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.

Intake of Seven Essential Amino Acids Improves Cognitive Function and Psychological and Social Function in Middle-Aged and Older Adults: A Double-Blind, Randomized, Placebo-Controlled Trial

“…It is possible that Amino LP7 acts via multiple mechanisms, including neurotransmitter compensation ( 8 ) and competitive inhibition of neurotoxic substance influx into the brain. As the constituents of Amino LP7 have high rates of influx into the brain via specific transporters (e.g., LAT-1), it is plausible that Amino LP7 not only delivers the neurotransmitter substrate into the brain but also competitively inhibits the blood-to-brain transfer of toxic amino acid metabolites, such as kynurenine, that share the same transporters ( 38 , 39 ). These metabolites are known to exert proinflammatory effects that induce neuroinflammation ( 40 , 41 ), and thus, competitive inhibition of these neurotoxic metabolites may be involved in the efficacy observed herein.…”

Kynurenine metabolism and inflammation-induced depressed mood: A human experimental study

“…Nevertheless, a recent pre-clinical study has shown that the blockade of KYN transport across the blood-brain barrier by leucine effectively abrogates inflammationinduced depression-like behavior in mice. (Walker et al, 2018) KYN metabolism is increasingly recognized as a key neurochemical pathway in the link between inflammation and depression (Reus et al, 2015;Savitz, 2019). Inflammatory mediators activate IDO, an enzyme that converts Trp to KYN.…”

FGF21 Attenuated LPS-Induced Depressive-Like Behavior via Inhibiting the Inflammatory Pathway

“…Depression behavior was monitored by increased duration of immobility in the forced swim test (FST) and decreased sucrose preference; meanwhile, sickness behavior was measured by body weight loss, reduced food intake, and locomotor activity. It has been reported that LPS-induced depression-like behaviors can be dissociated from sickness from 24 h after LPS administration (Walker et al, 2013;Walker et al, 2019). The sickness responses and behavior (piloerection, ptosis and lethargy) was usually measured during peak period of sickness at 6 h after LPS administration (Silverman et al, 2013;Walker et al, 2019).…”

“…It has been reported that LPS-induced depression-like behaviors can be dissociated from sickness from 24 h after LPS administration (Walker et al, 2013;Walker et al, 2019). The sickness responses and behavior (piloerection, ptosis and lethargy) was usually measured during peak period of sickness at 6 h after LPS administration (Silverman et al, 2013;Walker et al, 2019). In our behavioral experiment, we forced on examining the effects of rhFGF21 on depression-like behavior measured at 24 h after LPS, which include FST and locomotor activity monitored by tail suspension test (TST) and open field test (OFT) (n = 9) (Yu et al, 2019).…”