title: 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 protein-restricted (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.
authors: UMR 1280 Physiologie des Adaptations Nutritionnelles, INRA-Université de Nantes, Nantes, France.|Departamento de Anatomia, Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil.
authors: Paula
authors: P
authors: Honório de Melo Martimiano
authors: UMR 1280 Physiologie des Adaptations Nutritionnelles, INRA-Université de Nantes, Nantes, France.|Departamento de Anatomia, Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil.
authors: André
authors: A
authors: de Sa Braga Oliveira
authors: UMR 1280 Physiologie des Adaptations Nutritionnelles, INRA-Université de Nantes, Nantes, France.|Centre de Recherche en Nutrition Humaine de l'Ouest, Nantes, France.
authors: Véronique
authors: V
authors: Ferchaud-Roucher
authors: UMR 1280 Physiologie des Adaptations Nutritionnelles, INRA-Université de Nantes, Nantes, France.|Centre de Recherche en Nutrition Humaine de l'Ouest, Nantes, France.
authors: Mikaël
authors: M
authors: Croyal
authors: UMR 1280 Physiologie des Adaptations Nutritionnelles, INRA-Université de Nantes, Nantes, France.|Centre de Recherche en Nutrition Humaine de l'Ouest, Nantes, France.
authors: Audrey
authors: A
authors: Aguesse
authors: UMR 1280 Physiologie des Adaptations Nutritionnelles, INRA-Université de Nantes, Nantes, France.
authors: Isabelle
authors: I
authors: Grit
authors: UMR 1280 Physiologie des Adaptations Nutritionnelles, INRA-Université de Nantes, Nantes, France.
authors: Khadija
authors: K
authors: Ouguerram
authors: Departamento de Anatomia, Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil.
authors: Sandra
authors: S
authors: Lopes de Souza
authors: UMR 1280 Physiologie des Adaptations Nutritionnelles, INRA-Université de Nantes, Nantes, France.
authors: Bertrand
authors: B
authors: Kaeffer
authors: UMR 1280 Physiologie des Adaptations Nutritionnelles, INRA-Université de Nantes, Nantes, France.
authors: Francisco
authors: F
authors: Bolaños-Jiménez
mesh_terms: D000367:Age Factors; D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D004044:Dietary Proteins; D005260:Female; D007736:Kynurenic Acid / Q000378:metabolism*; D007737:Kynurenine / Q000378:metabolism*; D007774:Lactation / Q000378:metabolism*; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000209:etiology / Q000378:metabolism*; D011488:Protein Deficiency / Q000150:complications / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004044:Dietary Proteins; D007737:Kynurenine; D007736:Kynurenic Acid
keywords: Fœtus; brain; kynurenine; metabolic programming; protein restriction; serotonin