An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid

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

doi:10.1016/0006-8993(82)91048-4

Cited by 797 publications

(427 citation statements)

References 6 publications

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“…Whereas QA is a neurotoxin that in elevated concentrations can act as an agonist of the NMDA receptor, and 3HK is a potent free radical donor that promotes oxidative stress, and KA acts as an antagonist of both the glycine co-agonist site of the NMDA receptor and the a7 nicotinic receptor situated on glutamatergic neuronal terminals in the hippocampus and other brain regions, reducing glutamate release (Hilmas et al, 2001;Kessler et al, 1989;Perkins and Stone, 1982;Potter et al, 2010;Schwarcz et al, 1983).…”

Section: Discussionmentioning

confidence: 99%

“…At least a subgroup of individuals with MDD also display putative signs of inflammation such as elevated circulating concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), and interleukin-1b (IL-1b) (Dowlati et al, 2010;Howren et al, 2009). Inflammation can also lead to the activation of the tryptophan (TRP)-degrading enzyme indoleamine 2,3 dioxygenase (IDO), ultimately increasing the formation of kynurenine (KYN) metabolites, including kynurenic acid (KA), a putatively neuroprotective antagonist of N-methyl-D-aspartate (NMDA) receptors that also decreases glutamate levels via inhibition of a7 nicotinic receptors 3-hydroxykynurenine (3HK), a free radical generator, and quinolinic acid (QA), an NMDA receptor agonist that also exerts neurotoxic effects via lipid peroxidation, and disruption of the blood-brain barrier (Dantzer et al, 2011;Maes et al, 2011;Perkins and Stone, 1982;Schwarcz et al, 2012;Schwarcz et al, 1983) (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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Putative Neuroprotective and Neurotoxic Kynurenine Pathway Metabolites Are Associated with Hippocampal and Amygdalar Volumes in Subjects with Major Depressive Disorder

Savitz

Drevets

Smith

et al. 2014

Neuropsychopharmacol

213

139

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Inflammation-related changes in the concentrations of kynurenine pathway metabolites occur in depression secondary to medical conditions but are not firmly established in primary mood disorders. Reductions in hippocampal and amygdalar volume that putatively reflect dendritic atrophy are widely reported in major depressive disorder (MDD). Here we tested whether the relative serum concentrations of putatively neuroprotective (kynurenic acid (KA)) and neurotoxic (3-hydroxykynurenine (3HK) and quinolinic acid (QA)) kynurenine pathway metabolites were altered in primary MDD and whether these metabolites were associated with hippocampal and amygdalar volume. A total of 29 moderately to severely depressed unmedicated subjects who met DSM-IV criteria for MDD and 20 healthy controls (HCs) completed a structural MRI scan and provided blood sample for kynurenine metabolite analysis, performed using high-performance liquid chromatography with tandem mass spectrometry. Cytokine concentrations were measured with ELISA and gray matter volumes were measured with the automated segmentation software, FreeSurfer. An a priori defined variable of interest, the KA/ QA ratio, a putative neuroprotective index, trended lower in the MDD versus the HC group and correlated negatively with anhedonia but positively with the total hippocampal and amygdala volume in the MDD subjects. The post hoc data reduction methods yielded three principal components. Component 1 (interleukin-1 receptor antagonist, QA, and kynurenine) was significantly elevated in MDD participants versus the HCs, whereas component 2 (KA, tryptophan, and kynurenine) was positively correlated with hippocampal and amygdala volume within the MDD group. Our results raise the possibility that an immune-related imbalance in the relative metabolism of KA and QA predisposes to depression-associated dendritic atrophy and anhedonia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Putative Neuroprotective and Neurotoxic Kynurenine Pathway Metabolites Are Associated with Hippocampal and Amygdalar Volumes in Subjects with Major Depressive Disorder

Savitz

Drevets

Smith

et al. 2014

Neuropsychopharmacol

213

139

View full text Add to dashboard Cite

show abstract

“…KA is known as a noncompetitive NMDA receptor antagonist [60]. Therefore, KA might counteract the neurotoxic effect of QUIN.…”

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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“…, 1986). The systemic administration of the non specific glutamate antagonist kynurenic acid (Perkins and Stone, 1982) reduced the amount of histological damage in a survival MCA occlusion model in the rat (Simon et aI. , 1986).…”

Section: Volumetric Assessment Of the Ischemic Damagementioning

confidence: 99%

Protective Effect of the Glutamate Antagonist, MK-801 in Focal Cerebral Ischemia in the Cat

Özyurt

Graham

Woodruff

et al. 1988

J Cereb Blood Flow Metab

360

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Summary:The effects of the glutamate N-methyl-D aspartate (NMDA) receptor antagonist, MK-801, upon ischemic brain damage has been examined in anesthe tized cats. Focal cerebral ischemia was produced by per manent occlusion of one middle cerebral artery and the animals were killed 6 h later. The amount of early isch emic damage was assessed in coronal sections at 16 pre determined stereotactic planes. Pretreatment with MK-801 (5 mg/kg, i.v.). 30 min before occlusion of the Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system. The ac tions of glutamate are mediated via three pharma cologically distinct subtypes of receptor, the no menclature of which reflects the preferred agonist at each receptor subtype viz. the quisqualate-, kainate-, and N-methyl-D-aspartate-(NMDA)-pre ferring receptor (Greenamyre et aL, 1985). Gluta mate has recently been implicated in the patho physiology of cerebral ischemia (Meldrum 1985; Rothman and Olney, 1986). Glutamate itself is neu rotoxic when injected into cerebral tissue (Rothman and Olney, 1986). Cerebral ischemia is associated with a massive increase in extracellular glutamate concentrations (Benveniste et aL, 1984;Hagberg et aL, 1985). Destruction of glutamatergic afferent pathways or intracerebral administration of NMDA receptor antagonists can reduce the early ischemic damage to the hippocampus in cerebral ischemia and the neuronal necrosis which is observed sev eral days after a period of cerebral ischemia or se-

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An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid

Cited by 797 publications

References 6 publications

Putative Neuroprotective and Neurotoxic Kynurenine Pathway Metabolites Are Associated with Hippocampal and Amygdalar Volumes in Subjects with Major Depressive Disorder

Putative Neuroprotective and Neurotoxic Kynurenine Pathway Metabolites Are Associated with Hippocampal and Amygdalar Volumes in Subjects with Major Depressive Disorder

IDO expression in the brain: a double-edged sword

Protective Effect of the Glutamate Antagonist, MK-801 in Focal Cerebral Ischemia in the Cat

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