Inflammation is a leading cause of depression in physically ill patients. Using clinical and preclinical approaches we have demonstrated that peripheral inflammation activates the tryptophan-degrading enzyme indoleamine 2, 3 dioxygenase (IDO1), which promotes the transition from sickness to depression. IDO1 metabolizes tryptophan into kynurenine that is transported into the brain and metabolized further into neurotoxic kynurenine metabolites by activated microglia. The objective of this grant application is to determine whether inflammation-induced depression can be targeted at the level of the blood-brain barrier transport mechanisms that mediate the influx and efflux of tryptophan and kynurenine. There is already evidence that kynurenine does not diffuse passively across the blood-brain barrier but is transported into the brain from the periphery via the same transporter as the one that mediates tryptophan influx into the brain. This transporter is known as system L and its catalytic unit is the large neutral amino acid transporter LAT1. Using an in vitro model of the blood brain barrier based on primary cultures of brain endothelial cells we have obtained preliminary evidence that exposure of microvascular endothelial cells to lipopolysaccharide (LPS) and interferon-? (IFN?) a classical inducer of IDO1, induces expressio of IDO1 in these cells and enhances at the same time transport functionality for tryptophan. This facilitates the influx of tryptophan into the brain, which is further strengthened by kynurenine as addition of kynurenine to the culture increases tryptophan permeability. Such a process could help the brain maintain high concentrations of tryptophan despite decreasing concentrations of this amino acid in the general circulation. These preliminary results are important as they indicate that (a) IDO1 activation in blood-brain barrier endothelial cells could be an important source of kynurenine influx in the brain, and (b) blood-brain barrier transport mechanisms of large neutral amino acids are sensitive to inflammation and to variations in concentrations of LAT1 substrates. Proof of principle experiments with systemic administration of leucine in vivo confirm the feasibility of this approach as they reveal an anti-depressant activity profile of this LAT1 substrate. Further understanding of the role of kynurenine generated at the level of the blood-brain barrier and the movements of tryptophan and kynurenine across the blood-brain barrier during inflammation opens the possibility of preventing inflammation-induced depression by administering compounds that compete with these movements. To reach this objective, we have assembled a multidisciplinary research team with expertise in brain transport systems in inflammation and in inflammation-induced depression. We will use both in vitro and in vivo approaches to identify ways of interfering with transport mechanisms of kynurenine across the blood-brain barrier. The planed use of mice with cell specific deletion of IDO1 in their brain vasculature is an important asset of the proposed project.

Public Health Relevance

Major depressive disorders are the second largest burden of disease in the developed world and a leading cause of disability. Although inflammation is already known to induce depression in physically ill patients by producing neurotoxic kynurenine metabolites, we do not how it impacts on the mechanisms that control the transport of kynurenine across the blood-brain barrier. In this project we will examine for the first time these mechanisms in order to discover how to interfere with them in order to abrogate the deleterious effects of peripheral inflammation on the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21MH104694-01A1
Application #
8892351
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Desmond, Nancy L
Project Start
2015-05-15
Project End
2017-03-31
Budget Start
2015-05-15
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Walker, Adam K; Wing, Emily E; Banks, William A et al. (2018) Leucine competes with kynurenine for blood-to-brain transport and prevents lipopolysaccharide-induced depression-like behavior in mice. Mol Psychiatry :
Meier, Timothy B; Drevets, Wayne C; Teague, T Kent et al. (2018) Kynurenic acid is reduced in females and oral contraceptive users: Implications for depression. Brain Behav Immun 67:59-64
Vichaya, Elisabeth G; Dantzer, Robert (2018) Inflammation-induced motivational changes: Perspective gained by evaluating positive and negative valence systems. Curr Opin Behav Sci 22:90-95
Dantzer, Robert (2018) Neuroimmune Interactions: From the Brain to the Immune System and Vice Versa. Physiol Rev 98:477-504
Colpo, Gabriela D; Leboyer, Marion; Dantzer, Robert et al. (2018) Immune-based strategies for mood disorders: facts and challenges. Expert Rev Neurother 18:139-152
Khandaker, G M; Dantzer, R; Jones, P B (2017) Immunopsychiatry: important facts. Psychol Med 47:2229-2237
Dantzer, Robert (2017) Role of the Kynurenine Metabolism Pathway in Inflammation-Induced Depression: Preclinical Approaches. Curr Top Behav Neurosci 31:117-138
LaVoy, Emily C P; Fagundes, Christopher P; Dantzer, Robert (2016) Exercise, inflammation, and fatigue in cancer survivors. Exerc Immunol Rev 22:82-93
Remus, Jennifer L; Dantzer, Robert (2016) Inflammation Models of Depression in Rodents: Relevance to Psychotropic Drug Discovery. Int J Neuropsychopharmacol 19: