Nicotinylalanine increases cerebral kynurenic acid content and has anticonvulsant activity

Connick, J.H.; Heywood, Geoffrey C.; Sills, Graeme J.; Thompson, George G.; Brodie, M.J.; Stone, T.W.

doi:10.1016/0306-3623(92)90017-e

Cited by 56 publications

(26 citation statements)

References 11 publications

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“…These results suggest that adenosine does not affect KYNA formation tonically, but that elevations of adenosine, as they occur for example after an ischemic insult (Melani et al 1999), stimulate KYNA production. In turn, increases in the extracellular levels of KYNA in the brain result in decreased vulnerability to seizures and neurodegenerative insults (Connick et al 1992;Pellicciari et al 1994;Harris et al 1998;Cozzi et al 1999). These effects, which are caused by KYNA's attenuation of NMDA and a7 nicotinic acetylcholine receptor function (Kessler et al 1989;Hilmas et al 2001), and to its ability to reduce extracellular glutamate concentrations (Carpenedo et al 2001), are qualitatively similar to the effects of A 1 receptor activation (cf.…”

Section: Discussionsupporting

confidence: 54%

Neuronal A₁ receptors mediate increase in extracellular kynurenic acid after local intrastriatal adenosine infusion

Fuxé

Schwarcz

2004

Journal of Neurochemistry

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The naturally occurring purine nucleoside adenosine has pronounced anticonvulsant and neuroprotective properties and plays a neuromodulatory role in the CNS. Kynurenic acid (KYNA) is an astrocyte-derived, endogenous neuroinhibitory compound, which shares several of adenosine's properties. In a first attempt to examine possible interactions between these two biologically active molecules, adenosine was focally applied into the striatum of freely moving rats by reverse microdialysis, and changes in extracellular KYNA were monitored over time. A 2-h infusion of adenosine increased KYNA levels in a dose-dependent manner, with 10 mM of adenosine causing a twofold elevation within 1 h. This effect was reversible and was effectively blocked by coinfusion of the specific A 1 adenosine receptor antagonist 8-cyclopentyltheophylline (100 lM). In contrast, coinfusion of adenosine with MSX-3 (100 lM), an A 2A receptor antagonist, did not affect the adenosine-induced increase in KYNA levels. Local striatal perfusion with the A 1 receptor agonist N 6 -cyclopentyladenosine (100 lM) mimicked the effect of adenosine, whereas perfusion with the A 2A receptor agonist CGS-21680 (100 lM) was ineffective. Finally, we tested the effect of adenosine (10 mM) on extracellular KYNA in striata that had been injected with quinolinate (60 nmol/1 lL) 7 days earlier. In this neuron-depleted tissue, perfusion with adenosine failed to affect extracellular KYNA levels. These data demonstrate that adenosine is capable of raising extracellular KYNA in the rat striatum by interacting with postsynaptic neuronal A 1 receptors. This mechanism may result in a synergism between the neurobiological effects of adenosine and KYNA.

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Section: Discussionsupporting

confidence: 54%

Neuronal A₁ receptors mediate increase in extracellular kynurenic acid after local intrastriatal adenosine infusion

Fuxé

Schwarcz

2004

Journal of Neurochemistry

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“…Similarly, peripheral administration of nicotinylalanine, an analogue of kynurenine that inhibits kynurenine hydroxylase and directs the¯ow of tryptophan metabolites toward the formation of kynurenate, doubled kynurenate concentrations, from baseline 64 values of $ 100 nM, in hippocampal extracellular uid and prevented audiogenic convulsions (Russi et al 1992). Connick et al (1992) have also reported that nicotinylalanine can inhibit seizures induced by leptazole or electroshock. Thus, although CNS tissue concentrations of kynurenate appear to be lower than those required to affect NMDA receptor function, under appropriate conditions, concentrations within the microenvironment of the synapse may well be high enough to inhibit NMDA receptor activation.…”

Section: Cns Tissuementioning

confidence: 94%

Glutamate and Kynurenate in the Rat Central Nervous System Following Treatments with Tail Ischaemia or Diclofenac

Edwards

Mather

Lin

et al. 2000

Journal of Pharmacy and Pharmacology

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Kynurenate is an endogenous antagonist at the allosteric glycine site on the N-methyl-Daspartate (NMDA) receptor, and may have a role in ameliorating nociceptive processes through modulation of NMDA receptor function. While antinociceptive effects of nonsteroidal anti-in¯ammatory drugs (NSAIDs) are mediated peripherally and possibly centrally through inhibition of prostaglandin synthesis, there is also evidence for centrally mediated prostaglandin-independent antinociceptive effects that may result from increased central nervous system (CNS) concentrations of kynurenate. We have investigated the effects of the NSAID diclofenac, (40 mg kg À1 , s.c.; administered to rats 1 h before killing) or the exposure of rats to noxious stimulation (tail ischaemia for 20 min before killing), on the concentrations of glutamate and kynurenate in discrete CNS regions.Regional CNS tissue concentrations of diclofenac were between 3Á0±3Á8 nmol g À1 . The corresponding regional glutamate concentrations ranged between 4Á8±10Á6 mmol g À1 , and were signi®cantly lower in the ischaemia group when compared with both control (15%, P`0Á05) and diclofenac-treated (19%, P`0Á002) groups. Kynurenate concentrations in these CNS regions ranged between 3Á3±45Á8 pmol g À1

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“…Rasssi et al (1992) have reported that Nicala treatment reduces endotoxin-induced accumulation of QUIN and enhances the accumulation of kynurenic acid in the brain. In experimental animals, Nicala prevents chemically induced seizures, an effect that has been attributed to elevation of brain kynurenic acid (Connick et al 1992). We have examined the potential of Nicda to prevent excitotoxin-induced d m g e in the CNS and have found that systemic or central administration of this agent, when coupled with kynurenine and probenecid treatment, prevents QUIN-induced damage to the striatd NADPH-8 neurons at a dose elevating brain kynurenate level (Harris et d .…”

Section: Modulation Of Quin Excitotoxicity By Endogenous Mtagonistsmentioning

confidence: 97%

The 1993 Upjohn Award Lecture. Quinolinic acid induced brain neurotransmitter deficits: modulation by endogenous excitotoxin antagonists

Jhamandas

Boegman²,

Beninger³

1994

Can. J. Physiol. Pharmacol.

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Excitotoxins constitute a group of agents that are capable of activating excitatory amino acid receptors and producing axonsparing neuronal lesions. Focal injections of the exogenous excitotoxins kainic acid and ibotenic acid result in depletion of neurotransmitter markers in neuronal cell bodies located in areas of injection or in terminal zones of their projections. The discovery of endogenous agents that behave as excitotoxins has generated interest in the idea that excitotoxicity may contribute to the neuronal degeneration associated with a number of neurological diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease) which involve selective neurotransmitter deficits. Quinolinic acid (QUIN), a pyridine dicarboxylic acid and metabolite of tryptophan, which has been detected in the central nervous system (CNS), behaves as an excitotoxin. In the mammalian brain QUIN has been localized to glial and immune cells, and its content increases with age. The neuro-excitatory and neurotoxic actions of QUIN are mediated via the Mg(2+)-sensitive N-methyl-D-aspartate (NMDA) receptor. The toxicity of QUIN, like that of kainate, but not ibotenate, is dependent on the presence of an intact glutamate-aspartate afferent input to the target area. Focal injections of QUIN into the nucleus basalis magnocellularis (nbM), a major source of cholinergic innervation to diencephalic areas, produce sustained loss of cholinergic neuron markers in the neocortex and amygdala. The neurotoxic action of QUIN on nbM results in an impairment of performance on memory-related tasks. Cortical and amygdaloid projecting cholinergic neurons show differential sensitivity to QUIN and other excitotoxic agents. This factor may partly explain the reported discrepancy between mnemonic deficits and the loss of cholinergic markers in the cerebral cortex induced by intra-nbM injections of certain excitotoxins. Cortical muscarinic receptor function is not significantly influenced by QUIN injections into the nbM producing loss of cortical cholinergic neurons. In the striatum, focal QUIN injections have been found to largely replicate the neurotransmitter deficits prevailing in Huntington's disease, an inherited movement disorder. Intrastriatal QUIN produces a profound loss of the NADPH diaphorase staining neurons in the area of injection but relatively spares these in the adjacent transition zone. QUIN is also highly damaging to the striatopallidal enkephalinergic neurons. However, at doses that are neurotoxic to striatal neurons, QUIN and several other excitotoxins produce significant elevations in enkephalin levels both in the striatum and globus pallidus. This elevation reflects the presence of a plasticity in the striatal enkephalinergic neuron population. The metabolic pathway yielding QUIN produces a number of intermediates that act as excitotoxin antagonists.(ABSTRACT TRUNCATED AT 400 WORDS)

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Nicotinylalanine increases cerebral kynurenic acid content and has anticonvulsant activity

Cited by 56 publications

References 11 publications

Neuronal A₁ receptors mediate increase in extracellular kynurenic acid after local intrastriatal adenosine infusion

Neuronal A₁ receptors mediate increase in extracellular kynurenic acid after local intrastriatal adenosine infusion

Glutamate and Kynurenate in the Rat Central Nervous System Following Treatments with Tail Ischaemia or Diclofenac

The 1993 Upjohn Award Lecture. Quinolinic acid induced brain neurotransmitter deficits: modulation by endogenous excitotoxin antagonists

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Nicotinylalanine increases cerebral kynurenic acid content and has anticonvulsant activity

Cited by 56 publications

References 11 publications

Neuronal A1 receptors mediate increase in extracellular kynurenic acid after local intrastriatal adenosine infusion

Neuronal A1 receptors mediate increase in extracellular kynurenic acid after local intrastriatal adenosine infusion

Glutamate and Kynurenate in the Rat Central Nervous System Following Treatments with Tail Ischaemia or Diclofenac

The 1993 Upjohn Award Lecture. Quinolinic acid induced brain neurotransmitter deficits: modulation by endogenous excitotoxin antagonists

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Neuronal A₁ receptors mediate increase in extracellular kynurenic acid after local intrastriatal adenosine infusion

Neuronal A₁ receptors mediate increase in extracellular kynurenic acid after local intrastriatal adenosine infusion