Kynurenic acid antagonises responses to NMDA via an action at the strychnine-insensitive glycine receptor

Birch, P.J.; Grossman, Carol J.; Hayes, Ann G.

doi:10.1016/0014-2999(88)90367-6

Cited by 289 publications

(147 citation statements)

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“…7 Thus, several cytokines are able to induce or repress critical enzymes of the kynurenine pathway like indoleamine 2,3-dioxygenase (IDO) and kynurenine 3-monooxygenase (KMO), 22,23 leading to increased KYNA production. Kynurenic acid is an antagonist at the glycine site of the N-methyl-D-aspartate receptor 24,25 as well as at the cholinergic α7* nicotinic receptor, 26 and hence provides a potential link between the immune system and glutamatergic/ cholinergic neurotransmission. The elevation of KYNA in CSF from patients with bipolar disorder may therefore be causally related to the presently shown activation of IL-1β.…”

Section: Discussionmentioning

confidence: 99%

Elevation of cerebrospinal fluid interleukin-1β in bipolar disorder

Söderlund

Olsson

Samuelsson

et al. 2011

J Psychiatry Neurosci

168

121

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Background:In recent years, a role for the immune system in the pathogenesis of psychiatric diseases has gained increased attention.Although bipolar disorder appears to be associated with altered serum cytokine levels, a putative immunological contribution to its pathophysiology remains to be established. Hitherto, no direct analyses of cerebrospinal fluid (CSF) cytokines in patients with bipolar disorder have been performed. Methods: We analyzed CSF cytokine concentrations in euthymic patients with diagnosed bipolar dis order type I (n = 15) or type II (n = 15) and healthy volunteers (n = 30) using an immunoassay-based protein array multiplex system. Results: The mean interleukin (IL)-1β level (4.2 pg/mL, standard error of the mean [SEM] 0.5) was higher and the IL-6 level (1.5 pg/mL, SEM 0.2) was lower in euthymic bipolar patients than in healthy volunteers (0.8 pg/mL, SEM 0.04, and 2.6 pg/mL, SEM 0.2, respect ively). Patients with 1 or more manic/hypomanic episodes during the last year showed significantly higher levels of IL-1β (6.2 pg/mL, SEM 0.8; n = 9) than patients without a recent manic/hypomanic episode (3.1 pg/mL, SEM 1.0; n = 10). Limitations: All patients were in an euthymic state at the time of sampling. Owing to the large variety of drugs prescribed to patients in the present study, influence of medication on the cytokine profile cannot be ruled out. Conclusion: Our findings show an altered brain cytokine profile associated with the manifestation of recent manic/hypomanic episodes in patients with bipolar disorder. Although the causality remains to be established, these findings may suggest a pathophysiological role for IL-1β in bipolar disorder. In recent years, a role of the immune system in the pathogenesis of psychiatric diseases has gained increased attention. In this regard, many investigators have focused on cytokines, proteins that directly initiate and control immunological responses. We recently demonstrated a selective activation of brain interleukin (IL)-1β in schizophrenia, 2 a disease that appears similar to bipolar disorder with regard to symptomatology, treatment and risk genes. 3,4 Interestingly, a polymorphism in the promoter region of the IL1B gene has been suggested to comprise a shared genetic susceptibility for bipolar disorder and schizophrenia. 5 Indeed, bipolar disorder appears to be linked to inflammation, as indicated by genetic polymorphisms, gene expression and cytokine activation, 6 although direct evidence for a pathophysiological involvement of the immune system of the brain is still sparse. This may be 115 related to the fact that evaluation of cytokine levels in patients with bipolar disorder has been restricted to serum analyses. The bidirectional communication between the immune system of the brain and that of peripheral organs is complex, 7 and serum cytokines do not predict brain cytokine activation in healthy volunteers. 8 Hence, the immune system of the brain, including local cytokine release from microglia and astrocytes, may be independent of the immune sys...

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Section: Discussionmentioning

confidence: 99%

Elevation of cerebrospinal fluid interleukin-1β in bipolar disorder

Söderlund

Olsson

Samuelsson

et al. 2011

J Psychiatry Neurosci

168

121

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“…KYNA is a noncompetitive antagonist of the NMDA receptor ion-channel complex, acting on the strychnine-insensitive glycine recognition site (Birch et al, 1988), with an IC 50 in the low micromolar range (IC 50 ¼ 7.9 mM; Ganong and Cotman, 1986;Kessler et al, 1989;Parsons et al, 1997). Furthermore, a recent study showed that KYNA blocks the a7* nicotinic receptor with the same IC 50 value as for the glycine-site of the NMDA receptors (Hilmas et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Action of Clozapine on Rat Ventral Tegmental Area Dopamine Neurons Following Increased Levels of Endogenous Kynurenic Acid

Schwieler

Erhardt

2003

Neuropsychopharmacol

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The mode of action by which the atypical antipsychotic drug clozapine exerts its superior efficacy to ameliorate both positive and negative symptoms is still unknown. In the present in vivo electrophysiological study, we investigate the effects of haloperidol (a typical antipsychotic drug) and clozapine on ventral tegmental area (VTA) dopamine (DA) neurons in a situation of hyperdopaminergic activity in order to mimic tentatively a condition similar to that seen in schizophrenia. Increased DA transmission was induced by elevating endogenous levels of the N-methyl-D-aspartate receptor and a7* nicotinic receptor antagonist kynurenic acid (KYNA; by means of PNU 156561A, 40 mg /kg, i.v.). In control rats, i.v. administered haloperidol (0.05-0.8 mg/kg) or clozapine (1.25-10 mg/kg) was associated with increased firing rate and burst firing activity of VTA DA neurons. However, in rats displaying hyperdopaminergia (induced by elevated levels of KYNA), the effects of clozapine on VTA DA neurons were converted into pure inhibitory responses, including decrease in burst firing activity. In contrast, haloperidol still produced an excitatory action on VTA DA neurons in rats with elevated levels of endogenous brain KYNA. The results of the present study suggest that clozapine facilitates or inhibits VTA DA neurotransmission, depending on brain concentration of KYNA. Such an effect of clozapine may be related to its unique effect in also ameliorating negative symptoms of schizophrenia.

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“…To determine whether there was durable improvement in survival, unanesthetized and unrestrained animals with or without KYNA should be exposed to heat stress in future studies. Recent findings have documented that unanesthetized, unrestrained rodents display thermoregulatory deficits (eg, the heatstroke animals showed hypothermia when exposed to room temperature, 26 °C) 4 h after the initiation of heat stress [17,18] . The heatstroke-induced thermoregulatory deficits may have resulted from neuronal apoptosis and cell degeneration in the hypothalamus (as demonstrated in the current study).…”

Section: Discussionmentioning

confidence: 99%

Kynurenic acid attenuates multiorgan dysfunction in rats after heatstroke

Hsieh

Chen

Yeh³

et al. 2011

Acta Pharmacol Sin

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IntroductionHeatstroke is defined as a form of excessive hyperthermia (>40 °C) associated with a systemic inflammatory response that leads to multi-organ dysfunction in which central nervous system (CNS) disorders such as delusion, convulsion and coma predominate [1] . Our recent results have demonstrated that heatstroke rodents display hypotension, systemic inflammatory responses, hypothalamic ischemia and neuronal damage, and multi-organ dysfunction [2][3][4] .Kynurenic acid (KYNA) or its metabolic precursor L-kynurenine may be of therapeutic value in neurodegenerative diseased models [5,6] . For example, systemically administered high doses of KYNA had a neuroprotective effect in the gerbil model of global ischemia [7] . Both the homocysteine-induced impairment of endothelial cells [8] and the motility and inflammatory activation in the early phase of acute experimental colitis in the rat [9] were significantly reduced by administration of KYNA. The aim of this study was to investigate whether the heatstroke induced hypotension, systemic inflammatory responses, hypothalamic ischemia and damage, and multiorgan dysfunction could be attenuated by KYNA preconditioning. Accordingly, the temporal profiles of the apoptotic cell numbers of spleen, kidney, liver, lung, and hypothalamus, Kynurenic acid attenuates multiorgan dysfunction in rats after heatstroke Aim: To assess whether systemic delivery of kynurenic acid improves the outcomes of heatstroke in rats. Methods: Anesthetized rats were divided into 2 major groups and given vehicle solution (isotonic saline 0.3 mL/kg rat weight) or kynurenic acid (30-100 mg in 0.3 mL saline/kg) 4 h before the start of thermal experiments. They were exposed to an ambient temperature of 43 ºC for 68 min to induce heatstroke. Another group of rats were exposed to room temperature (26 ºC) and used as normothermic controls. Their core temperatures, mean arterial pressures, serum levels of systemic inflammatory response molecules, hypothalamic values of apoptotic cells and neuronal damage scores, and spleen, liver, kidney and lung values of apoptotic cells were determined. Results: The survival time values during heatstroke for vehicle-treated rats were decreased from the control values of 475-485 min to new values of 83-95 min. Treatment with KYNA (30-100 mg/kg, iv) 4 h before the start of heat stress significantly and dose-dependently decreased the survival time to new values of 152-356 min (P<0.05). Vehicle-treated heatstroke rats displayed hypotension, hypothalamic neuronal degeneration and apoptosis, increased serum levels of tunor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and interleukin-10 (IL-10), and spleen, liver, kidney, and lung apoptosis. KYNA preconditioning protected against hypotension but not hyperthermia and attenuated hypothalamic neuronal degeneration and apoptosis during heatstroke. KYNA preconditioning attenuated spleen, kidney, liver, and lung apoptosis and up-regulated serum IL-10 levels but down-regulated serum TNF-α and ICAM-1 lev...

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Kynurenic acid antagonises responses to NMDA via an action at the strychnine-insensitive glycine receptor

Cited by 289 publications

References 3 publications

Elevation of cerebrospinal fluid interleukin-1β in bipolar disorder

Elevation of cerebrospinal fluid interleukin-1β in bipolar disorder

Inhibitory Action of Clozapine on Rat Ventral Tegmental Area Dopamine Neurons Following Increased Levels of Endogenous Kynurenic Acid

Kynurenic acid attenuates multiorgan dysfunction in rats after heatstroke

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