Metformin inhibits OCT3-mediated serotonin transport in the placenta.

Proper fetal development requires tight regulation of serotonin concentrations within the fetoplacental unit. This homeostasis is partly maintained by the placental transporter OCT3/SLC22A3, which takes up serotonin from the fetal circulation. Metformin, an antidiabetic drug commonly used to treat gestational diabetes mellitus, was shown to inhibit OCT3.

Cannabidiol disrupts tryptophan metabolism in the human term placenta.

The increasing use of cannabis during pregnancy raises concerns about its impact on fetal development. While cannabidiol (CBD) shows therapeutic promise, its effects during pregnancy remain uncertain. We investigated CBD's influence on tryptophan (TRP) metabolism in the human placenta.

Developmental expression of catecholamine system in the human placenta and rat fetoplacental unit.

Catecholamines norepinephrine and dopamine have been implicated in numerous physiological processes within the central nervous system. Emerging evidence has highlighted the importance of tightly regulated monoamine levels for placental functions and fetal development. However, the complexities of synthesis, release, and regulation of catecholamines in the fetoplacental unit have not been fully unraveled.

Metabolomic analysis of the human placenta reveals perturbations in amino acids, purine metabolites, and small organic acids in spontaneous preterm birth.

Spontaneous preterm delivery presents one of the most complex challenges in obstetrics and is a leading cause of perinatal morbidity and mortality. Although it is a common endpoint for multiple pathological processes, the mechanisms governing the etiological complexity of spontaneous preterm birth and the placental responses are poorly understood. This study examined placental tissues collected between May 2019 and May 2022 from a well-defined cohort of women who experienced spontaneous preterm birth (n = 72) and healthy full-term deliveries (n = 30).

Pathological shifts in tryptophan metabolism in human term placenta exposed to LPS or poly I:C†.

Maternal immune activation during pregnancy is a risk factor for offspring neuropsychiatric disorders. Among the mechanistic pathways by which maternal inflammation can affect fetal brain development and programming, those involving tryptophan (TRP) metabolism have drawn attention because various TRP metabolites have neuroactive properties. This study evaluates the effect of bacterial (lipopolysaccharides/LPS) and viral (polyinosinic:polycytidylic acid/poly I:C) placental infection on TRP metabolism using an ex vivo model.

Characterization of a human placental clearance system to regulate serotonin levels in the fetoplacental unit.

Background: Serotonin (5-HT) is a biogenic monoamine with diverse functions in multiple human organs and tissues. During pregnancy, tightly regulated levels of 5-HT in the fetoplacental unit are critical for proper placental functions, fetal development, and programming. Despite being a non-neuronal organ, the placenta expresses a suite of homeostatic proteins, membrane transporters and metabolizing enzymes, to regulate monoamine levels.

Biomarkers of oxidative stress and reproductive complications.

Oxidative stress is the result of an imbalance between the formation of reactive oxygen species (ROS) and the levels of enzymatic and non-enzymatic antioxidants. The assessment of biological redox status is performed by the use of oxidative stress biomarkers. An oxidative stress biomarker is defined as any physical structure or process or chemical compound that can be assessed in a living being (in vivo) or in solid or fluid parts thereof (in vitro), the determination of which is a reproducible and reliable indicator of oxidative stress.

Precision-cut rat placental slices as a model to study sex-dependent inflammatory response to LPS and Poly I:C.

Introduction: Maternal inflammation in pregnancy represents a major hallmark of several pregnancy complications and a significant risk factor for neurodevelopmental and neuropsychiatric disorders in the offspring. As the interface between the mother and the fetus, the placenta plays a crucial role in fetal development and programming. Moreover, studies have suggested that the placenta responds to an inflammatory environment in a sex-biased fashion.

Perfused rat term placenta as a preclinical model to investigate placental dopamine and norepinephrine transport.

The placenta represents a non-neuronal organ capable of transporting and metabolizing monoamines. Since these bioactive molecules participate in numerous processes essential for placental and fetal physiology, any imbalance in their levels during pregnancy may affect brain development, projecting a higher risk of behavioral disorders in childhood or adulthood. Notably, the monoamine system in the placenta is a target of various psychoactive drugs and can be disrupted in several pregnancy pathologies.

Functional reorganization of monoamine transport systems during villous trophoblast differentiation: evidence of distinct differences between primary human trophoblasts and BeWo cells.

Background: Three primary monoamines-serotonin, norepinephrine, and dopamine-play major roles in the placenta-fetal brain axis. Analogously to the brain, the placenta has transport mechanisms that actively take up these monoamines into trophoblast cells. These transporters are known to play important roles in the differentiated syncytiotrophoblast layer, but their status and activities in the undifferentiated, progenitor cytotrophoblast cells are not well understood.

Functional characterization of dopamine and norepinephrine transport across the apical and basal plasma membranes of the human placental syncytiotrophoblast.

The human placenta represents a unique non-neuronal site of monoamine transporter expression, with pathophysiological relevance during the prenatal period. Monoamines (serotonin, dopamine, norepinephrine) are crucial neuromodulators for proper placenta functions and fetal development, including cell proliferation, differentiation, and neuronal migration. Accumulating evidence suggests that even a transient disruption of monoamine balance during gestation may lead to permanent changes in the fetal brain structures and functions, projecting into adulthood.

Development of a Rat Model of Intra-Amniotic Inflammation Ultrasound-Guided Administration of a Triggering Agent in the Gestational Sac to Enable Analysis of Individual Amniotic Fluid Samples.

To develop a rat model of intra-amniotic inflammation, characterized by the concentration of interleukin-6 in the amniotic fluid, induced by an ultrasound-guided transabdominal administration of lipopolysaccharide into individual gestational sacs. An ultrasound-guided transabdominal intra-amniotic administration of lipopolysaccharide or phosphate-buffered saline (PBS) as control was performed in rats on embryonic day 18. Only accessible gestational sacs with precise recording of their positions were injected.

Effect of Mg-Gluconate on the Osmotic Fragility of Red Blood Cells, Lipid Peroxidation, and Ca-ATPase (PMCA) Activity of Placental Homogenates and Red Blood Cell Ghosts From Salt-Loaded Pregnant Rats.

Preeclampsia (PE) is a pregnancy-specific syndrome with multisystem involvement which leads to fetal, neonatal, and maternal morbidity and mortality. A model of salt-loaded pregnant rats has been previously studied, sharing several pathological characteristics of preeclamptic women. In this study, it was compared the effects of the treatment with an oral magnesium salt, magnesium gluconate (Mg-gluconate), on the osmotic fragility of red blood cells, lipid peroxidation, and PMCA activity of placental homogenates and red blood cell ghosts in salt-loaded pregnant rats.

Effect of Selected Antidepressants on Placental Homeostasis of Serotonin: Maternal and Fetal Perspectives.

Depression is a prevalent condition affecting up to 20% of pregnant women. Hence, more than 10% are prescribed antidepressant drugs, mainly serotonin reuptake inhibitors (SSRIs) and selective serotonin and noradrenaline reuptake inhibitors (SNRIs). We hypothesize that antidepressants disturb serotonin homeostasis in the fetoplacental unit by inhibiting serotonin transporter (SERT) and organic cation transporter 3 (OCT3) in the maternal- and fetal-facing placental membranes, respectively.

Prenatal inflammation as a link between placental expression signature of tryptophan metabolism and preterm birth.

Spontaneous preterm birth is a serious medical condition responsible for substantial perinatal morbidity and mortality. Its phenotypic characteristics, preterm labor with intact membranes (PTL) and preterm premature rupture of the membranes (PPROM), are associated with significantly increased risks of neurological and behavioral alterations in childhood and later life. Recognizing the inflammatory milieu associated with PTL and PPROM, here, we examined expression signatures of placental tryptophan metabolism, an important pathway in prenatal brain development and immunotolerance.

Dynamics of Tryptophan Metabolic Pathways in Human Placenta and Placental-Derived Cells: Effect of Gestation Age and Trophoblast Differentiation.

L-Tryptophan is an essential amino acid and a precursor of several physiologically active metabolites. In the placenta, the serotonin and kynurenine metabolic pathways of tryptophan metabolism have been identified, giving rise to various molecules of neuroactive or immunoprotective properties, such as serotonin, melatonin, kynurenine, kynurenic acid, or quinolinic acid. Current literature suggests that optimal levels of these molecules in the fetoplacental unit are crucial for proper placenta functions, fetal development and programming.

Profiling of Tryptophan Metabolic Pathways in the Rat Fetoplacental Unit During Gestation.

Placental homeostasis of tryptophan is essential for fetal development and programming. The two main metabolic pathways (serotonin and kynurenine) produce bioactive metabolites with immunosuppressive, neurotoxic, or neuroprotective properties and their concentrations in the fetoplacental unit must be tightly regulated throughout gestation. Here, we investigated the expression/function of key enzymes/transporters involved in tryptophan pathways during mid-to-late gestation in rat placenta and fetal organs.

Oxidative stress and mitochondrial dysfunction in early-onset and late-onset preeclampsia.

Preeclampsia is a pregnancy-specific syndrome with multisystem involvement which leads to foetal, neonatal, and maternal morbidity and mortality. This syndrome is characterized by the onset of clinical signs and symptoms and delivery before (early-onset preeclampsia, eoPE), or after (late-onset preeclampsia, loPE), the 34 weeks of gestation. Preeclampsia is a mitochondrial disorder where its differential involvement in eoPE and loPE is unclear.

Serotonin homeostasis in the materno-foetal interface at term: Role of transporters (SERT/SLC6A4 and OCT3/SLC22A3) and monoamine oxidase A (MAO-A) in uptake and degradation of serotonin by human and rat term placenta.

Aim: Serotonin is crucial for proper foetal development, and the placenta has been described as a 'donor' of serotonin for the embryo/foetus. However, in later stages of gestation the foetus produces its own serotonin from maternally-derived tryptophan and placental supply is no longer needed. We propose a novel model of serotonin homeostasis in the term placenta with special focus on the protective role of organic cation transporter 3 (OCT3/SLC22A3).

Oxidative stress: Normal pregnancy versus preeclampsia.

The role of oxidative stress in the physiopathology of human pregnancy is of particular interest. Pregnancy is well-known to increase the oxidative stress, mainly produced by a normal systemic inflammatory response, which results in high amounts of circulating reactive oxygen species (ROS) and reactive nitrogen species (RNS). Both ROS and RNS play an important role as secondary messengers in many intracellular signalling cascades.

Osmotic fragility of red blood cells, lipid peroxidation and Ca²⁺-ATPase activity of placental homogenates and red blood cell ghosts in salt-loaded pregnant rats.

Objective: To evaluate the osmotic fragility of red blood cells and the level of lipid peroxidation, the Ca(2+)-ATPase activity of red cell ghosts and placental homogenates from salt-loaded pregnant rats.

Methods: Salt-loaded pregnant rats received 1.8% NaCl solution ad libitum as a beverage for seven days, starting on 15th day of pregnancy.

Na⁺, K⁺-ATPase and Ca²⁺-ATPase activities in basal and microvillous syncytiotrophoblast membranes from preeclamptic human term placenta.

Objective: The aim of this study is to evaluate the effect of preeclampsia on the level of lipid peroxidation, activity and expression of both plasma membrane Ca(2+)- and Na(+), K(+)-ATPases in syncytiotrophoblast.

Methods: The level of lipid peroxidation was estimated by measuring TBARS. ATPase activities were quantified by a colorimetric method measuring the amount of inorganic phosphate during the assay.

Effect of hypoxia on the calcium and magnesium content, lipid peroxidation level, and Ca²⁺-ATPase activity of syncytiotrophoblast plasma membranes from placental explants.

In the current study the possible relationship between the Ca(2+)/Mg(2+) ratio of human syncytiotrophoblast plasma membranes and their lipid peroxidation and Ca(2+)-ATPase activity was determined. Syncytiotrophoblast plasma membranes of placental explants cultured under hypoxia increased their lipid peroxidation and Ca(2+) content, diminished their Ca(2+)-ATPase activity, and kept their Mg(2+) content unchanged. Membranes preincubated with different concentrations of Ca(2+) increased their Ca(2+) content without changes in their Mg(2+) content.

Preeclampsia, placenta, oxidative stress, and PMCA.

Objective: The aim of this study is to summarize the reported evidence on the possible relationship between preeclampsia, placenta, oxidative stress and plasma membrane Ca-ATPase (PMCA) activity, responsible for fine control of intracellular calcium concentration.

Methods: Literature search was conducted in MEDLINE/PubMed and several unpublished results from our laboratory were included.

Results: Lipid peroxidation in placental and red blood cell plasma membranes during preeclampsia and a concomitant diminution of their PMCA activity are described.