 32082385; PMCID: PMC7012241. https://doi.org/10.1155/2019/6568394 PMid:32082385 PMCid:PMC7012241 |
||||
| 41. Berbets AM Sleep disorders in pregnant women with intrauterine growth retardation. Bulletin of Vinnytsia National Medical University. 2018 22 (1): 160-163. | ||||
| 42. Berbets A, Koval H, Barbe A, Albota O, Yuzko O. Melatonin decreases and cytokines increase in women with placental insufficiency. J Matern Fetal Neonatal Med. 2021 Feb;34(3):373-378. doi: 10.1080/14767058.2019.1608432. Epub 2019 Apr 25. PMID: 31023180. https://doi.org/10.1080/14767058.2019.1608432 PMid:31023180 |
||||
| 43. Najafi M, Shirazi A, Motevaseli E, Rezaeyan AH, Salajegheh A, Rezapoor S. Melatonin as an anti-inflammatory agent in radiotherapy. Inflammopharmacology. 2017 Aug;25(4):403-413. doi: 10.1007/s10787-017-0332-5. Epub 2017 Mar 2. PMID: 28255737. https://doi.org/10.1007/s10787-017-0332-5 PMid:28255737 |
||||
| 44. Peraçoli JC, Rudge MV, Peraçoli MT. Tumor necrosis factor-alpha in gestation and puerperium of women with gestational hypertension and pre-eclampsia. Am J Reprod Immunol. 2007 Mar;57(3):177-85. doi: 10.1111/j.1600-0897.2006.00455.x. PMID: 17295896. https://doi.org/10.1111/j.1600-0897.2006.00455.x PMid:17295896 |
||||
| 45. Alijotas-Reig J, Esteve-Valverde E, Ferrer-Oliveras R, Llurba E, Gris JM. Tumor Necrosis Factor-Alpha and Pregnancy: Focus on Biologics. An Updated and Comprehensive Review. Clin Rev Allergy Immunol. 2017 Aug;53(1):40-53. doi: 10.1007/s12016-016-8596-x. PMID: 28054230. https://doi.org/10.1007/s12016-016-8596-x PMid:28054230 |
||||
| 46. Al-Azemi M, Raghupathy R, Azizieh F. Pro-inflammatory and anti-inflammatory cytokine profiles in fetal growth restriction. Clin Exp Obstet Gynecol. 2017;44(1):98-103. PMID: 29714875. | ||||
| 47. Renshall LJ, Morgan HL, Moens H, Cansfield D, Finn-Sell SL, Tropea T, Cottrell EC, Greenwood S, Sibley CP, Wareing M, Dilworth MR. Melatonin Increases Fetal Weight in Wild-Type Mice but Not in Mouse Models of Fetal Growth Restriction. Front Physiol. 2018 Aug 15;9:1141. doi: 10.3389/fphys.2018.01141. PMID: 30158878; PMCID: PMC6104307. https://doi.org/10.3389/fphys.2018.01141 PMid:30158878 PMCid:PMC6104307 |
||||
| 48. Hua-Long Zhu, Xue-Ting Shi, Xiao-Feng Xu, Guo-Xiang Zhou, Yong-Wei Xiong, Song-Jia Yi, Wei-Bo Liu, Li-Min Dai, Xue-Lin Cao, De-Xiang Xu, Hua Wang. Melatonin protects against environmental stress-induced fetal growth restriction via suppressing ROS-mediated GCN2/ATF4/BNIP3-dependent mitophagy in placental trophoblasts. Redox Biol. 2021 40:101854. doi:10.1016/j.redox.2021.101854. https://doi.org/10.1016/j.redox.2021.101854 PMid:33454563 PMCid:PMC7811044 |
||||
| 49. Miller SL, Yawno T, Alers NO, Castillo-Melendez M, Supramaniam VG, VanZyl N, Sabaretnam T, Loose JM, Drummond GR, Walker DW, Jenkin G, Wallace EM. Antenatal antioxidant treatment with melatonin to decrease newborn neurodevelopmental deficits and brain injury caused by fetal growth restriction. J Pineal Res. 2014 Apr;56(3):283-94. doi: 10.1111/jpi.12121. Epub 2014 Feb 22. PMID: 24456220. https://doi.org/10.1111/jpi.12121 PMid:24456220 |
||||
| 50. Berbets A, Konkov D, Bulavenko O, Taran O, Bakun O. Melatonin, placental growth factor and placental hormones at placental insufficiency. Cell and Organ Transplantology. 2019; 7(2):103-107. doi:10.22494/cot.v7i2.100. https://doi.org/10.22494/cot.v7i2.100 |
||||
Berbets A. Plasma levels of melatonin, certain cytokines and placental growth factor at non-pharmacological correction of pineal function in pregnant women with intrauterine growth restriction. Cell and Organ Transplantology. 2020; 8(2):in press. doi:10.22494/cot.v8i2.113