Quinolinic acid promotes albumin deposition in Purkinje cell, astrocytic activation and lipid peroxidation in fetal brain.
In high concentrations or after prolonged exposure, the N-methyl-D-aspartate receptor agonist quinolinic acid (QUIN) induces lipid peroxidation, oxidative stress, and cell death in the adult brain, and after i.c.v. injection induces seizures and increases blood-brain barrier permeability. As QUIN is substantially increased in plasma and brain of fetal sheep after endotoxin treatment or maternal tryptophan loading, we examined the effects of increasing plasma QUIN concentrations on the brain of late gestation fetal sheep. Continuous fetal infusion of QUIN (0.1 mmol/h i.v.; n=4) for 12 h increased plasma QUIN concentrations from 22.3+/-6.0-210.8+/-31.4 microM; the infusion of vehicle [normal saline] had no effect on QUIN concentrations (n=4). At 24 h after QUIN infusion glial fibrillary acidic protein immunoreactivity was significantly increased in cerebral gray matter and the granule cell layer of cerebellum, and the lipid peroxide product 4-hydroxynonenal-immunoreactivity and albumin-immunoreactivity were present throughout the cytoplasm of cerebellar Purkinje cells. Extravasation of albumin into the brain was not observed, indicating the cerebral microvasculature with respect to permeability to plasma proteins was normal at the time of analysis. We suggest that increased glial fibrillary acidic protein and 4-hydroxynonenal result from oxidative stress induced by QUIN, and that the increased intracellular albumin in cerebellar Purkinje cells may be an adaptive response.
Yan
E
E
Fetal and Neonatal Research Group, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
Castillo-Meléndez
M
M
Smythe
G
G
Walker
D
D
D000418:Albumins / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001784:Blood Gas Analysis / Q000379:methods; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000196:embryology; D004622:Embryo, Mammalian; D018690:Excitatory Amino Acid Agonists / Q000097:blood / Q000494:pharmacology*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D037102:Lectins / Q000378:metabolism; D011247:Pregnancy; D011689:Purkinje Cells / Q000187:drug effects* / Q000378:metabolism; D017378:Quinolinic Acid / Q000097:blood / Q000494:pharmacology*; D012756:Sheep; D013997:Time Factors
D000418:Albumins; D000447:Aldehydes; D018690:Excitatory Amino Acid Agonists; D005904:Glial Fibrillary Acidic Protein; D037102:Lectins; D017378:Quinolinic Acid; C027576:4-hydroxy-2-nonenal