EFFECT OF MELATONIN ON THE LEVEL OF CYTOKINES IN PREECLAMPSIA

Abstract

Introduction. The literature reports a decrease in melatonin levels in preeclampsia, when the degree of decrease correlates with the severity of the process, as well as a decrease in the expression of melatonin receptors in the placental tissue in case of fetal growth restriction. Regarding changes in the cytokine profile in PE: there is evidence that the levels of proinflammatory cytokines, namely TNF-α and IL-6, increase in preeclampsia, while the concentrations of anti-inflammatory cytokines, namely IL-4 and IL-10, decrease. Melatonin, on the contrary, reduces the secretion of proinflammatory cytokines, in particular TNF-α, and increases the production of anti-inflammatory cytokines, namely IL-10. Therefore, normalization of melatonin levels may be a promising direction in the treatment of PE in pregnant women. Objective of the study. Assess the pathogenetic mechanisms of complications arising from a decrease in melatonin, and, in particular, find out more about the changes in melatonin, IL-6 and IL-10, determine the correlation between them. Material and research methods The study conducted at the Department of Pregnancy Pathology of the Chernivtsi Regional Perinatal Center, involved 32 women whose pregnancy was complicated by preeclampsia. The control group consisted of 33 women with uncomplicated pregnancies observed in the antenatal clinic of the Chernivtsi Regional Perinatal Center. The patient's informed consent form and the patient's examination card were approved by the Biomedical Ethics Committee of Bukovinian State Medical University (BSMU) of the Ministry of Health of Ukraine (Chernivtsi). The work was guided by the general provisions of the Declaration of Helsinki "Recommendations for Physicians for Biomedical Research Involving Human Subjects" (1964), the World Medical Association on Ethical Principles for Scientific Medical Research Involving Human Subjects (1964-2000), considering the requirements of Directive 2001/20/EC of the European Parliament and of the Council, ICH GCP, the Council of Europe Convention on Human Rights and Biomedicine (04.04.1997), Order of the Ministry of Health of Ukraine No. 690 of 23.09.2009. Statistical data were calculated using MedCalc software developed by MedCalc Software (Ostend, Belgium). The results were evaluated using the Mann-Whitney U-test for small groups. The P value of <0.05 was considered valid. Correlation and regression statistical evaluations were also performed using the aforementioned software. R&D «Preservation and restoration of reproductive health of women and girls in obstetric and gynecological pathology». State registration number: 0121U110020. Terms of execution: 01.2021–12.2025 yy. Research results. The level of melatonin in venous blood taken from women with diagnosed PE was significantly lower (p=0.029), as well as levels of placental growth factor PlGF (p<0.0001), compared to healthy women. In our study we also found that the concentrations of both proinflammatory IL-6 and anti-inflammatory IL-10 were elevated in women with PE compared to women with uncomplicated pregnancies. We performed a prognostic assessment of the impact of the biochemical parameters we studied on the outcome of pregnancies in the examined patients. Melatonin, if present in the blood of a pregnant woman in a concentration higher than the threshold values we established (6.71 pg/ml), reduces the chances of clinical manifestations of severe preeclampsia with a high degree of reliability (p=0.00173). We assume that placental dysfunction in particular leads to impaired synthesis of the antioxidant melatonin, which causes disorders in the tissues of the mother, placenta and fetus and, as a result, provokes clinical manifestations of preeclampsia. The condition of the placenta also worsens the subclinical inflammatory process, as evidenced by an increase in IL-6 levels in patients with diagnosed preeclampsia; an increase in IL-10 in the study group, in our opinion, is a kind of compensatory reaction that prevents preterm labour. In women with pregnancies complicated by preeclampsia, melatonin is a prognostic criterion for delivery before 38 weeks of gestation, and this delivery is mainly associated with the progression of preeclampsia to its severe stage. In the group of patients with uncomplicated pregnancy, proinflammatory interleukin-6 is predictive of spontaneous onset of labour before 38 weeks of gestation. Placental growth factor PlGF was a predictor of the birth of children with a body weight of less than 3000 g in both study groups. Conclusions. Concentrations of melatonin and of placental growth factor in venous blood in women whose pregnancy was complicated by preeclampsia in the third trimester of pregnancy are significantly lower compared to uncomplicated pregnancies. On the other hand, the levels of proinflammatory IL-6 and anti-inflammatory IL-10 were significantly increased in the group of patients with diagnosed preeclampsia compared with normal pregnancy.

Keywords

• Melatonin; PlGF; Cytokines; Preeclampsia