Quinolinate in brain and cerebrospinal fluid in rat models of congenital hyperammonemia.
Children with inborn errors of urea synthesis who survive neonatal hyperammonemic coma commonly exhibit cognitive deficits and neurologic abnormalities. Yet, there is evidence that ammonia is not the only neurotoxin. Hyperammonemia appears to induce a number of neurochemical alterations. In rodent models of hyperammonemia, uptake of L-tryptophan into brain is increased. It has been reported that in an experimental rat model of hepatic encephalopathy, in the ammonium acetate-injected rat, and in patients with hepatic failure and inborn errors of ammonia metabolism, quinolinate, a tryptophan metabolite, is increased. Elevations in quinolinate are of particular concern, as quinolinate could excessively activate the N-methyl-D-aspartate subclass of excitatory amino acid receptors, thereby causing selective neuronal necrosis. We sought to identify an animal model that would replicate the increases in quinolinate that have been associated with hyperammonemia in humans. Levels of quinolinate were measured in hyperammonemic urease-infused rats and ammonium acetate-injected rats. In the urease-infused rat, brain tryptophan was doubled, and serotonin and its metabolite 5-hydroxyindoleacetic acid were significantly increased. Yet, despite the increase in tryptophan and evidence for increased metabolism of tryptophan to serotonin, there were no observed increases of quinolinate in brain, cerebrospinal fluid, or plasma. In the ammonium acetate-injected rat, significant increases of 5-hydroxyindoleacetic acid in cerebral cortex were also observed, but quinolinate did not change in cerebrospinal fluid or cerebral cortex. In summary, we were unable to demonstrate an increase of quinolinate in brain or cerebrospinal fluid in these rat models of hyperammonemia.
D000085:Acetates; D000641:Ammonia / Q000097:blood*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D006897:Hydroxyindoleacetic Acid / Q000134:cerebrospinal fluid; D008297:Male; D008661:Metabolism, Inborn Errors / Q000209:etiology / Q000378:metabolism*; D017378:Quinolinic Acid / Q000134:cerebrospinal fluid / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014364:Tryptophan / Q000378:metabolism; D014510:Urease
D000085:Acetates; D006897:Hydroxyindoleacetic Acid; D000641:Ammonia; D014364:Tryptophan; D014510:Urease; D017378:Quinolinic Acid; C018824:ammonium acetate