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

Molecular Psychiatry volume 24, pages 1523–1532 (2019)Cite this article

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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.

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Acknowledgements

This work was supported by the University of Texas MD Anderson Cancer Center [Support Grant CA016672], National Institutes of Health (R21MH104694), and the National Institutes of Health National Institute of Neurological Disorders and Stroke [R01-NS073939]. R.D. has received honorarium from the Danone Nutricia Research for work not related to this study. A.K.W. is supported by a National Breast Cancer Foundation fellowship (PF-15-014). We thank Dr. Subhashree Kumaravel and Ms. Darlene Estrada for their help with the determination of the effects of leucine on kynurenine transport in the brain. We thank Jasmin Walker for her artistic input.

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  1. Adam K. Walker

    Present address: Neural Regulation of Cancer Laboratory, Drug Discovery Biology, Faculty of Pharmacy and Pharmaceutical Sciences, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia

Authors and Affiliations

  1. Laboratory of Neuroimmunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Adam K. Walker & Robert Dantzer

  2. Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, 1660 South Columbian Way, Seattle, WA, 98108, USA

    Emily E. Wing & William A. Banks

  3. Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, 98108, USA

    William A. Banks

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Correspondence to Robert Dantzer.

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R.D. has received honoraria from the Danone Nutricia Research, France, that are not related to the work presented in this article. The remaining authors declare no conflict of interest.

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Walker, A.K., Wing, E.E., Banks, W.A. et al. Leucine competes with kynurenine for blood-to-brain transport and prevents lipopolysaccharide-induced depression-like behavior in mice. Mol Psychiatry 24, 1523–1532 (2019). https://doi.org/10.1038/s41380-018-0076-7

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