NDLI: Excitotoxicity of quinolinic acid: Modulation by endogenous antagonists

Content Provider	Springer Nature Link
Author	Jhamandas, K. H. Boegman, R. J. Beninger, R. J. Miranda, A. F. Lipic, K. A.
Copyright Year	2000
Abstract	Quinolinic acid (QUIN), a product of tryptophan metabolism by the kynurenine pathway, produces excitotoxicity by activation of NMDA receptors. Focal injections of QUIN can deplete biochemical markers for dopaminergic, cholinergic, gabaergic, enkepha-linergic and NADPH diaphorase neurons, which differ in their sensitivity to its neurotoxic action. This effect of QUIN differs from that of other NMDA receptor agonists in terms of its dependency on the afferent glutamatergic input and its sensitivity to the receptor antagonists. The enzymatic pathway yielding QUIN produces metabolites that inhibit QUIN-induced neurotoxicity. The most active of these metabolites, kynurenic acid (KYNA), blocks NMDA and non-NMDA receptor activity. Treatment with kynurenine hydroxylase and kynureninase inhibitors increases levels of endogenous KYNA in the brain and protects against QUIN-induced neurotoxicity. Other neuroprotective strategies involve reduction in QUIN synthesis from its immediate precursor, or endogenous synthesis of 7-chloro-kynurenic acid, a NMDA antagonist, from its halogenated precursor. Several other tryptophan metabolites — quinaldic acid, hydroxyquinaldic acid and picolinic acid — also inhibit excitotoxic damage but their presence in the brain is uncertain. Picolinic acid is of interest since it inhibits excitotoxic but not neuroexcitatory responses. The mechanism of its anti-excitotoxic action is unclear but might involve zinc chelation.Neurotoxic actions of QUIN is modulated by nitric oxide (NO). Treatment with inhibitors of NO synthase can augment QUIN toxicity in some models of excitotoxicity suggesting a neuroprotective potential of endogenous NO. In recent studies, certain nitroso compounds which could be NO donors have been reported to reduce the NMDA receptor-mediated neurotoxicity.The existence of endogenous compounds which inhibit excitotoxicity provides a basis for future development of novel and effective neuroprotectants
Starting Page	139
Ending Page	155
Page Count	17
File Format	PDF
ISSN	10298428
Journal	Neurotoxicity Research
Volume Number	2
Issue Number	2-3
e-ISSN	14763524
Language	English
Publisher	Springer-Verlag
Publisher Date	2000-01-01
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Excitotoxicity Kynurenic acid Neuroprotection Nitric oxide Quinolinic acid Neurosciences Pharmaceutical Sciences/Technology Neurology Neurochemistry Pharmacology/Toxicology Neurobiology
Content Type	Text
Resource Type	Article
Subject	Neuroscience Toxicology

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