Quinolinate-induced injury is enhanced in developing rat brain.
Quinolinate, a metabolite of tryptophan in the kynurenine pathway, has been hypothesized to play a role in neuronal injury through activation of the N-methyl-D-aspartate (NMDA) receptor. We evaluated the ontogeny and neuroprotective pharmacology of quinolinate-induced injury in the immature rat brain. Unilateral striatal microinjections of quinolinate (150 nmol/0.5 microliter) were performed at seven ages between postnatal day (PND) 1 and 90. Injury was assessed by comparing the cross-sectional areas of the cerebral hemispheres ipsilateral and contralateral to the injection site in Nissl-stained coronal sections. The susceptibility to quinolinate-induced injury was enhanced in the immature brain with peak toxicity at PND 7 when the ipsilateral cerebral hemisphere was reduced by 16.1 +/- 3.2%. In a dose-response comparison with NMDA-induced injury at PND 7, quinolinate injury was directly related to the dose injected (r2 = 0.73, P < 0.0001), but the neurotoxicity of quinolinate was 20-times less potent than NMDA. In the PND 7 rat brain, quinolinate-induced injury was completely blocked by MK-801 (1 mg/kg, i.p.) and CGS-19755 (10 mg/kg). Dextromethorphan (20 mg/kg) and dextrorphan (20 mg/kg) were partially protective. Ifenprodil, carbamazepine, and nifedipine did not significantly protect against quinolinate-induced injury. Finally, pretreatment with MK-801 (1 mg/kg) 24 h before intracerebral injection of quinolinate resulted in greater injury compared to controls. The findings indicate that quinolinate-induced injury is enhanced in the immature brain in a pattern that is similar to NMDA-induced injury.
Trescher
W H
WH
Department of Neurology, Johns Hopkins University, Baltimore, MD.
McDonald
J W
JW
Johnston
M V
MV
D000367:Age Factors; D000818:Animals; D002220:Carbamazepine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D017072:Neostriatum / Q000187:drug effects* / Q000473:pathology; D017378:Quinolinic Acid / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*
D016194:Receptors, N-Methyl-D-Aspartate; D002220:Carbamazepine; D016291:Dizocilpine Maleate; D017378:Quinolinic Acid