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 mu l) 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 (r(2) = 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.