Presence of Kynurenic Acid in the Mammalian Brain

Moroni, Flavio; Russi, P.; Lombardi, Grazia; Beni, M.; Carlà, Vincenzo

doi:10.1111/j.1471-4159.1988.tb04852.x

Cited by 259 publications

(163 citation statements)

References 22 publications

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“…Changes in brain KYNA levels including those observed in schizophrenia, may be caused by impairment in one or more of these processes. Since KYNA cannot be cleared by cellular reuptake or enzymatic degradation, efflux through a nonspecific, PBCD-sensitive organic acid transporter appears to be the major mode of its elimination from the brain (Moroni et al, 1988;Turski and Schwarcz, 1988).…”

Section: Discussionmentioning

confidence: 99%

Micromolar Brain Levels of Kynurenic Acid are Associated with a Disruption of Auditory Sensory Gating in the Rat

Shepard

Joy

Clerkin

et al. 2003

Neuropsychopharmacol

127

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Brain levels of kynurenic acid (KYNA), an endogenous antagonist of glycine B /NMDA and a-7 nicotinic acetylcholine receptors, are elevated in individuals with schizophrenia. Both receptors are broadly implicated in the pathophysiology of this disease, particularly in the deficits many patients show in filtering the sensorium. In the present study, we sought to determine whether elevated brain levels of KYNA disrupt auditory gating in anesthetized rats. A mid-latency evoked potential was recorded from the hippocampus in response to a pair of auditory tones. Gating was assessed by determining the ratio of the amplitude of test and conditioning responses (T/C ratio) in rats that had received KYNA's precursor L-kynurenine (KYN; 150 mg/kg, i.p.) together with probenecid (PBCD; 200 mg/kg, i.p.) 2 h prior to the start of the recording session. KYNA levels in the hippocampus of KYN+PBCD-treated rats were increased 500-fold, and accompanied by a significant increase in T/C ratio consistent with a disruption in sensory gating. PBCD alone increased hippocampal KYNA 12-fold, but did not significantly elevate T/C ratio. L-701,324 (3-30 mg/kg, i.v.), a centrally acting glycine B site antagonist, also failed to disrupt gating; however, large quantities of the competitive NMDA receptor antagonist DL-2-amino-5-phosphopentanoate (200 nmol, i.c.v.) markedly increased T/C ratio. Thus, while total blockade of NMDA receptors disrupts auditory gating, partial blockade achieved by antagonism of its glycine coagonist binding site does not. These observations indicate that the disruption in auditory processing in rats with greatly elevated KYNA levels is not attributable to the compound's antagonist actions at the glycine B receptor.

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Section: Discussionmentioning

confidence: 99%

Micromolar Brain Levels of Kynurenic Acid are Associated with a Disruption of Auditory Sensory Gating in the Rat

Shepard

Joy

Clerkin

et al. 2003

Neuropsychopharmacol

127

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“…Third, KYNA is not taken up by glia or neurons. 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).…”

Section: Kynurenic Acid (Kyna)mentioning

confidence: 99%

“…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

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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.

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“…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

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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)....

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Presence of Kynurenic Acid in the Mammalian Brain

Cited by 259 publications

References 22 publications

Micromolar Brain Levels of Kynurenic Acid are Associated with a Disruption of Auditory Sensory Gating in the Rat

Micromolar Brain Levels of Kynurenic Acid are Associated with a Disruption of Auditory Sensory Gating in the Rat

Unconventional ligands and modulators of nicotinic receptors

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

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