Maternal protein restriction during gestation and lactation in the rat results in increased brain levels of kynurenine and kynurenic acid in their adult offspring

Abstract

Early malnutrition is a risk factor for depression and schizophrenia. Since the offspring of malnourished dams exhibit increased brain levels of serotonin (5-HT), a tryptophan-derived neurotransmitter involved in the pathophysiology of these mental disorders, it is believed that the deleterious effects of early malnutrition on brain function are due in large part to altered serotoninergic neurotransmission resulting from impaired tryptophan (Trp) metabolism. However, tryptophan is also metabolized through the kynurenine (KYN) pathway yielding several neuroactive compounds including kynurenic (KA), quinolinic (QA) and xanthurenic (XA) acids. Nevertheless, the impact of perinatal malnutrition on brain kynurenine pathway metabolism has not been examined to date. Here, we used ultra-performance liquid chromatography-tandem mass spectrometry for the simultaneous quantification of tryptophan and a set of seven compounds spanning its metabolism through the serotonin and kynurenine pathways, in the brain of embryos and adult offspring of rat dams fed a proteinrestricted (PR) diet. Protein-restricted embryos showed reduced brain levels of Trp, serotonin and KA, but not of KYN, XA, or QA. In contrast, PR adult rats exhibited enhanced levels of Trp in the brainstem and cortex along with increased concentrations of 5-HT, kynurenine and XA. The levels of XA and KA were also increased in the hippocampus of adult PR rats. These results show that early protein deficiency induces selective and long-lasting changes in brain kynurenine metabolism. Given the regulatory role of KYN pathway metabolites on brain development and function, these changes might contribute to the risk of developing psychiatric disorders induced by early malnutrition. Keywords: brain, Foetus, kynurenine, metabolic programming, protein restriction, serotonin. A large body of epidemiological evidence indicates that malnutrition during in utero and/or neonatal development results in long-lasting learning deficits and a high risk of developing neurological and psychiatric disorders in later life such as depression and schizophrenia (Brown et al. 2000;Costello et al. 2007;Brown and Susser 2008;Xu et al. 2009). In rodents, the offspring of malnourished dams exhibit impaired learning (Tonkiss and Galler 1990;Fukuda et al. 2002) and enhanced behavioural responses to stress (Trzct nska et al. 1999;Levay et al. 2008), and these alterations are associated with a number of neuroanatomical and neurochemical changes including a reduced number of Received May 13, 2016; revised manuscript received September 14, 2016; accepted October 14, 2016. Address correspondence and reprint requests to Francisco Bolaños-Jim enez, CHU-Hôtel Dieu, HNB1-UMR PhAN, 1280 Physiologie des Adaptations Nutritionnelles, Place AlexisRicordeau 44096 Nantes, Cedex 1, France. E-mail: Francisco.Bolanos@univ-nantes.frAbbreviations used: 5-HIAA, 5-hydroxy-indole acetic acid; 5-HT, serotonin; CA, cafeic acid; CAD, 2-chloroadenosin; DA, dopamine; HAAO, 3-hydroxyanthranilate 3,4-dioxygenase; IDO...

Associations Among Obesity, Inflammation, and Tryptophan Catabolism in Pregnancy

“…We also did not have measures of a number of additional variables that could have affected TRP levels, including diet, medications, ingestion of alcoholic and common hot drinks, use of illicit drugs, exercise, and mild stressors (Badawy, 2010). Severe malnutrition is also likely to decrease brain levels of TRP and increase levels of KYN (Honorio de Melo Martimiano et al, 2017). We explored the potential relationship between activation of IDO-1 and depression using a measure of depressive mood that has not been well validated in pregnancy.…”

Learning Deficits Induced by High-Calorie Feeding in the Rat are Associated With Impaired Brain Kynurenine Pathway Metabolism

“…Tryptophan and the metabolites generated by its catabolism through the serotonin (5-HT) and KYN pathways were quantified in the brain-stem, hippocampus, frontal cortex and serum by ultra-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) using the methodology described in detail by Zheng et al and Martimiano et al 52 , 53 In brief 50 mg of tissue or 50 µL of serum were homogenized in 200 µL of an ice-cold solution of 2.7 mM EDTA containing 1% formic acid and mixed with 10 µL of a pool of exogenous internal standards (500 µM D 5 -TRP, 2000 µM cafeic acid and 50 µM 2-CAD). Subsequently, 200 µL of the homogenate were mixed with 500 µL of ice-cold acetonitrile and, after centrifugation at 15 000 g for 15 minutes at 4°C, the supernatant was recovered and evaporated to dryness under a stream of nitrogen at room temperature.…”

Gestational Factors throughout Fetal Neurodevelopment: The Serotonin Link

“…Notably, some studies used isocaloric protein diets in which the low protein diets were adjusted with a higher content of carbohydrates, thereby creating low-protein high-carbohydrate diets. Such low-protein high-carbohydrate diets reduced maternal plasma tryptophan levels and increased maternal plasma 5-HT levels and the offspring's brain 5-HT levels after birth [106,107]. It remains unclear whether the exposure to such diets decreases or increases placental and fetal 5-HT levels [106,107].…”

“…Such low-protein high-carbohydrate diets reduced maternal plasma tryptophan levels and increased maternal plasma 5-HT levels and the offspring's brain 5-HT levels after birth [106,107]. It remains unclear whether the exposure to such diets decreases or increases placental and fetal 5-HT levels [106,107]. When using a low-protein high-carbohydrate diet supplemented with tryptophan, neither the maternal nor fetal 5-HT system is altered [108].…”

“…With regard to lasting effects within specific brain regions in the offspring, (isocaloric) maternal low-protein diets, irrespective of the gestational period, resulted in increased 5-HT levels in the mPFC, hypothalamus, and hippocampus throughout life [106,[110][111][112]. However, a few studies were not able to replicate adult hypothalamic and hippocampal 5-HT increments [107,[113][114][115].…”