Identification and quantification of kynurenic acid in human brain tissue

Turski, Waldemar A.; Nakamura, Masayuki; Todd, W. P.; Carpenter, Barry K.; Whetsell, William O.; Schwarcz, Robert

doi:10.1016/0006-8993(88)90815-3

Cited by 200 publications

(98 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although endogenous KYNA can also activate the G-protein-coupled receptor GPR35 (Cosi et al, 2010;Wang et al, 2006), inhibition of a7nAChRs and, possibly, NMDARs appears to be the primary physiological function of extracellular KYNA in the mammalian brain (see below). As both a7nAChRs and NMDARs are critically involved in many important physiological functions, including cognitive processes (Bannerman et al, 2006;Levin et al, 2006;Robbins and Murphy, 2006;Thomsen et al, 2010), and also have a role in the etiology of neurodegenerative and other catastrophic brain diseases (Kalia et al, 2008;Kantrowitz and Javitt, 2010;Martin and Freedman, 2007;Mudo et al, 2007), detection of KYNA in the mammalian brain (Moroni et al, 1988;Turski et al, 1988) immediately suggested an important role of the metabolite in both physiology and pathology (Pereira et al, 2002;Schwarcz et al, 1992). The idea was reinforced by the discovery of specific mechanisms controlling KYNA synthesis in the brain (Gramsbergen et al, 1997) and, in particular, by reports of abnormal KYNA levels in nervous tissue and body fluids in a host of neurological and psychiatric disorders (for review see Chen et al, 2009;Nemeth et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…KYNA fluctuations may be especially consequential in the human brain, where KYNA levels are an order of magnitude higher than in rodents (Moroni et al, 1988;Turski et al, 1988). Moreover, KYNA levels are significantly elevated in the brain and the cerebrospinal fluid of individuals with schizophrenia, and in the brain of Alzheimer's disease patients, raising the possibility that enhanced inhibition of a7nAChRs and NMDARs by KYNA has a causative role in the defining cognitive deficits seen in these diseases (Baran et al, 1999;Erhardt et al, 2001;Schwarcz et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Pocivavsek

Potter

et al. 2011

Neuropsychopharmacol

Self Cite

141

158

View full text Add to dashboard Cite

Kynurenic acid (KYNA), an astrocyte-derived metabolite, antagonizes the a7 nicotinic acetylcholine receptor (a7nAChR) and, possibly, the glycine co-agonist site of the NMDA receptor at endogenous brain concentrations. As both receptors are involved in cognitive processes, KYNA elevations may aggravate, whereas reductions may improve, cognitive functions. We tested this hypothesis in rats by examining the effects of acute up-or downregulation of endogenous KYNA on extracellular glutamate in the hippocampus and on performance in the Morris water maze (MWM). Applied directly by reverse dialysis, KYNA (30-300 nM) reduced, whereas the specific kynurenine aminotransferase-II inhibitor (S)-4-(ethylsulfonyl)benzoylalanine (ESBA; 0.3-3 mM) raised, extracellular glutamate levels in the hippocampus. Co-application of KYNA (100 nM) with ESBA (1 mM) prevented the ESBA-induced glutamate increase. Comparable effects on hippocampal glutamate levels were seen after intra-cerebroventricular (i.c.v.) application of the KYNA precursor kynurenine (1 mM, 10 ml) or ESBA (10 mM, 10 ml), respectively. In separate animals, i.c.v. treatment with kynurenine impaired, whereas i.c.v. ESBA improved, performance in the MWM. I.c.v. co-application of KYNA (10 mM) eliminated the pro-cognitive effects of ESBA. Collectively, these studies show that KYNA serves as an endogenous modulator of extracellular glutamate in the hippocampus and regulates hippocampus-related cognitive function. Our results suggest that pharmacological interventions leading to acute reductions in hippocampal KYNA constitute an effective strategy for cognitive improvement. This approach might be especially useful in the treatment of cognitive deficits in neurological and psychiatric diseases that are associated with increased brain KYNA levels.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Pocivavsek

Potter

et al. 2011

Neuropsychopharmacol

Self Cite

141

158

View full text Add to dashboard Cite

show abstract

“…The only known mechanism that clears KYNA from the extracellular space in the CNS is a probenecid-sensitive transporter (reviewed in Moroni et al, 1988). Under normal physiologic conditions, KYNA levels in brains of nonprimates and primates (including humans) are in the low nanomolar to low micromolar range (Moroni et al, 1988;Turski et al, 1988). Pharmacologic manipulations of the kynurenine pathway in laboratory animals have supported findings from in vitro experiments that whereas increased KYNA levels are neuroprotective and anticonvulsant, decreased levels of the metabolite increase neuronal vulnerability (Pellicciari et al, 1994;Poeggeler et al, 1998;Cozzi et al, 1999).…”

Section: Kynurenic Acid (Kyna)mentioning

confidence: 99%

Unconventional ligands and modulators of nicotinic receptors

et al. 2002

View full text Add to dashboard Cite

ABSTRACT:Evidence gathered from epidemiologic and behavioral studies have indicated that neuronal nicotinic receptors (nAChRs) are intimately involved in the pathogenesis of a number of neurologic disorders, including Alzheimer's disease, Parkinson's disease, and schizophrenia. In the mammalian brain, neuronal nAChRs, in addition to mediating fast synaptic transmission, modulate fast synaptic transmission mediated by the major excitatory and inhibitory neurotransmitters glutamate and GABA, respectively. Of major interest, however, is the fact that the activity of the different subtypes of neuronal nAChR is also subject to modulation by substances of endogenous origin such as choline, the tryptophan metabolite kynurenic acid, neurosteroids, and ␤-amyloid peptides and by exogenous substances, including the so-called nicotinic allosteric potentiating ligands, of which galantamine is the prototype, and psychotomimetic drugs such as phencyclidine and ketamine. The present article reviews and discusses the effects of unconventional ligands on nAChR activity and briefly describes the potential benefits of using some of these compounds in the treatment of neuropathologic conditions in which nAChR function/expression is known to be altered.

show abstract

“…Thus, both the tissue and the extracellular concentration of KYNA in the mammalian brain range from low to high nanomolar (Moroni et al, 1988;Turski et al, 1988;Swartz et al, 1990), and even significant surges in these endogenous levels are insufficient to antagonize massive insults caused, for example, by focal injections of NMDA ( Fig. 3; cf.…”

Section: Discussionmentioning

confidence: 99%

Dopamine receptor activation reveals a novel, kynurenate-sensitive component of striatal N-methyl-d-aspartate neurotoxicity

Pöeggeler

Rassoulpour

et al. 2007

Neuroscience

View full text Add to dashboard Cite

The N-methyl-D-aspartate (NMDA) subtype of glutamate receptors plays an important role in brain physiology, but excessive receptor stimulation results in seizures and excitotoxic nerve cell death. NMDA receptor-mediated neuronal excitation and injury can be prevented by high, nonphysiological concentrations of the neuroinhibitory tryptophan metabolite kynurenic acid (KYNA). Here we report that endogenous KYNA, which is formed in and released from astrocytes, controls NMDA receptors in vivo. This was revealed with the aid of the dopaminergic drugs d-amphetamine and apomorphine, which cause rapid, transient decreases in striatal KYNA levels in rats. Intrastriatal injections of the excitotoxins NMDA or quinolinate (but not the non-NMDA receptor agonist kainate) at the time of maximal KYNA reduction resulted in 2-3-fold increases in excitotoxic lesion size. Pretreatment with kynurenine 3-hydroxylase inhibitors or dopamine receptor antagonists, two classes of pharmacological agents that prevented the reduction in brain KYNA caused by dopaminergic stimulation, abolished the potentiation of neurotoxicity. Thus, the present study identifies a previously unappreciated role of KYNA as a functional link between dopamine receptor stimulation and NMDA neurotoxicity in the striatum. KeywordsAmphetamine; Astrocyte; Basal Ganglia; Dopamine; Kynurenine 3-hydroxylase; Quinolinic acid Glutamatergic neurotransmission mediated by N-methyl-D-aspartate (NMDA) receptors plays important roles in striatal physiology. Because of the discrete pre-and postsynaptic, and intraand extrasynaptic, localization of the various receptor subunits (Bernard and Bolam, 1998;Wang and Pickel, 2000;Dunah and Standaert, 2003;Galvan et al., 2006), striatal NMDA receptor stimulation has multiple and complex functional effects. Moderate activation of NMDA receptors controls, for example, monoaminergic, cholinergic, glutamatergic and peptidergic neurotransmission (Becquet et al., 1990;Young and Bradford, 1993;Knauber et al., 1999;Hathway et al., 2001;Radke et al., 2001;Marti et al., 2005) and, as a consequence, affects synaptic plasticity (Centonze et al., 2004;Dang et al., 2006), motor function (Hallett et al., 2005;Gardoni et al., 2006) and cellular bioenergetics (Moncada and Bolanos, 2006 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. stimulation of striatal NMDA receptors, on the other hand, triggers excitotoxicity, a mode of neuronal death that is believed to play a causative role in neurodegenerative diseases affecting the basal ganglia (Sonsalla et al., 1998;Waxman and Lynch, 2005;Fan and Raymond, 2006)....

show abstract

Identification and quantification of kynurenic acid in human brain tissue

Cited by 200 publications

References 16 publications

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Unconventional ligands and modulators of nicotinic receptors

Dopamine receptor activation reveals a novel, kynurenate-sensitive component of striatal N-methyl-d-aspartate neurotoxicity

Contact Info

Product

Resources

About