Quinolinic Acid and Kynurenic Acid in the Mammalian Brain

Schwarcz, Robert; Du, Fuliang

doi:10.1007/978-1-4684-5952-4_17

Cited by 22 publications

(15 citation statements)

References 64 publications

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“…The demonstration of 3HA0 in striatal astrocytes is consistent KGhler et al, 1988a,b;Schwartz and Du, 1991). Although 3HAO-i astrocytes appear to constitute a homogeneous population at the light microscopic level, two subtypes can be distinguished by electron microscopy, based on the presence or absence of nuclear staining.…”

Section: Discussionsupporting

confidence: 81%

“…For example, while it has been established that astrocytes have a limited capacity to store newly synthesized QUIN and are capable of releasing QUIN into the extracellular compartment (Speciale and Schwartz, 1993), the metabolic control of brain 3-hydroxyanthranilic acid, the substrate of 3HA0, has so far not been elucidated. Moreover, the function of the QUIN-degrading enzyme quinolinic acid phosphoribosyltransferase, which is also largely contained in astrocytes (Kiihler et al, 1987;Du et al, 1991), has not been clarified to date. Eventually, relevant information is expected to come from studies using selective pharmacological agents such as 3HA0 inhibitors (Walsh et al, 1991(Walsh et al, , 1994.…”

Section: Discussionmentioning

confidence: 99%

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3-Hydroxyanthranilic acid oxygenase-containing astrocytic processes surround glutamate-containing axon terminals in the rat striatum

Roberts

McCarthy

et al. 1995

J. Neurosci.

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Glutamate, the major transmitter of the corticostriatal pathway, is present in abundance in the striatum. 3-Hydroxyanthranilic acid oxygenase (3HAO) is the biosynthetic enzyme for quinolinic acid, an endogenous agonist of the NMDA glutamate receptor subtype and a potent neurotoxin. In order to explore the anatomical basis of possible functional interactions between glutamate and quinolinic acid in the rat striatum, pre- and postembedding immunocytochemical methods were used to localize 3HAO immunoreactivity (-i) and glutamate-i at the electron microscopic level. In accordance with previous light microscopic and biochemical studies, 3HAO-i was detected exclusively in astrocytes throughout the striatum. Notably, 3HAO-i was present in fine- caliber glial processes that often surrounded or abutted synaptic profiles, both asymmetric and symmetric. Glutamate-i was heavily deposited (3–13-fold higher gold particle density than tissue average) in axon terminals forming asymmetric synapses with spines and, occasionally, dendrites. In contrast, terminals forming symmetric synapses, dendrites, neuronal somata, and glial cells contained significantly less labeling than terminals forming asymmetric synapses. In double-labeled material, 3HAO-i was observed in glial processes that partially surrounded or were adjacent to glutamate-labeled terminals forming asymmetric synapses. 3HAO-labeled glial processes were also adjacent to unlabeled terminals forming symmetric synapses. Since quinolinic acid is known to enter the extracellular compartment readily, these results suggest that astrocytic quinolinic acid may participate in the regulation of glutamatergic neurotransmission in the rat striatum.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

3-Hydroxyanthranilic acid oxygenase-containing astrocytic processes surround glutamate-containing axon terminals in the rat striatum

Roberts

McCarthy

et al. 1995

J. Neurosci.

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“…1992). The cellular localization of kynurenine 3‐hydroxylase in the brain has not been clarified, but lesion studies indicate that the enzyme, like other elements of the cerebral kynurenine pathway (Schwarcz & Du 1991; Espey et al . 1997), is preferentially contained in glial cells (Guidetti et al .…”

Section: Discussionmentioning

confidence: 99%

“…Blood-derived L-3-HK uses the large neutral amino acid transporter to penetrate into the brain (Fukui et al, 1991) and to enter brain cells (Eastman et al, 1992). The cellular localization of kynurenine 3-hydroxylase in the brain has not been clari®ed, but lesion studies indicate that the enzyme, like other elements of the cerebral kynurenine pathway (Schwarcz & Du, 1991;Espey et al, 1997), is preferentially contained in glial cells (Guidetti et al, 1995). Among the most interesting features of the brain's kynurenine pathway is the fact that a delicate balance exists between the production of L-3-HK and QUIN on one hand and the formation of the neuroprotectant kynurenic acid on the other (Stone, 1993), and that the immunocompromised brain synthesizes increased quantities of L-3-HK and QUIN which in turn may play a causal role in pathological phenomena (Saito et al, 1992;Heyes et al, 1993;Sardar et al, 1995;Kerr et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

3‐Hydroxykynurenine potentiates quinolinate but not NMDA toxicity in the rat striatum

Guidetti

Schwarcz

1999

Eur J of Neuroscience

154

112

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L-3-Hydroxykynurenine (L-3-HK) and quinolinate (QUIN) are two metabolites of the kynurenine pathway, the major route of tryptophan degradation in mammals. L-3-HK is a known generator of highly reactive free radicals, whereas QUIN is an endogenous excitotoxin acting specifically at N-methyl-D-aspartate (NMDA) receptors. This study was designed to examine possible synergistic interactions between L-3-HK and QUIN in the rat brain in vivo. Intrastriatal coinjection of 5 nmol L-3-HK and 15 nmol QUIN, i.e. doses which caused no or minimal neurodegeneration on their own, resulted in substantial neuronal loss, determined both behaviourally (apomorphine-induced rotations) and histologically (quantitative assessment of lesion size). The excitotoxic nature of the lesion was verified by tyrosine hydroxylase immunohistochemistry, showing the survival of dopaminergic striatal afferents. There was also a relative sparing of large striatal neurons, and neurodegeneration was prevented both by NMDA receptor blockade (using CGP 40116) and free radical scavenging [using N-tert-butyl-alpha-(2-sulphophenyl)-nitrone, S-PBN]. The pro-excitotoxic features of L-3-HK were especially pronounced at low QUIN doses and were not observed when QUIN was substituted by NMDA. Notably, the effect of L-3-HK was not due to its intracerebral conversion to QUIN and was duplicated by equimolar D,L-3-HK. These data indicate that an elevation of L-3-HK levels constitutes a significant hazard in situations of excitotoxic injury. Pharmacological interventions aimed at decreasing L-3-HK formation may therefore be particularly useful for the treatment of neurological diseases which are associated with an abnormally enhanced flux through the kynurenine pathway.

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“…However, the responses to glutamate occurred even in the presence of the nonspecific excitatory amino acid antagonist KY (Fig. 4a), which blocks both N-methyl-D-aspartate (NMDA) and ionotropic (kainate and AMPA) glutamate receptors (Schwarcz and Du, 1991). This suggests that the responses to glutamate were not solely due to stimulation of ionotropic glutamate receptors.…”

Section: Ionotropic and Metabotropic Glutamate Receptorsmentioning

confidence: 96%

GFAP‐positive hippocampal astrocytes in situ respond to glutamatergic neuroligands with increases in [Ca²⁺]_i

Porter

McCarthy

1995

Glia

191

121

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It is becoming increasingly clear that astrocytes play very dynamic and interactive roles that are important for the normal functioning of the central nervous system. In culture, astrocytes express many receptors coupled to increases in intracellular calcium ([Ca2+]i). In vivo, it is likely that these receptors are important for the modulation of astrocytic functions such as the uptake of neurotransmitters and ions. Currently, however, very little is known about the expression or stimulation of such astrocytic receptors in vivo. To address this issue, confocal microscopy and calcium-sensitive fluorescent dyes were used to examine the dynamic changes in astrocytic [Ca2+]i within acutely isolated hippocampal slices. Astrocytes were subsequently identified by immunocytochemistry for glial fibrillary acidic protein. In this paper, we present data indicating that hippocampal astrocytes in situ respond to glutamate, kainate, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), 1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD), N-methyl-D-aspartate (NMDA), and depolarization with increases in [Ca2+]i. The increases in [Ca2+]i occurred in both the astrocytic cell bodies and the processes. Temporally the changes in [Ca2+]i were very dynamic, and various patterns ranging from sustained elevations to oscillations of [Ca2+]i were observed. Individual astrocytes responded to neuroligands selective for both ionotropic and metabotropic glutamate receptors with increases in [Ca2+]i. These findings indicate that astrocytes in vivo contain glutamatergic receptors coupled to increases in [Ca2+]i and are able to respond to neuronally released neurotransmitters.

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Quinolinic Acid and Kynurenic Acid in the Mammalian Brain

Cited by 22 publications

References 64 publications

3-Hydroxyanthranilic acid oxygenase-containing astrocytic processes surround glutamate-containing axon terminals in the rat striatum

3-Hydroxyanthranilic acid oxygenase-containing astrocytic processes surround glutamate-containing axon terminals in the rat striatum

3‐Hydroxykynurenine potentiates quinolinate but not NMDA toxicity in the rat striatum

GFAP‐positive hippocampal astrocytes in situ respond to glutamatergic neuroligands with increases in [Ca²⁺]_i

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Quinolinic Acid and Kynurenic Acid in the Mammalian Brain

Cited by 22 publications

References 64 publications

3-Hydroxyanthranilic acid oxygenase-containing astrocytic processes surround glutamate-containing axon terminals in the rat striatum

3-Hydroxyanthranilic acid oxygenase-containing astrocytic processes surround glutamate-containing axon terminals in the rat striatum

3‐Hydroxykynurenine potentiates quinolinate but not NMDA toxicity in the rat striatum

GFAP‐positive hippocampal astrocytes in situ respond to glutamatergic neuroligands with increases in [Ca2+]i

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GFAP‐positive hippocampal astrocytes in situ respond to glutamatergic neuroligands with increases in [Ca²⁺]_i