Quinolinic acid: A potent endogenous excitant at amino acid receptors in CNS

Stone, T.W.; Perkins, M.N.

doi:10.1016/0014-2999(81)90587-2

Cited by 701 publications

(375 citation statements)

References 2 publications

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“…QUIN is an endogen Nmethyl-D-aspartate (NMDA) receptor agonist [55]. At micromolar concentrations, the excitotoxic effect of QUIN can be mimicked in primary cortical neuronal cell cultures [56].…”

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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Section: Possible Mechanisms Of Ido-mediated Tolerance Inductionmentioning

confidence: 99%

IDO expression in the brain: a double-edged sword

2007

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“…One endogenous pathway which is known to include compounds capable of modifying NMDA receptor function is the kynurenine pathway of tryptophan oxidative metabolism (Stone, 1993(Stone, , 2001Stone and Darlington, 2002). This pathway -the major route of tryptophan metabolism -includes quinolinic acid, an agonist at NMDARs (Stone and Perkins, 1981) and kynurenic acid Protein expression was examined in embryos 5 and 24 hours after the administration of Ro61-8048 and in the brains of offspring at 21 days of age (P21), the time of weaning. The data reveal immediate effects of kynurenine pathway inhibition on NMDA receptor expression with additional, substantial changes at P21 in the expression of several proteins of importance to brain development.…”

Section: Introductionmentioning

confidence: 99%

Prenatal inhibition of the tryptophan–kynurenine pathway alters synaptic plasticity and protein expression in the rat hippocampus

et al. 2013

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Glutamate receptors sensitive to N-methyl-D-aspartate (NMDA) are important in early brain development, influencing cell proliferation and migration, neuritogenesis, axon guidance and synapse formation. The kynurenine pathway of tryptophan metabolism includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at these receptors.Rats were treated in late gestation with 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]-benzene-sulphonamide (Ro61-8048), an inhibitor of kynurenine-3-monoxygenase which diverts kynurenine metabolism to kynurenic acid. Within 5h of drug administration there was a significant decrease in GluN2A expression and increased GluN2B in the embryo brains, with changes in sonic hedgehog at 24h. When injected dams were allowed to litter normally, the brains of offspring were removed at postnatal day 21 (P21). Recordings of hippocampal field excitatory synaptic potentials (fEPSPs) showed that prenatal exposure to Ro61-8048 increased neuronal excitability and paired-pulse facilitation. Long-term potentiation was also increased, with no change in long-term depression. At this time, levels of GluN2A, GluN2B and postsynaptic density protein PSD-95 were all increased.Among several neurodevelopmental proteins, the expression of sonic hedgehog was increased, but DISC1 and dependence receptors were unaffected, while raised levels of doublecortin and Proliferating Cell Nuclear Antigen (PCNA) suggested increased neurogenesis. The results reveal that inhibiting the kynurenine pathway in utero leads to molecular and functional synaptic changes in the embryos and offspring, indicating that the pathway is active during gestation and plays a significant role in the normal early development of the embryonic and neonatal nervous system. 3

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“…There is much evidence supporting the hypothesis that the kynurenine pathway plays a critical causative role in the pathophysiology of several neurodegenerative disorders. Quinolinate selectively activates NMDA receptors, which can lead to excitotoxicity, and intrastriatal injections of this metabolite lead to axon-sparing neuronal lesions proximal to the site of injection [13,14]. Quinolate has been also related to mitochondrial dysfunction [15]) and has been demonstrated to cause neurodegeneration in cultures of rat corticostriatal system [16].…”

Section: Discussionmentioning

confidence: 99%

A Novel p.Glu298Lys Mutation in the ACMSD Gene in Sporadic Parkinson’s Disease

Vilas

Fernández‐Santiago

Sánchez

et al. 2017

JPD

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Abstract.Background: Common genetic variability in the ACMSD gene has been associated with increased risk for Parkinson's disease (PD) but ACMSD mutations in clinical cases of PD have so far not been reported. Objective: To describe a case of sporadic PD carrying a novel ACMSD mutation. Methods: As part of a genetic study to identify potential pathogenic gene defects related to PD in the Mediterranean island Menorca, an initial group of 62 PD patients underwent mutational screening using a panel-based sequencing approach. Results: We report a 74-years-old man with sporadic PD who developed tremor in his right hand and slowness. On examination, moderate rigidity, asymmetric bradykinesia, and bilateral action tremor were present. He was started on levodopa with significant improvement. Two years later, he developed wearing off phenomena. The genetic study in the patient identified a novel ACMSD mutation resulting in p.Glu298Lys amino-acid change which was not present in neurologically normal population. Conclusions: Our data suggest that not only common genetic variability but also rare variants in ACMSD alone or in combination with other risk factors might increase the risk of PD.

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Quinolinic acid: A potent endogenous excitant at amino acid receptors in CNS

Cited by 701 publications

References 2 publications

IDO expression in the brain: a double-edged sword

IDO expression in the brain: a double-edged sword

Prenatal inhibition of the tryptophan–kynurenine pathway alters synaptic plasticity and protein expression in the rat hippocampus

A Novel p.Glu298Lys Mutation in the ACMSD Gene in Sporadic Parkinson’s Disease

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