Blood–Brain Barrier Transport of Kynurenines: Implications for Brain Synthesis and Metabolism

Fukui, Sugao; Schwarcz, Robert; Rapoport, Stanley I.; Takada, Yoshiaki; Smith, Quentin R.

doi:10.1111/j.1471-4159.1991.tb03460.x

Cited by 667 publications

(545 citation statements)

References 46 publications

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“…These post-translational factors constitute novel targets for regulating stress-induced increased IDO1-KYN pathway activity. The IDO1 enzyme catalyzes TRP-KYN pathway activity in periphery and brain, and TRP, KYN and 3-HK are also transported actively across the bloodbrain-barrier via a large neutral amino acid transporter (Fukui et al, 1991). Regarding the site-of-action of IDOInh on the KYN pathway, the in vitro and in vivo data indicate that its main effect is in the periphery: the estimated protein-unbound IDOInh exposure in blood was 1.8x and in CSF only 0.2x its IC 50 for IDO1.…”

Section: Ido1 Inhibition Blocks Kynurenine Pathway Activation and Excmentioning

confidence: 99%

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Fuertig

Azzinnari

Bergamini

et al. 2016

Brain, Behavior, and Immunity

118

125

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Psychosocial stress is a major risk factor for mood and anxiety disorders, in which excessive reactivity to aversive events/stimuli is a major psychopathology. In terms of pathophysiology, immuneinflammation is an important candidate, including high blood and brain levels of metabolites belonging to the kynurenine pathway. Animal models are needed to study causality between psychosocial stress, immune-inflammation and hyper-reactivity to aversive stimuli. The present mouse study investigated effects of psychosocial stress as chronic social defeat (CSD) versus control-handling (CON) on: Pavlovian tone-shock fear conditioning, activation of the kynurenine pathway, and efficacy of a specific inhibitor (IDOInh) of the tryptophan-kynurenine catabolizing enzyme indoleamine 2,3-dioxygenase (IDO1), in reversing CSD effects on the kynurenine pathway and fear. CSD led to excessive fear learning and memory, whilst repeated oral escitalopram (antidepressant and anxiolytic) reversed excessive fear memory, indicating predictive validity of the model. CSD led to higher blood levels of TNF-, IFN-, kynurenine (KYN), 3-hydroxykynurenine (3-HK) and kynurenic acid, higher KYN and 3-HK in amygdala and hippocampus. However, CSD was without effect on IDO1 gene or protein expression in spleen, ileum and liver, whilst increasing liver TDO2 gene expression. Nonetheless, oral IDOInh reduced blood and brain levels of KYN and 3-HK in CSD mice to CON levels, and we therefore infer that CSD increases IDO1 activity by increasing its post-translational activation. Furthermore, repeated oral IDOInh reversed excessive fear memory in CSD mice to CON levels. IDOInh reversal of CSD-induced hyper-activity in the kynurenine pathway and fear system contributes significantly to the evidence for a causal pathway between psychosocial stress, immune-inflammation and the excessive fearfulness that is a major psychopathology in stress-related neuropsychiatric disorders. ABSTRACTPsychosocial stress is a major risk factor for mood and anxiety disorders, in which excessive reactivity to aversive events/stimuli is a major psychopathology. In terms of pathophysiology, immune-inflammation is an important candidate, including high blood and brain levels of metabolites belonging to the kynurenine pathway. Animal models are needed to study causality between psychosocial stress, immune-inflammation and hyper-reactivity 3-HK in CSD mice to CON levels, and we therefore infer that CSD increases IDO1 activity by increasing its post-translational activation. Furthermore, repeated oral IDOInh reversed excessive fear memory in CSD mice to CON levels. IDOInh reversal of CSD-induced hyperactivity in the kynurenine pathway and fear system contributes significantly to the evidence for a causal pathway between psychosocial stress, immune-inflammation and the excessive fearfulness that is a major psychopathology in stress-related neuropsychiatric disorders.3

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Section: Ido1 Inhibition Blocks Kynurenine Pathway Activation and Excmentioning

confidence: 99%

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Fuertig

Azzinnari

Bergamini

et al. 2016

Brain, Behavior, and Immunity

118

125

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“…However, in the absence of local inflammatory signals, the vast majority of Trp is not degradative to neurotoxic substances [78]. L-Kynurenine is also imported into the CNS by large neutral amino acid transporters and subsequently taken up by astrocytes and maybe microglia [79]. 3-Hydroxykynurenine is incorporated in the same way as L-kynurenine.…”

Section: Possible Mechanisms Of Ido-mediated Tolerance Inductionmentioning

confidence: 99%

IDO expression in the brain: a double-edged sword

2007

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The tryptophan-catabolizing enzyme indoleamine-2,3-dioxygenase (IDO) initiates the first and ratelimiting step of the kynurenine pathway. It is induced by proinflammatory cytokines such as interferon-β and interferon-γ and has established effects in the control of intracellular parasites. The recent detection of its decisive function in immune tolerance at the maternal-fetal interface stimulated various studies unraveling its regulatory effect on T cells in many pathologies. In the brain, IDO can be induced in microglia by interferon-γ-producing T helper (Th) 1 cells, thereby initiating a negative feedback loop which downmodulates neuroinflammation in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). This protective effect could to be counteracted by the production of neurotoxic metabolites of the kynurenine pathway such as quinolinic acid, which are produced upon IDO induction. Some metabolites of the kynurenine pathway can pass the blood-brain barrier and thus could act as neurotoxins, e.g., during systemic infection. In this paper, we give a brief overview on established immune regulatory functions of IDO, review recent data on IDO expression in the brain, and propose that autoimmune neuroinflammation and the increasingly appreciated neuronal damage in MS are linked by Th1-mediated IDO induction through subsequent synthesis of toxic metabolites of tryptophan.

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“…8,12 IDO is also expressed in brain endothelial cells, perivascular macrophages, astrocytes and microglia, 13 so that fluctuations in its enzymatic activity can alter brain tryptophan metabolism. Alternatively, the major product of peripheral tryptophan degradation by IDO, kynurenine, is readily transported across the blood-brain barrier 14 into the brain where it can be further metabolized by perivascular macrophages, microglia and astrocytes to generate neuroactive glutamatergic compounds. 13 In fact, heightened glutamate receptor activity may play an important role in major depression.…”

Section: Introductionmentioning

confidence: 99%

“…48,49 While kynurenine itself is not neuroactive, it readily crosses the bloodbrain barrier via the large neutral amino-acid transporter. 14 The kynurenine pathway results in the generation of three neuroactive compounds, all of which are derived from L-kynurenine. 3-Hydroxykynurenine and quinolinic acid are generated in route to nicotinamide adenine dinucleotide production, while kynurenic acid is formed in a 'dead-end' branch of the pathway.…”

mentioning

confidence: 99%

Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

O’Connor

Lawson²,

André³

et al. 2008

Mol Psychiatry

1,123

992

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Although elevated activity of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) has been proposed to mediate comorbid depression in inflammatory disorders, its causative role has never been tested. We report that peripheral administration of lipopolysaccharide (LPS) activates IDO and culminates in a distinct depressive-like behavioral syndrome, measured by increased duration of immobility in both the forced-swim and tail suspension tests. Blockade of IDO activation either indirectly with the anti-inflammatory tetracycline derivative minocycline, that attenuates LPS-induced expression of proinflammatory cytokines, or directly with the IDO antagonist 1-methyltryptophan (1-MT), prevents development of depressive-like behavior. Both minocycline and 1-MT normalize the kynurenine/tryptophan ratio in the plasma and brain of LPS-treated mice without changing the LPS-induced increase in turnover of brain serotonin. Administration of L-kynurenine, a metabolite of tryptophan that is generated by IDO, to naive mice dose dependently induces depressive-like behavior. These results implicate IDO as a critical molecular mediator of inflammation-induced depressive-like behavior, probably through the catabolism of tryptophan along the kynurenine pathway.

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Blood–Brain Barrier Transport of Kynurenines: Implications for Brain Synthesis and Metabolism

Cited by 667 publications

References 46 publications

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

IDO expression in the brain: a double-edged sword

Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

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