Modulation of Extracellular Kynurenic Acid Content by Excitatory Amino Acids in Primary Cultures of Rat Astrocytes

Curatolo, L.; Caccia, C.; Speciale, C.; Raimondi, Laura; Cini, M.; Marconi, Marina; Molinari, Agnese; Schwarcz, Robert

doi:10.1007/978-1-4613-0381-7_43

Cited by 16 publications

(21 citation statements)

References 5 publications

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“…In agreement with previous observations (Curatolo et al, 1996;Kiss et al, 2003), in this study KYNA synthesis in astrocytes was not affected by either of these agents. Glutamate inhibited KYNA synthesis in neurons more strongly than in astrocytes (IC 50 : 19.2 and 90.0 lM, respectively), the IC 50 for astrocytes being strikingly close to that reported earlier for a similar astrocytic culture (Curatolo et al, 1996). This higher sensitivity of neuronal KYNA synthesis to glutamate is likely to be due to the effects exerted by the interaction with ionotropic glutamate receptors.…”

Section: Discussionsupporting

confidence: 95%

“…In this study, the neuronal responses were directly compared with those in cultured astrocytes. Similarly to the case for rat (Curatolo et al, 1996; this study) or human (Kiss et al, 2003) astrocytes and C6 glioma cells (Kocki et al, 2002), KYNA synthesis in neurons was inhibited by L-system amino acids (BCH, Leu, Gln) that compete for the L-system-mediated cellular uptake with the KYNA precursor, kynurenine (Speciale et al, 1989;Brookes, 1993). It must be noted that Gln could also interfere with KYNA synthesis by other mechanisms, possibly via its degradation product, glutamate, or as a KAT I substrate (Malherbe et al, 1995).…”

Section: Discussionmentioning

confidence: 82%

“…In this study, we therefore compared KYNA synthesis and its modulation in cerebral cortical neurons and astrocytes in culture. The modulatory factors have been selected on the basis of their influence on KYNA synthesis in cultured astrocytes (Curatolo et al, 1996;Kiss et al, 2003), astrogliaderived cell line (Kocki et al, 2002), and brain slices (Gramsbergen et al, 1997;Urbańska et al, 1997;Hodgkins et al, 1999, Battaglia et al, 2000. The factors tested included 1) leucine (Leu) and other amino acids competing with the KYNA precursor kynurenine for Lsystem cell membrane transport (Speciale et al, 1989;Brookes, 1993); 2) glutamate and ionotropic glutamate receptor ligands; 3) cell membrane-depolarizing agents; 4) glutamine (Gln), which is both a kynurenine transport competitor and an astrocytic KYNA precursor; and 5) a-ketoisocaproic acid (KIC), a Leu transamination product, synthesized mainly in astrocytes and shuttled to neurons to control the intraneuronal glutamate level (Yudkoff, 1997).…”

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confidence: 99%

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Demonstration of kynurenine aminotransferases I and II and characterization of kynurenic acid synthesis in cultured cerebral cortical neurons

Rzeski

Kocki

Dybel

et al. 2005

J of Neuroscience Research

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The present study characterizes the synthesis of kynurenic acid (KYNA) from exogenously added kynurenine and its regulation by extrinsic factors, in cultured cerebral cortical neurons and, for comparison, in astrocytes incubated under identical conditions. The neuronal culture showed positive immunostaining for both kynurenic acid aminotransferase (KAT) isoforms I and II. Neurons synthesized KYNA at a rate about 2.3 times higher than astrocytes. Neuronal, but not astrocytic, KYNA synthesis was lowered approximately 30% by ionotropic glutamate receptor agonists [(R,S)-3-hydroxy-5-methoxyloxasole-4-propionic acid (AMPA; 100 microM) and N-methyl-D-aspartic acid (NMDA; 100 microM)] and depolarizing agents [KCl (50 mM) and 4-aminopyridine (4-AP; 10 microM)]. Neuronal and astrocytic synthesis alike were vulnerable to inhibition exerted by the aminotransferase inhibitor aminooxyacetic acid (AOAA), glutamate (IC50: 31 and 85 microM, respectively), substrates of the L-amino transport system [leucine (Leu); IC50: 19 and 42 microM, respectively] and 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid (BCH; IC50: 19 and 28 microM, respectively). Glutamine (Gln), which is a metabolic precursor of glutamate in astrocytes and L-system substrate in both cell types, inhibited KYNA synthesis both in neurons and in astrocytes (IC50: 268 and 318 microM, respectively). alpha-Ketoisocaproic acid (KIC), a Leu transamination product that is produced mainly in astrocytes and shuttled to neurons to modulate intraneuronal concentration of glutamate, stimulated KYNA synthesis in neurons but did not affect the synthesis in astrocytes. In conclusion, this study is the first to demonstrate active, regulation-prone KYNA synthesis in neurons.

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Section: Discussionsupporting

confidence: 95%

Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 99%

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Demonstration of kynurenine aminotransferases I and II and characterization of kynurenic acid synthesis in cultured cerebral cortical neurons

Rzeski

Kocki

Dybel

et al. 2005

J of Neuroscience Research

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“…Although several of these enzymes may participate in cerebral KYNA biosynthesis under physiological and pathological conditions, it appears that the pool of KYNA that can be most readily mobilized in the brain is largely provided by KAT-II (Amori et al, 2009). This enzyme is almost exclusively localized in astrocytes (Guidetti et al, 2007b;Guillemin et al, 2001), which rapidly liberate newly synthesized KYNA into the extracellular milieu (Curatolo et al, 1996;Guillemin et al, 2000). Although the precise mechanism controlling the release of KYNA has not been elucidated, this insight led to the development of specific KAT-II inhibitors, which are designed to target astrocytes and reduce extracellular KYNA concentrations.…”

Section: Discussionmentioning

confidence: 99%

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Pocivavsek

Potter

et al. 2011

Neuropsychopharmacol

141

158

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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.

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“…KYNA has the ability to control the vulnerability of striatal neurons to QUIN (Hilmas et al, 2001). However, ionotropic glutamate receptor ligands such as glutamate, and likely QUIN, can inhibit KYNA synthesis by rat astrocytes (Curatolo et al, 1996). Changes in KYNA concentrations have been described in several neurological disorders (Stone, 1993).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Kynurenine Pathway in Human Neurons

et al. 2007

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The kynurenine pathway is a major route of L-tryptophan catabolism producing neuroactive metabolites implicated in neurodegeneration and immune tolerance. We characterized the kynurenine pathway in human neurons and the human SK-N-SH neuroblastoma cell line and found that the kynurenine pathway enzymes were variably expressed. Picolinic carboxylase was expressed only in primary and some adult neurons but not in SK-N-SH cells. Because of this difference, SK-N-SH cells were able to produce the excitotoxin quinolinic acid, whereas human neurons produced the neuroprotectant picolinic acid. The net result of kynurenine pathway induction in human neurons is therefore predicted to result in neuroprotection, immune regulation, and tumor inhibition, whereas in SK-N-SH cells, it may result in neurotoxicity, immune tolerance, and tumor promotion. This study represents the first comprehensive characterization of the kynurenine pathway in neurons and the first description of the involvement of the kynurenine pathway as a mechanism for controlling both tumor cell neurotoxicity and persistence.

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Modulation of Extracellular Kynurenic Acid Content by Excitatory Amino Acids in Primary Cultures of Rat Astrocytes

Cited by 16 publications

References 5 publications

Demonstration of kynurenine aminotransferases I and II and characterization of kynurenic acid synthesis in cultured cerebral cortical neurons

Demonstration of kynurenine aminotransferases I and II and characterization of kynurenic acid synthesis in cultured cerebral cortical neurons

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Characterization of the Kynurenine Pathway in Human Neurons

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