Dataset Information

Leucine competes with kynurenine for blood-to-brain transport and prevents lipopolysaccharide-induced depression-like behavior in mice.

ABSTRACT: Inflammation activates indoleamine 2,3-dioxygenase (IDO) which metabolizes tryptophan into kynurenine. Circulating kynurenine is transported into the brain by the large amino transporter LAT1 at the level of the blood-brain barrier. We hypothesized that administration of leucine that has a high affinity for LAT1 should prevent the entry of kynurenine into the brain and attenuate the formation of neurotoxic kynurenine metabolites. To test whether leucine could prevent inflammation-induced depression-like behavior, mice were treated with lipopolysaccharide (LPS, 0.83?mg/kg IP) or saline and treated with L-leucine (50?mg/kg, IP) or vehicle administered before and 6?h after LPS. Depression-like behavior was measured by increased duration of immobility in the forced swim test and decreased sucrose preference. Leucine decreased brain kynurenine levels, blocked LPS-induced depression-like behavior and had antidepressant-like effects in control mice. Leucine had no effect of its own on sickness behavior and neuroinflammation. To confirm that leucine acts by interfering with the transport of kynurenine into the brain, mice were injected with L-leucine (300?mg/kg, IP) immediately before kynurenine (33?mg/kg IP) and brain kynurenine and depression-like behavior were measured 3?h later. Leucine did prevent the entry of exogenous kynurenine into the brain and abrogated depression-like behavior measured by increased duration of immobility in the forced swim test. Additional experiments using an in vitro model of the blood-brain barrier confirmed that kynurenine competes with leucine at the level of the amino acid transporter LAT1 for brain uptake. These experiments also revealed that efflux was the dominant direction of kynurenine transport and was largely independent of LAT1 and leucine, which explains why leucine could block brain uptake of kynurenine without affecting brain clearance. These findings demonstrate that leucine has antidepressant properties vis-à-vis inflammation-induced depression and one mechanism for this is by blocking the ability of kynurenine to enter the brain.

SUBMITTER: Walker AK

PROVIDER: S-EPMC6326900 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Leucine competes with kynurenine for blood-to-brain transport and prevents lipopolysaccharide-induced depression-like behavior in mice.

Walker Adam K AK Wing Emily E EE Banks William A WA Dantzer Robert R

Molecular psychiatry 20180709 10

Inflammation activates indoleamine 2,3-dioxygenase (IDO) which metabolizes tryptophan into kynurenine. Circulating kynurenine is transported into the brain by the large amino transporter LAT1 at the level of the blood-brain barrier. We hypothesized that administration of leucine that has a high affinity for LAT1 should prevent the entry of kynurenine into the brain and attenuate the formation of neurotoxic kynurenine metabolites. To test whether leucine could prevent inflammation-induced depress ...[more]

PMID: 29988087

Similar Datasets

Project description:Viral infection and chronic maternal inflammation during pregnancy are correlated with a higher prevalence of autism spectrum disorder (ASD). However, the pathoetiology of ASD is not fully understood; moreover, the key molecules that can cross the placenta following maternal inflammation and contribute to the development of ASD have not been identified. Recently, the pro-inflammatory cytokine, interleukin-17A (IL-17A) was identified as a potential mediator of these effects. To investigate the impact of maternal IL-17A on offspring, C57BL/6J dams were injected with IL-17A-expressing plasmids via the tail vein on embryonic day 12.5 (E12.5), and maternal IL-17A was expressed continuously throughout pregnancy. By adulthood, IL-17A-injected offspring exhibited behavioral abnormalities, including social and cognitive defects. Additionally, maternal IL-17A promoted metabolism of the essential amino acid tryptophan, which produces several neuroactive compounds and may affect fetal neurodevelopment. We observed significantly increased levels of kynurenine in maternal serum and fetal plasma. Thus, we investigated the effects of high maternal concentration of kynurenine on offspring by continuously administering mouse dams with kynurenine from E12.5 during gestation. Obviously, maternal kynurenine administration rapidly increased kynurenine levels in the fetal plasma and brain, pointing to the ability of kynurenine to cross the placenta and change the KP metabolites which are affected as neuroactive compounds in the fetal brain. Notably, the offspring of kynurenine-injected mice exhibited behavioral abnormalities similar to those observed in offspring of IL-17A-conditioned mice. Several tryptophan metabolites were significantly altered in the prefrontal cortex of the IL-17A-conditioned and kynurenine-injected adult mice, but not in the hippocampus. Even though we cannot exclude the possibility or other molecules being related to ASD pathogenesis and the presence of a much lower degree of pathway activation, our results suggest that increased kynurenine following maternal inflammation may be a key factor in changing the balance of KP metabolites in fetal brain during neuronal development and represents a therapeutic target for inflammation-induced ASD-like phenotypes.

Dataset Information

Leucine competes with kynurenine for blood-to-brain transport and prevents lipopolysaccharide-induced depression-like behavior in mice.

Publications

Leucine competes with kynurenine for blood-to-brain transport and prevents lipopolysaccharide-induced depression-like behavior in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets