Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection
Gilles J. Guillemin,Stephen J. Kerr,George A. Smythe,Danielle G. Smith,Vimal Kapoor,Patricia J. Armati,Juliana Croitoru,Bruce J. Brew +7 more
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It is shown that kynurenine in concentrations comparable with those produced by astrocytes led to significant production of QUIN by macrophages, suggesting that astroCytes alone are neuroprotective by minimizing QUIN production and maximizing synthesis of kynurenic acid.Abstract:
There is good evidence that the kynurenine pathway (KP) and one of its products, quinolinic acid (QUIN), play a role in the pathogenesis of neurological diseases, in particular AIDS dementia complex. Although QUIN has been shown to be produced in neurotoxic concentrations by macrophages and microglia, the role of astrocytes in QUIN production is controversial. Using cytokine-stimulated cultures of human astrocytes, we assayed key enzymes and products of the KP. We found that human astrocytes lack kynurenine hydroxylase so that large amounts of kynurenine and the QUIN antagonist kynurenic acid were produced. However, the amounts of QUIN that were synthesized were subsequently completely degraded. We then showed that kynurenine in concentrations comparable with those produced by astrocytes led to significant production of QUIN by macrophages. These results suggest that astrocytes alone are neuroprotective by minimizing QUIN production and maximizing synthesis of kynurenic acid. However, it is likely that, in the presence of macrophages and/or microglia, astrocytes become indirectly neurotoxic by the production of large concentrations of kynurenine that can be secondarily metabolized by neighbouring or infiltrating monocytic cells to form the neurotoxin QUIN.read more
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Kynurenines in the mammalian brain: when physiology meets pathology
TL;DR: With recently developed pharmacological agents, it is now possible to restore metabolic equilibrium and envisage novel therapeutic interventions on the basis of the kynurenine pathway.
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Endogenous kynurenines as targets for drug discovery and development
Trevor W. Stone,L. G. Darlington +1 more
TL;DR: The kynurenine pathway is the main pathway for tryptophan metabolism and generates compounds that can modulate activity at glutamate receptors and possibly nicotinic receptors, in addition to some as-yet-unidentified sites.
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Tryptophan and the immune response.
TL;DR: The issue of immunomodulatory actions of tryptophan catabolites is examined in detail, and the possible involvement of quinolinate as a means of replenishing NAD + in leucocytes, which is depleted by oxidative stress during an immune response.
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The new '5-HT' hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression.
TL;DR: It is concluded that activation of the TRYCAT pathway by IDO and TDO may be associated with the development of depressive symptoms through tryptophan depletion and the detrimental effects of TRYCats.
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Manipulation of Brain Kynurenines: Glial Targets, Neuronal Effects, and Clinical Opportunities
TL;DR: Pharmacological agents targeting specific KP enzymes can be used to normalize KP defects, show remarkable efficacy in animal models of central nervous system disorders, and offer novel therapeutic opportunities.
References
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Prevention of allogeneic fetal rejection by tryptophan catabolism
David H. Munn,Min Zhou,John T. Attwood,Igor Bondarev,Simon J. Conway,Brendan Marshall,Corrie C. Brown,Andrew L. Mellor +7 more
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Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain
TL;DR: Intracerebral injection of the neuroexcitatory tryptophan metabolite, quinolinic acid, has behavioral, neurochemical and neuropathological consequences reminiscent of those of exogenous excitotoxins, such as kainic and ibotenic acids.
Journal Article
Neuropharmacology of quinolinic and kynurenic acids.
TL;DR: Whatever the specific nature of their physiological roles, the presence of an endogenous selective agonist and antagonist acting at NMDA receptors must continue to present exciting possibilities for understanding the pathological basis of several CNS disorders as well as developing new therapeutic approaches.
Journal ArticleDOI
An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid
TL;DR: It is reported that kynurenine, kynurenic acid, nicotinic acid do not excite neurones in the cerebral cortex, but that quinolinic acid is an effective excitant.
Journal ArticleDOI
Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease.
Melvyn P. Heyes,Kuniaki Saito,Jeffrey S. Crowley,L. E. Davis,M. A. Demitrack,M. Der,L. A. Dilling,J. Elia,M. J. P. Kruesi,Andrew A. Lackner,S. A. Larsen,K. Lee,H. L. Leonard,Sanford P. Markey,Alex Martin,S. Milstein,M. Maral Mouradian,M. R. Pranzatelli,Bonnie J. Quearry,Andres M. Salazar,M. Smith,S. E. Strauss,T. Sunderland,S. W. Swedo,W. W. Tourtellotte +24 more
TL;DR: It is concluded that inflammatory diseases are associated with accumulation of QUIN, kynurenic acid and L-kynurenine within the central nervous system, but that the available data do not support a role for QUIN in the aetiology of Huntington's disease or Alzheimer's disease.