Role of kynurenines in the neurotoxic actions of kainic acid.
The neurotoxic actions of kainic acid can be partly suppressed by antagonists acting at N-methyl-D-aspartate (NMDA) receptors. The present study examined the possible role of endogenous components of the kynurenine pathway to this phenomenon. Administration of kainate (2 nmols) into the hippocampus of anaesthetized rats produced damage in the CA1 and CA3 regions. The involvement of NMDA receptors was confirmed by the ability of dizocilpine (1 mg kg(-1)) to reduce cell loss in the CA1 region from 92 to 42%. The co-administration of m-nitrobenzoylalanine (20 nmols into the hippocampus), an inhibitor of kynurenine hydroxylase and kynureninase, together with a systemic injection of the compound (100 mg kg(-1), i.p.), afforded some protection against kainate, reducing cell loss from 91 to 48%. Protection was not exerted against damage by quinolinic acid or NMDA, excluding a direct interaction between m-nitrobenzoylalanine and NMDA receptors. The protective effect of m-nitrobenzoylalanine was not prevented by glycine, which would be expected to reverse protection caused by an elevation in the levels of endogenous kynurenic acid, arguing against a major role for increased levels of kynurenic acid. The results indicate that inhibition of the kynurenine pathway offers protection against kainate-induced damage. One possible mechanism for the protection is that an increased production of quinolinic acid in the brain, possibly from glial cells and macrophages activated by the initial kainate insult, normally contributes to the local activation of NMDA receptors and thus to kainate-induced cerebral insults. This generation of endogenous quinolinic acid would be suppressed by m-nitrobenzoylalanine.
Behan
W M
WM
Department of Pathology, University of Glasgow, Glasgow G12 8QQ. Institute of Biomedical & Life Sciences, West Medical Building, University of Glasgow, Glasgow G12 8QQ.
Stone
T W
TW
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007608:Kainic Acid / Q000633:toxicity*; D007737:Kynurenine / Q000502:physiology*; D008297:Male; D017378:Quinolinic Acid / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects
D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; C086214:(3-nitrobenzoyl)alanine; D007737:Kynurenine; D016291:Dizocilpine Maleate; D017378:Quinolinic Acid; D000409:Alanine; D007608:Kainic Acid; D005998:Glycine