Impact of Melatonin on Full-Term Fetal Brain Development and Transforming Growth Factor-β Level in a Rat Model of Preeclampsia

El-Malkey, Nanees F.; Aref, Mohammed; Emam, Hassan; Khalil, Sama S.

doi:10.1007/s43032-021-00497-3

Cited by 6 publications

(10 citation statements)

References 56 publications

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“…Unfortunately, clinical trials in PE patients and animal models have demonstrated that melatonin exerts a relatively weak effect on the alleviation of hypertension and proteinuria. Further, long‐term melatonin supplementation also results in decreased fetal birth weight 9,11,13,31–34,58,59 . The elucidation of the orchestrated feedback network comprising T 0 , E 2 , and melatonin in the present study sheds light on the underlying mechanisms responsible for this effect.…”

Section: Discussionmentioning

confidence: 54%

“…Further, long-term melatonin supplementation also results in decreased fetal birth weight. 9,11,13,[31][32][33][34]58,59 The elucidation of the orchestrated feedback network comprising T 0 , E 2 , and melatonin in the present study sheds light on the underlying mechanisms responsible for this effect. As summarized in Figure 7, in PE placenta, a decrease in melatonin levels is, at least in part, the consequence of androgen excess and the subsequent repression of E 2 -GPER1-PKA signaling.…”

Section: Discussionmentioning

confidence: 70%

“…However, most clinical studies and animal experiments have yielded disappointing results. 9,11,[31][32][33][34] For instance, while melatonin supplementation reduces the need for higher doses of antihypertensive medication, it also leads to lower fetal birth weight and exerts an insignificant effect on repressing the production of soluble fms-like tyrosine kinase (sFlt-1) and soluble endoglin (sEng). 34 sFlt-1 and sEng are antagonistic receptors for vascular endothelial growth factor/placental growth factor (PlGF) and TGF-β, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…Considering the common reduction of melatonin in PE patients and its potential to reduce blood pressure through antioxidant properties, such as decreasing intracellular superoxide anion and renal MDA levels, or elevating erythrocyte glutathione peroxidase activity, 30 melatonin supplementation has been proposed as an intervention for PE. However, most clinical studies and animal experiments have yielded disappointing results 9,11,31–34 . For instance, while melatonin supplementation reduces the need for higher doses of antihypertensive medication, it also leads to lower fetal birth weight and exerts an insignificant effect on repressing the production of soluble fms‐like tyrosine kinase (sFlt‐1) and soluble endoglin (sEng) 34 .…”

Section: Introductionmentioning

confidence: 99%

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Orchestrated feedback regulation between melatonin and sex hormones involving GPER1‐PKA‐CREB signaling in the placenta

Shao,

Yang,

Liu

et al. 2023

Journal of Pineal Research

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Maintaining placental endocrine homeostasis is crucial for a successful pregnancy. Pre‐eclampsia (PE), a gestational complication, is a leading cause of maternal and perinatal morbidity and mortality. Aberrant elevation of testosterone (T0) synthesis, reduced estradiol (E2), and melatonin productions have been identified in preeclamptic placentas. However, the precise contribution of disrupted homeostasis among these hormones to the occurrence of PE remains unknown. In this study, we established a strong correlation between suppressed melatonin production and decreased E2 as well as elevated T0 synthesis in PE placentas. Administration of the T0 analog testosterone propionate (TP; 2 mg/kg/day) to pregnant mice from E7.5 onwards resulted in PE‐like symptoms, along with elevated T0 production and reduced E2 and melatonin production. Notably, supplementation with melatonin (10 mg/kg/day) in TP‐treated mice had detrimental effects on fetal and placental development and compromised hormone synthesis. Importantly, E2, but not T0, actively enhanced melatonin synthetase AANAT expression and melatonin production in primary human trophoblast (PHT) cells through GPER1‐PKA‐CREB signaling pathway. On the other hand, melatonin suppressed the level of estrogen synthetase aromatase while promoting the expressions of androgen synthetic enzymes including 17β‐HSD3 and 3β‐HSD1 in PHT cells. These findings reveal an orchestrated feedback mechanism that maintains homeostasis of placental sex hormones and melatonin. It is implied that abnormal elevation of T0 synthesis likely serves as the primary cause of placental endocrine disturbances associated with PE. The suppression of melatonin may represent an adaptive strategy to correct the imbalance in sex hormone levels within preeclamptic placentas. The findings of this study offer novel evidence that identifies potential targets for the development of innovative therapeutic strategies for PE.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Orchestrated feedback regulation between melatonin and sex hormones involving GPER1‐PKA‐CREB signaling in the placenta

Shao,

Yang,

Liu

et al. 2023

Journal of Pineal Research

View full text Add to dashboard Cite

show abstract

“…PE‐like rat models also exhibited a delay in brain vascularization during the PE period 24 . Brain morphological studies have reported a loss of neuronal cell outlines with an accumulation of cellular debris in the fetal brain of PE pregnancies in a PE‐melatonin‐treated rat model 25 . However, it is not clear whether these aberrant microstructural changes in the human brain of PE/GH with FGR fetuses begin in utero.…”

Section: Discussionmentioning

confidence: 99%

Diffusion‐Weighted MRI of the Fetal Brain in Fetal Growth Restriction With Maternal Preeclampsia or Gestational Hypertension

Zheng

Yan

Jiang

et al. 2023

Magnetic Resonance Imaging

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BackgroundThe fetal neurodevelopmental microstructural alterations of intrauterine exposure to preeclampsia (PE) or gestational hypertension (GH) remain unknown.PurposeTo evaluate the differences in diffusion‐weighted imaging (DWI) of the fetal brain between normotensive pregnancies and PE/GH pregnancies, with a focus on PE/GH pregnancies with fetal growth restriction (FGR).Study TypeRetrospective matched case–control study.Population40 singleton pregnancies with PE/GH complicated by FGR, and 3 paired control groups (PE/GH without FGR, normotensive FGR, normotensive pregnancies) (28–38 gestational weeks).Field Strength/SequenceDWI with single‐shot echo‐planar imaging at 1.5 Tesla.AssessmentThe apparent diffusion coefficient (ADC) values were calculated in the centrum semi‐ovale (CSO), parietal white matter (PWM), frontal white matter (FWM), occipital white matter (OWM), temporal white matter (TWM), basal ganglia, thalamus (THAL), pons, and cerebellar hemisphere.Statistical TestsStudent t test or Wilcoxon matched test was used to reveal the difference of ADC values among the investigated brain regions. A correlation between gestational age (GA) and ADC values was determined by linear regression analysis.ResultsCompared with fetuses in PE/GH without FGR and those with normotensive pregnancies, fetuses in the PE/GH with FGR group had significantly lower average ADC measurements of supratentorial regions (1.65 ± 0.09 vs. 1.71 ± 0.10 10−3 mm2/sec; vs. 1.73 ± 0.11 10−3 mm2/sec, respectively). Regions of significantly decreased ADC values in the fetal brain included CSO, FWM, PWM, OWM, TWM and THAL in cases of PE/GH with FGR. ADC values from supratentorial regions in PE/GH pregnancies were not significantly correlated with GA (P = 0.12, 0.26); however, this trend was statistically significant in the normotensive groups.Data ConclusionADC values may indicate fetal brain developmental alterations in PE/GH with FGR fetuses but more microscopic and morphological studies are necessary to provide additional evidence to offer a different interpretation of this trend in fetal brain.Level of Evidence4Technical Efficacy Stage3

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Exploring melatonin’s multifaceted role in female reproductive health: From follicular development to lactation and its therapeutic potential in obstetric syndromes

Li,

Zheng,

Chen

et al. 2024

Journal of Advanced Research

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Impact of Melatonin on Full-Term Fetal Brain Development and Transforming Growth Factor-β Level in a Rat Model of Preeclampsia

Cited by 6 publications

References 56 publications

Orchestrated feedback regulation between melatonin and sex hormones involving GPER1‐PKA‐CREB signaling in the placenta

Orchestrated feedback regulation between melatonin and sex hormones involving GPER1‐PKA‐CREB signaling in the placenta

Diffusion‐Weighted MRI of the Fetal Brain in Fetal Growth Restriction With Maternal Preeclampsia or Gestational Hypertension

Exploring melatonin’s multifaceted role in female reproductive health: From follicular development to lactation and its therapeutic potential in obstetric syndromes

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