3-Hydroxykynurenine potentiates quinolinate but not NMDA toxicity in the rat striatum.
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.
Guidetti
P
P
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD 21228, USA.
Schwarcz
R
R
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000494:pharmacology; D000344:Afferent Pathways / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004357:Drug Synergism; D003576:Electron Transport Complex IV / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016202:N-Methylaspartate / Q000633:toxicity*; D017378:Quinolinic Acid / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D001557:Benzenesulfonates; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D016166:Free Radical Scavengers; D016194:Receptors, N-Methyl-D-Aspartate; C094272:N-tert-butyl-(2-sulfophenyl)nitrone; C064539:2-amino-4-methyl-5-phosphono-3-pentenoic acid; C005045:3-hydroxykynurenine; D007737:Kynurenine; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D014446:Tyrosine 3-Monooxygenase; D003576:Electron Transport Complex IV; D017378:Quinolinic Acid