scholarly journals Prenatal Dynamics of Kynurenine Pathway Metabolism in Mice: Focus on Kynurenic Acid

2017 ◽  
Vol 39 (6) ◽  
pp. 519-528 ◽  
Author(s):  
Nick Goeden ◽  
Francesca M. Notarangelo ◽  
Ana Pocivavsek ◽  
Sarah Beggiato ◽  
Alexandre Bonnin ◽  
...  
Keyword(s):  
Kynurenic Acid ◽  
Ex Vivo ◽  
Fetal Brain ◽  
Maternal Plasma ◽  
Kynurenine Pathway ◽  
Special Focus ◽  
Maternal Circulation ◽  
Placental Perfusion ◽  
Fetal Plasma

The kynurenine pathway (KP), the major catabolic route of tryptophan in mammals, contains several neuroactive metabolites, including kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK). KP metabolism, and especially the fate of KYNA, during pregnancy is poorly understood, yet it may play a significant role in the development of psychiatric disorders later in life. The present study was designed to investigate the prenatal features of KP metabolism in vivo, with special focus on KYNA. To this end, pregnant CD-1 mice were treated systemically with kynurenine (100 mg/kg), KYNA (10 mg/kg), or saline on embryonic day 18. As expected, administration of either kynurenine or KYNA increased KYNA levels in the maternal plasma and placenta. Maternal kynurenine treatment also raised kynurenine levels in the fetal plasma and brain, demonstrating the ability of this pivotal KP metabolite to cross the placenta and increase the levels of both KYNA and 3-HK in the fetal brain. In contrast, maternal administration of KYNA caused only a small, nonsignificant elevation in KYNA levels in fetal plasma and brain. Complementary experiments using an ex vivo placental perfusion procedure confirmed the significant transplacental transfer of kynurenine and demonstrated that only a very small fraction of maternal kynurenine is converted to KYNA in the placenta and released into the fetal compartment under physiological conditions. Jointly, these results help to clarify the contributions of the maternal circulation and the placenta to fetal KYNA in the late prenatal period.

scholarly journals l -Tryptophan–Induced Vasodilation Is Enhanced in Preeclampsia

Hypertension ◽  
2020 ◽  
Vol 76 (1) ◽  
pp. 184-194 ◽  
Author(s):  
Michelle Broekhuizen ◽  
Theo Klein ◽  
Emilie Hitzerd ◽  
Yolanda B. de Rijke ◽  
Sam Schoenmakers ◽  
...  
Keyword(s):  
Amino Acid ◽  
Ex Vivo ◽  
Ultra Performance Liquid Chromatography ◽  
Interferon Γ ◽  
Kynurenine Pathway ◽  
Maternal Circulation ◽  
Placental Perfusion ◽  
Ido1 Expression ◽  
Tryptophan Uptake

l -tryptophan induces IDO (indoleamine 2,3-dioxygenase) 1–dependent vasodilation. IDO1 is expressed in placental endothelial cells and downregulated in preeclampsia. Hypothesizing that this may contribute to diminished placental perfusion, we studied l -tryptophan–induced vasodilation in healthy and early-onset preeclampsia placental arteries, focusing on placental kynurenine pathway alterations. Despite IDO1 downregulation, kynurenine pathway metabolite concentrations (measured with ultra-performance liquid chromatography-tandem mass spectrometry) were unaltered in preeclamptic versus healthy placentas. Most likely, this is due to enhanced l -tryptophan uptake, evidenced by increased l -tryptophan levels in preeclamptic placentas. Ex vivo perfused cotyledons from healthy and preeclamptic placentas released similar amounts of l -tryptophan and kynurenine pathway metabolites into the circulations. This release was not altered by adding l -tryptophan in the maternal circulation, suggesting that l -tryptophan metabolites act intracellularly. Maternally applied l -tryptophan did appear in the fetal circulation, confirming placental passage of this essential amino acid. After in vitro incubation of placental arteries with IDO1-upregulating cytokines interferon-γ and tumor necrosis factor-α, l -tryptophan induced vasodilation. This vasodilation was attenuated by both IDO1 and nitric oxide (NO) synthase inhibitors. Despite IDO1 downregulation, l -tryptophan–induced relaxation was enhanced in preeclamptic versus healthy placental arteries. However, cytokine stimulation additionally upregulated the LAT ( l -type amino acid transporter) 1 in preeclamptic placental arteries only. Vasodilation to the lipophilic, transporter independent ethyl ester of l -tryptophan was reduced in preeclamptic versus healthy placental arteries, in agreement with reduced IDO1 expression. In conclusion, l -tryptophan induces IDO1- and NO-dependent relaxation in placental arteries, which is determined by l -tryptophan uptake rather than IDO1 expression. Increased l -tryptophan uptake might compensate for reduced IDO1 expression in preeclamptic placentas.

scholarly journals Restraint Stress during Pregnancy Rapidly Raises Kynurenic Acid Levels in Mouse Placenta and Fetal Brain

2016 ◽  
Vol 38 (6) ◽  
pp. 458-468 ◽  
Author(s):  
Francesca M. Notarangelo ◽  
Robert Schwarcz
Keyword(s):  
Brain Development ◽  
Restraint Stress ◽  
Kynurenic Acid ◽  
Acute Stress ◽  
Fetal Brain ◽  
Maternal Plasma ◽  
Stressful Events ◽  
Fetal Plasma ◽  
Maternal Liver

Stressful events during pregnancy adversely affect brain development and may increase the risk of psychiatric disorders later in life. Early changes in the kynurenine (KYN) pathway (KP) of tryptophan (TRP) degradation, which contains several neuroactive metabolites, including kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN), may constitute a molecular link between prenatal stress and delayed pathological consequences. To begin testing this hypothesis experimentally, we examined the effects of a 2-h restraint stress on KP metabolism in pregnant FVB/N mice on gestational day 17. TRP, KYN, KYNA, 3-HK, and QUIN levels were measured in maternal and fetal plasma and brain, as well as in the placenta, immediately after stress termination and 2 h later. In the same animals, we determined the activity of TRP 2,3-dioxygenase (TDO) in the maternal liver and in the placenta. Compared to unstressed controls, mostly transient changes in KP metabolism were observed in all of the tissues examined. Specifically, stress caused significant elevations of KYNA levels in the maternal plasma, placenta, and fetal brain, and also resulted in increased levels of TRP and KYN in the placenta, fetal plasma, and fetal brain. In contrast, 3-HK and QUIN levels remained unchanged from control values in all tissues at any time point. In the maternal liver, TDO activity was increased 2 h after stress cessation. Taken together, these findings indicate that an acute stress during the late gestational period preferentially affects the KYNA branch of KP metabolism in the fetal brain. Possible long-term consequences for postnatal brain development and pathology remain to be examined.

Glucose and lactate metabolism in vivo in ovine fetus

1980 ◽  
Vol 239 (3) ◽  
pp. E208-E214 ◽  
Author(s):  
R. L. Prior
Keyword(s):  
Specific Activity ◽  
Maternal Plasma ◽  
Fetal Weight ◽  
Plasma Lactate ◽  
Fetal Plasma ◽  
Lactate Turnover ◽  
Ovine Placenta ◽  
Brachial Vein ◽  
Ovine Fetus

The metabolism of glucose and lactate by the ovine fetus (123-128 days of gestation) was studied; a primed, continuous infusion of [2-3H]glucose and [U-14C]lactate into the brachial vein of six fetuses was used. Fetal plasma lactate concentrations averaged 2.12 +/- 0.25 mM and glucose concentrations averaged 9.3 +/- 1.3 mg/100 ml. Total plasma turnover of lactate was 5.22 +/- 0.7 nmol/h and that of glucose was 3.48 +/- 0.63 nmol x h-1 x kg fetal weight-1. Lactate was converted to glucose at a rate of 1.35 +/- 0.64 mmol x h-1 x kg fetal weight-1, which represented 21.6 +/- 6.0% of the lactate turnover. The percentage of glucose coming from lactate was 48.9 +/- 15.2. The specific activity of maternal plasma glucose was less than 4% of the specific activity of glucose observed in fetal plasma. No radioactivity could be detected in maternal plasma lactate. The data show that the ovine fetus or the fetal-placental unit can convert lactate to glucose by days 123-128 of gestation. A general model presented describes carbohydrate metabolism in the ovine placenta and fetus.

scholarly journals Inhibition of Brain Prostaglandin Endoperoxide Synthase-2 Prevents the Preparturient Increase in Fetal Adrenocorticotropin Secretion in the Sheep Fetus

Endocrinology ◽  
2008 ◽  
Vol 149 (8) ◽  
pp. 4128-4136 ◽  
Author(s):  
Jason Gersting ◽  
Christine E. Schaub ◽  
Maureen Keller-Wood ◽  
Charles E. Wood
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Fetal Brain ◽  
Brain Regions ◽  
Acth Secretion ◽  
Fetal Sheep ◽  
Prostaglandin Endoperoxide ◽  
Fetal Plasma ◽  
Prostaglandin Endoperoxide Synthase

Maturation of the fetal hypothalamus-pituitary-adrenal axis is critical for the timely somatic development of the fetus and readiness for birth. Recently, we proposed that prostaglandin generation within the fetal central nervous system is critical for the modulation of hypotension-induced fetal ACTH secretion. The present study was designed to test the hypothesis that the preparturient increase in fetal ACTH secretion is dependent upon fetal central nervous system prostaglandin synthesis mediated by the activity of prostaglandin endoperoxide synthase (PGHS)-2 (cyclooxygenase-2) in the fetal brain. We performed two studies in chronically catheterized fetal sheep. In the first study, we infused nimesulide or vehicle intracerebroventricularly (icv) into singleton fetal sheep and collected blood samples until spontaneous parturition. Nimesulide significantly delayed parturition, and inhibited fetal ACTH and proopiomelanocortin secretion but did not prevent the preparturient increase in fetal plasma cortisol concentration. In the second study, we used twin fetuses. One fetus received intracerebroventricular nimesulide and the other intracerebroventricular vehicle. Nimesulide reduced brain tissue concentrations of prostaglandin estradiol, while not affecting plasma prostaglandin E2 concentrations, demonstrating an action restricted to the fetal brain. Nimesulide reduced PGHS-2 mRNA and increased PGHS-2 protein, while not altering PGHS-1 mRNA or protein in most brain regions, suggesting an effect of the inhibitor on PGHS-2 turnover and relative specificity for PGHS-2 in vivo. We conclude that the preparturient increase in fetal ACTH and proopiomelanocortin is dependent upon the activity of PGHS-2 in the fetal brain. However, we also conclude that the timing of parturition is not solely dependent upon ACTH in this species.

The effect of thyroxine, 3,5-dimethyl-3'-isopropyl-L-thyronine and iodized oil on fetal brain development in the iodine-deficient sheep

1989 ◽  
Vol 121 (1) ◽  
pp. 7-15 ◽  
Author(s):  
M. T. Mano ◽  
B.J. Potter ◽  
G. B. Belling ◽  
D. M. Martin ◽  
B. G. Gragg ◽  
...  
Keyword(s):  
Brain Development ◽  
Thyroid Function ◽  
Iodine Deficiency ◽  
Fetal Brain ◽  
Maternal Plasma ◽  
Iodized Oil ◽  
Irreversible Damage ◽  
Fetal Plasma ◽  
Fetal Brain Development ◽  
Fetal Thyroid

Abstract. Studies have been carried out to investigate the role of maternal and fetal thyroid function in the effects of iodine deficiency on fetal brain development in sheep. Iodine deficiency was established with an especially prepared low-iodine diet of maize and pea pollard. The iodine-deficient sheep were mated and at the end of the second trimester of pregnancy (100 days gestation) were divided into groups which received either a sc injection of T4 or 3,5-dimethyl-3'-isopropyl-L-thyronine or an im injection of iodized oil. At 140 days gestation (10 days prior to parturition) comparison of the fetuses delivered by hysterotomy revealed that the retarded fetal brain development observed in iodine deficiency was greatly improved by T4 and by iodized oil. However, T4 and iodized oil failed to correct the reduction in the number and the increase in the length of synaptic appositions which were observed in the fetal cerebral cortex after iodine deficiency. In addition, the histological appearance of the fetal thyroid gland and the levels of plasma thyroid hormones were restored to normal. The administration of 3,5-dimethyl-3'-isopropyl-L-thyronine had no effect on the retarded fetal brain and body development of the iodine-deficient fetuses. The lack of response may be due to the inability of 3,5-dimethyl-3'-isopropyl-L-thyronine to cross the ovine placenta as no reduction in the abnormally elevated fetal plasma TSH was observed in spite of a fall in maternal plasma TSH and apparent restoration of maternal thyroid function. It is concluded that the retarded fetal brain development observed during iodine deficiency in sheep can be substantially improved by iodized oil or to a lesser extent by T4 administration at 100 days gestation and that this is dependent on the restoration of both maternal and fetal thyroid function which supports previous observations from this laboratory following fetal and maternal thyroidectomy. The persistence of some effects of iodine deficiency on the fetal brain suggests that irreversible damage may have occurred.

Determination of insulin-like growth factor-2 in feto-maternal circulation during human pregnancy

1992 ◽  
Vol 127 (4) ◽  
pp. 359-365 ◽  
Author(s):  
Toshiro Kubota ◽  
Shusaku Kamada ◽  
Makoto Taguchi ◽  
Takeshi Aso
Keyword(s):  
Amniotic Fluid ◽  
Umbilical Vein ◽  
Maternal Plasma ◽  
Cross Reactivity ◽  
Main Peak ◽  
Gel Chromatography ◽  
High Concentration ◽  
Maternal Circulation ◽  
Human Pregnancy ◽  
Fetal Plasma

In order to clarify the roles of insulin-like growth factors (IGFs) on the human maternal-fetal environment, IGF-2 and IGF-1 levels were investigated in human plasma and amniotic fluid during pregnancy. Initially, new radio-immunoassay (RIA) systems for human IGF-2 could be developed. The sensitivity of this assay was 17.5 pg/tube and the cross-reactivity with IGF-1 was 0.64%. The pattern of change of maternal plasma IGF-2 in early pregnancy differed from that of IGF-1, but both IGF levels increased progressively in the second half of gestation, and decreased to non-pregnancy levels in the puerperium. Maternal levels of IGF-2 were approximately seven times greater than those of IGF-1. The ratio of IGF-2 to IGF-1 was 3.2 in amniotic fluid. The IGF concentrations in amniotic fluid obtained in the second trimester were significantly greater than those of term specimens, and closely related to those of prolactin (PRL) in amniotic fluid. The highest IGF-2 to IGF-1 ratio (1 5.9) was found in umbilical vein plasma. On Sephadex G-150 gel-chromatography of maternal and fetal plasma at term, two apparent peaks of unsaturated IGF-2 binding protein (BP) could be detected in both 150 and 40 kilo dalton (kD) regions. One main peak of unsaturated IGF-2 BP could be determined in the 40 kD region in the amniotic fluid at term. High concentration of IGF-2 could be detected in feto-maternal circulation during human pregnancy. Moreover, it is strongly suggested that the releasing systems of IGFs in amniotic fluid are different from those in maternal or umbilical circulation.

An in vivo study of ovine placental transport of essential amino acids

2001 ◽  
Vol 280 (1) ◽  
pp. E31-E39 ◽  
Author(s):  
Cinzia L. Paolini ◽  
Giacomo Meschia ◽  
Paul V. Fennessey ◽  
Adrian W. Pike ◽  
Cecilia Teng ◽  
...  
Keyword(s):  
Amino Acids ◽  
Plasma Concentration ◽  
Essential Amino Acids ◽  
Maternal Plasma ◽  
Transport Systems ◽  
Fetal Plasma ◽  
Placental Transport ◽  
Rate Limiting ◽  
Pulse Flux

Under normal physiological conditions, essential amino acids (EA) are transported from mother to fetus at different rates. The mechanisms underlying these differences include the expression of several amino acid transport systems in the placenta and the regulation of EA concentrations in maternal and fetal plasma. To study the relation of EA transplacental flux to maternal plasma concentration, isotopes of EA were injected into the circulation of pregnant ewes. Measurements of concentration and molar enrichment in maternal and fetal plasma and of umbilical plasma flow were used to calculate the ratio of transplacental pulse flux to maternal concentration (clearance) for each EA. Five EA (Met, Phe, Leu, Ile, and Val) had relatively high and similar clearances and were followed, in order of decreasing clearance, by Trp, Thr, His, and Lys. The five high-clearance EA showed strong correlation ( r 2 = 0.98) between the pulse flux and maternal concentration. The study suggests that five of the nine EA have similar affinity for a rate-limiting placental transport system that mediates rapid flux from mother to fetus, and that differences in transport rates within this group of EA are determined primarily by differences in maternal plasma concentration.

scholarly journals Placental Villous Explant Culture 2.0: Flow Culture Allows Studies Closer to the In Vivo Situation

2021 ◽  
Vol 22 (14) ◽  
pp. 7464
Author(s):  
Nadja Kupper ◽  
Elisabeth Pritz ◽  
Monika Siwetz ◽  
Jacqueline Guettler ◽  
Berthold Huppertz
Keyword(s):  
Fluid Shear Stress ◽  
Maternal Plasma ◽  
Explant Culture ◽  
Placental Perfusion ◽  
In Vitro System ◽  
In Utero Environment ◽  
Static Conditions ◽  
Study Designs

During pregnancy, freely floating placental villi are adapted to fluid shear stress due to placental perfusion with maternal plasma and blood. In vitro culture of placental villous explants is widely performed under static conditions, hoping the conditions may represent the in utero environment. However, static placental villous explant culture dramatically differs from the in vivo situation. Thus, we established a flow culture system for placental villous explants and compared commonly used static cultured tissue to flow cultured tissue using transmission and scanning electron microscopy, immunohistochemistry, and lactate dehydrogenase (LDH) and human chorionic gonadotropin (hCG) measurements. The data revealed a better structural and biochemical integrity of flow cultured tissue compared to static cultured tissue. Thus, this new flow system can be used to simulate the blood flow from the mother to the placenta and back in the most native-like in vitro system so far and thus can enable novel study designs.

High-density lipoproteins (HDL) stimulate placental lactogen secretion in pregnant ewes: further evidence for a role of HDL in placental lactogen secretion during pregnancy

1989 ◽  
Vol 120 (3) ◽  
pp. 423-427 ◽  
Author(s):  
A. Grandis ◽  
V. Jorgensen ◽  
L. Kodack ◽  
S. Quarfordt ◽  
S. Handwerger
Keyword(s):  
Physiological Role ◽  
Maternal Plasma ◽  
High Density ◽  
Placental Lactogen ◽  
High Density Lipoproteins ◽  
Indwelling Catheter ◽  
Fetal Plasma ◽  
Sds Page

ABSTRACT Previous studies from our laboratory showed that high-density lipoproteins (HDL) stimulate the release of human placental lactogen (PL) from cultured trophoblast cells from normal pregnant women. To determine whether HDL stimulates PL secretion in vivo, ovine HDL was infused over 2–5 min into 11 pregnant ewes (22 separate experiments) at 86–130 days of gestation via an indwelling catheter into the maternal jugular vein. The HDL, freshly prepared from the plasma of pregnant ewes by differential flotation ultracentrifugation, was greater than 99% purified as judged by SDS-PAGE. Plasma samples were obtained from the ewes before and at 0·5-h intervals for 6 h following the infusions and were assayed for PL by a specific homologous radioimmunoassay. The maternal infusion of HDL at doses of 302–784 mg (5·3–13·8 mg/kg body weight) stimulated significant increases in maternal plasma PL concentrations in six out of eight experiments (six ewes), and the infusion of 108–264 mg (1·9–4·6 mg/kg) stimulated plasma PL concentrations in two out of six experiments. In contrast, HDL at doses < 100 mg were without effect in eight experiments. The response to the HDL infusions was characterized by a sustained increase in plasma PL concentrations beginning 1·5–2·5 h after the infusions, reaching a maximum 274·2 ± 21·9% of the baseline value (P<0·001). In contrast, the maternal infusion of lipoprotein-free plasma proteins or saline had no effect on maternal plasma PL concentrations. Although the infusion of HDL into pregnant ewes stimulated an increase in maternal plasma PL concentrations, the infusion of HDL (0·8–22·0 mg/kg) into three fetuses in seven separate experiments had no effect on fetal plasma PL concentrations. The demonstration that HDL stimulates an increase in plasma PL concentrations in pregnant ewes strongly supports a novel physiological role for HDL in the regulation of PL secretion. Journal of Endocrinology (1989) 120, 423–427

scholarly journals Subchronic N-acetylcysteine Treatment Decreases Brain Kynurenic Acid Levels and Improves Cognitive Performance in Mice

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 147
Author(s):  
Tonali Blanco Ayala ◽  
Daniela Ramírez Ortega ◽  
Paulina Ovalle Rodríguez ◽  
Benjamín Pineda ◽  
Gonzalo Pérez de la Cruz ◽  
...  
Keyword(s):  
Cognitive Performance ◽  
Kynurenic Acid ◽  
Ex Vivo ◽  
Cognitive Impairments ◽  
Prolonged Treatment ◽  
Biosynthetic Enzyme ◽  
Tissue Slices ◽  
Aspartate Receptor ◽  
The Brain

The tryptophan (Trp) metabolite kynurenic acid (KYNA) is an α7-nicotinic and N-methyl-d-aspartate receptor antagonist. Elevated brain KYNA levels are commonly seen in psychiatric disorders and neurodegenerative diseases and may be related to cognitive impairments. Recently, we showed that N-acetylcysteine (NAC) inhibits kynurenine aminotransferase II (KAT II), KYNA’s key biosynthetic enzyme, and reduces KYNA neosynthesis in rats in vivo. In this study, we examined if repeated systemic administration of NAC influences brain KYNA and cognitive performance in mice. Animals received NAC (100 mg/kg, i.p.) daily for 7 days. Redox markers, KYNA levels, and KAT II activity were determined in the brain. We also assessed the effect of repeated NAC treatment on Trp catabolism using brain tissue slices ex vivo. Finally, learning and memory was evaluated with and without an acute challenge with KYNA’s bioprecursor L-kynurenine (Kyn; 100 mg/kg). Subchronic NAC administration protected against an acute pro-oxidant challenge, decreased KYNA levels, and lowered KAT II activity and improved memory both under basal conditions and after acute Kyn treatment. In tissue slices from these mice, KYNA neosynthesis from Trp or Kyn was reduced. Together, our data indicate that prolonged treatment with NAC may enhance memory at least in part by reducing brain KYNA levels.

Sign in / Sign up

Export Citation Format

Share Document