Human microglia convert <scp>l</scp>-tryptophan into the neurotoxin quinolinic acid

Heyes, Melvyn P.; Achim, Cristian L.; Wiley, Clayton A.; Major, Eugene O.; Saito, Kuniaki; Markey, Sanford P.

doi:10.1042/bj3200595

Cited by 284 publications

(219 citation statements)

References 13 publications

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“…Endogenous in the brain, it has been reproducibly reported to be neurotoxic, both in vivo and in culture (Kim and Choi, 1987;Schwarcz et al, 1983). Although levels of Quin in the brain are reported not normally to rise above 1 mmol/L, millimolar levels have been reported in various infectious disease states (Heyes et al, 1996). Quinolinic acid has been reported to stimulate basal glutamate release and to inhibit glutamate uptake into astrocytes and synaptic vesicles (Tavares et al, 2000(Tavares et al, , 2002.…”

Section: Kynurenine Pathway Metabolitesmentioning

confidence: 99%

A Metabolomic Approach to Ionotropic Glutamate Receptor Subtype Function: A Nuclear Magnetic Resonance in vitro Investigation

Rae

Moussa

Griffin

et al. 2005

J Cereb Blood Flow Metab

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A range of behaviours are elucidated via ionotropic glutamate receptors (iGluR). In this work, we examined the acute activation of iGluRs by a range of receptor ligands and effectors to see whether distinguishable metabolic sequelae were elucidated by the activity. We used a guinea-pig brain cortical tissue slice model using targeted receptor ligands ((RS)-(tetrazol-5-yl)glycine (TZG),, as well as compounds (quinolinic acid and kynurenic acid (KynA)) involved in some neuroinflammatory responses. The data were derived using 13 C and 1 H NMR spectroscopy, and analysed by metabolomic approaches and multivariate statistics. The metabolic effects of agonists at the three major classes of iGluR were easily separated from each other using this method. The classical N-methyl-D-aspartate receptor agonist TZG and the antagonist CGS 19755 produced excitatory and inhibitory metabolic responses, respectively, while the blocker MK-801 resulted in a significant decrease in net metabolism and produced the largest decrease in all metabolite pool sizes seen by any glutamatergic ligand we have studied. Quinolinic acid and KynA produced similar acute metabolic responses, which were unlike those to TZG or CGS 19755, but similar to that of D-Ser. D-Ser was highly stimulatory of net flux into the Krebs cycle. These data show that the metabolic response to iGluR perturbation in vitro is a sensitive discriminator of function.

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Section: Kynurenine Pathway Metabolitesmentioning

confidence: 99%

A Metabolomic Approach to Ionotropic Glutamate Receptor Subtype Function: A Nuclear Magnetic Resonance in vitro Investigation

Rae

Moussa

Griffin

et al. 2005

J Cereb Blood Flow Metab

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“…In the brain, murine and human microglia have been shown to express IDO upon treatment with IFN-γ [6,7]. In peripheral tissues, IDO expression is a common mechanism to suppress the proliferation of infectious parasites such as Chlamydia trachomatis [8] and Toxoplasma gondii [9,10] through Trp depletion.…”

Section: Introductionmentioning

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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“…25,26 KYN is able to pass the BBB 27 and human microglia have been shown capable of metabolizing this substance into its toxic metabolites. 28 In addition, peripherally immune-induced IDO activation has been shown to increase QUIN in both plasma and CSF with a highly significant correlation between the two measurements. 29 This supports the hypothesis that peripherally induced IDO activation is able to cause a neurotoxic challenge.…”

mentioning

confidence: 98%

IDO and interferon-α-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity

et al. 2004

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Studies show that administration of interferon (IFN)-a causes a significant increase in depressive symptoms. The enzyme indoleamine 2,3-dioxygenase (IDO), which converts tryptophan (TRP) into kynurenine (KYN) and which is stimulated by proinflammatory cytokines, may be implicated in the development of IFN-a-induced depressive symptoms, first by decreasing the TRP availability to the brain and second by the induction of the KYN pathway resulting in the production of neurotoxic metabolites. Sixteen patients with chronic hepatitis C, free of psychiatric disorders and eligible for IFN-a treatment, were recruited. Depressive symptoms were measured using the Montgomery Asberg Depression Rating Scale (MADRS). Measurements of TRP, amino acids competing with TRP for entrance through the blood-brain barrier, KYN and kynurenic acid (KA), a neuroprotective metabolite, were performed using high-performance liquid chromatography. All assessments were carried out at baseline and 1, 2, 4, 8, 12 and 24 weeks after treatment was initiated. The MADRS score significantly increased during IFN-a treatment as did the KYN/TRP ratio, reflecting IDO activity, and the KYN/KA ratio, reflecting the neurotoxic challenge. The TRP/CAA (competing amino acids) ratio, reflecting TRP availability to the brain, did not significantly change during treatment. Total MADRS score was significantly associated over time with the KYN/KA ratio, but not with the TRP/CAA ratio. Although no support was found that IDO decreases TRP availability to the brain, this study does support a role for IDO activity in the pathophysiology of IFN-a-induced depressive symptoms, through its induction of neurotoxic KYN metabolites. Molecular Psychiatry (2005) 10, 538-544.

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Human microglia convert l-tryptophan into the neurotoxin quinolinic acid

Cited by 284 publications

References 13 publications

A Metabolomic Approach to Ionotropic Glutamate Receptor Subtype Function: A Nuclear Magnetic Resonance in vitro Investigation

A Metabolomic Approach to Ionotropic Glutamate Receptor Subtype Function: A Nuclear Magnetic Resonance in vitro Investigation

IDO expression in the brain: a double-edged sword

IDO and interferon-α-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity

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