Neurobiological characterization of an azoxymethane mouse model of acute liver failure.
Molecular biological approaches continue to lead to the identification of alterations in expression of genes coding for key central nervous system proteins involved in water homeostasis, energy metabolism and neurotransmitter regulation in acute liver failure (ALF). However, studies aimed at elucidating the pathophysiological consequences of these changes in gene expression are impeded by the lack of a suitable mouse model of ALF. A previous report described hepatic pathology characteristic of ALF resulting from the administration of azoxymethane (AOM) in mice [Matkowskyj, K.A., Marrero, J.A., Carroll, R.E., Danilkovich, A.V., Green, R.M., Benya, R.V., 1999. Azoxymethane-induced fulminant hepatic failure in C57BL/6J mice: characterization of a new animal model. Am. J. Physiol. 277, G455-G462]. In a series of experiments to further assess this treatment as an effective model of ALF, the effects of administration of AOM to male C57BL mice on hepatic and cerebral function were studied. With maintenance of body temperature at 37 degrees C and control of hypoglycemia, mice developed signs of encephalopathy (decreased locomotor activity followed by loss of righting and corneal reflexes) within 16 h of AOM treatment. AOM-treated mice were hyperammonemic, developed spontaneous hypothermia and brain edema. Brain ammonia concentrations were increased to 0.98+/-0.12 mM at coma stages of encephalopathy. Brain amino acid profiles determined by HPLC were typical of ALF in other species including humans. Mild hypothermia (35 degrees C) led to significant attenuation of brain edema, ammonia, and amino acid changes. These findings demonstrate that AOM treatment affords a simple, reproducible mouse model of ALF which may be suitable for the study of the effects of gene manipulation on the cerebral complications of ALF.
Neuroscience Research Unit, Hôpital Saint-Luc, CHUM, Montreal, Canada.
Mireille
M
Bélanger
Jean
J
Côté
Roger F
RF
Butterworth
D000596:Amino Acids / Q000032:analysis; D000641:Ammonia / Q000032:analysis / Q000097:blood; D000818:Animals; D001397:Azoxymethane; D001834:Body Water; D001923:Brain Chemistry; D004195:Disease Models, Animal; D007036:Hypothermia, Induced; D008099:Liver / Q000378:metabolism / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced* / Q000378:metabolism* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
D000596:Amino Acids; D000641:Ammonia; D001397:Azoxymethane