Metabolism of [5-(3)H]kynurenine in the developing rat brain in vivo: effect of intrastriatal ibotenate injections.
Two metabolites of the kynurenine pathway of tryptophan degradation, the neurotoxin quinolinic acid (QUIN) and the neuroprotectant kynurenic acid (KYNA), may play a role in the initiation or propagation of brain diseases. In order to study their disposition during the acute and chronic stages of neurodegeneration, effects of an excitotoxic insult on the de novo synthesis of several kynurenine pathway metabolites were examined in vivo. Neuronal injury and lesions were produced in 7-day (PND 7), 14-day (PND 14) and young adult rats by an intrastriatal injection of the excitotoxin ibotenic acid. At 2 h, 2, 7 and 28 days later, the formation of tritiated KYNA, 3-hydroxykynurenine (3HK), xanthurenic acid and QUIN was assessed after an acute intrastriatal injection of their common bioprecursor, [5-(3)H]kynurenine. In all three age groups, the acute insult resulted in a shift towards enhanced KYNA formation, as indicated by 2-4 fold decreases in the 3HK/KYNA and QUIN/KYNA ratios in ibotenate-treated striata. At later post-lesion intervals, age-specific several-fold changes were observed in the flux through both the KYNA and QUIN branches of the kynurenine pathway. With aging, kynurenine conversion to QUIN and especially to 3HK, became increasingly more prominent, though KYNA synthesis was substantially activated as well. The acute toxin-induced changes in kynurenine metabolism, the propensity of the lesioned immature striatum to increase KYNA production preferentially, and the pronounced lesion-induced long-term increases in cerebral KYNA, 3HK and QUIN formation may participate in the modulation of NMDA receptor function following injury. In particular, changes in the production of these kynurenine pathway metabolites may play a role in mechanisms involved in endogenous neuroprotection, delayed neurodegeneration and regenerative processes.
Ceresoli
G
G
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore 21228, USA.
Guidetti
P
P
Schwarcz
R
R
D000375:Aging / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D007839:Functional Laterality; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007051:Ibotenic Acid / Q000008:administration & dosage / Q000633:toxicity*; D007737:Kynurenine / Q000031:analogs & derivatives / Q000378:metabolism*; D008297:Male; D008845:Microinjections; D017378:Quinolinic Acid / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014316:Tritium; D014977:Xanthurenates / Q000378:metabolism
D014977:Xanthurenates; D014316:Tritium; D007051:Ibotenic Acid; C005045:3-hydroxykynurenine; D007737:Kynurenine; C028330:xanthurenic acid; D005968:Glutamate Decarboxylase; D017378:Quinolinic Acid