TY - JOUR
T1 - Quinolinate-induced injury is enhanced in developing rat brain
AU - Trescher, William H.
AU - McDonald, John W.
AU - Johnston, Michael V.
N1 - Funding Information:
This work was supported by National Institute of Health Grants KO8 NS01482 (W.H.T.) and ROt NS28208 (M.V.J.). The authors wish to thank Karen Smith-Connor for technical assistance, and Stephen L. Kinsman for critical review of the manuscript.
PY - 1994/12/16
Y1 - 1994/12/16
N2 - 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 μl) 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.
AB - 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 μl) 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.
KW - Cerebral hypoxia-ischemia
KW - Excitotoxicity
KW - Hyperammonemia
KW - Meningitis
KW - N-Methyl-d-aspartate
KW - Neonate
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U2 - 10.1016/0165-3806(94)00141-3
DO - 10.1016/0165-3806(94)00141-3
M3 - Article
C2 - 7697883
AN - SCOPUS:0028127308
SN - 0165-3806
VL - 83
SP - 224
EP - 232
JO - Developmental Brain Research
JF - Developmental Brain Research
IS - 2
ER -