Acute liver failure-induced death of rats is delayed or prevented by blocking NMDA receptors in brain.
Developing procedures to delay the mechanisms of acute liver failure-induced death would increase patients' survival by allowing time for liver regeneration or to receive a liver for transplantation. Hyperammonemia is a main contributor to brain herniation and mortality in acute liver failure (ALF). Acute ammonia intoxication in rats leads to N-methyl-D-aspartate (NMDA) receptor activation in brain. Blocking these receptors prevents ammonia-induced death. Ammonia-induced activation of NMDA receptors could contribute to ALF-induced death. If this were the case, blocking NMDA receptors could prevent or delay ALF-induced death. The aim of this work was to assess 1) whether ALF leads to NMDA receptors activation in brain in vivo and 2) whether blocking NMDA receptors prevents or delays ALF-induced death of rats. It is shown, by in vivo brain microdialysis, that galactosamine-induced ALF leads to NMDA receptors activation in brain. Blocking NMDA receptors by continuous administration of MK-801 or memantine through miniosmotic pumps affords significant protection against ALF-induced death, increasing the survival time approximately twofold. Also, when liver injury is not 100% lethal (1.5 g/kg galactosamine), blocking NMDA receptors increases the survival rate from 23 to 62%. This supports that blocking NMDA receptors could have therapeutic utility to improve survival of patients with ALF.
Cauli
Omar
O
Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Avda Autopista del Saler, 16, 46013 Valencia, Spain.
Rodrigo
Regina
R
Boix
Jordi
J
Piedrafita
Blanca
B
Agusti
Ana
A
Felipo
Vicente
V
D000641:Ammonia / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D005688:Galactosamine; D006501:Hepatic Encephalopathy / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D022124:Hyperammonemia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D015918:Infusion Pumps, Implantable; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008559:Memantine / Q000008:administration & dosage / Q000494:pharmacology*; D017551:Microdialysis; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012720:Severity of Illness Index; D013997:Time Factors
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D005688:Galactosamine; D000641:Ammonia; D008559:Memantine