Neurobiological characterization of an azoxymethane mouse model of acute liver failure

被引:59
作者
Bélanger, M
Côté, J
Butterworth, RF
机构
[1] CHUM, Hop St Luc, Neurosci Res Unit, Montreal, PQ H2X 3J4, Canada
[2] CHUM, Hop St Luc, Dept Pathol, Montreal, PQ, Canada
基金
加拿大健康研究院;
关键词
azoxymethane; acute liver failure; brain edema; amino acids; gene expression;
D O I
10.1016/j.neuint.2005.11.022
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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, AX, Green, R.M, Benya, RX, 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. (C) 2006 Elsevier Ltd. All rights reserved.
引用
收藏
页码:434 / 440
页数:7
相关论文
共 37 条
  • [1] Hepatic encephalopathy: molecular mechanisms underlying the clinical syndrome
    Albrecht, J
    Jones, EA
    [J]. JOURNAL OF THE NEUROLOGICAL SCIENCES, 1999, 170 (02) : 138 - 146
  • [2] Loss of expression of glial fibrillary acidic protein in acute hyperammonemia
    Bélanger, M
    Desjardins, P
    Chatauret, N
    Butterworth, RF
    [J]. NEUROCHEMISTRY INTERNATIONAL, 2002, 41 (2-3) : 155 - 160
  • [3] Burt AD, 1998, SEMIN DIAGN PATHOL, V15, P246
  • [4] Pathophysiology of hepatic encephalopathy: A new look at ammonia
    Butterworth, RF
    [J]. METABOLIC BRAIN DISEASE, 2002, 17 (04) : 221 - 227
  • [5] CAUSSE X, 1995, GASTROEN CLIN BIOL, V19, P66
  • [6] Effects of hypothermia on brain glucose metabolism in acute liver failure:: A 1H/13C-nuclear magnetic resonance study
    Chatauret, N
    Zwingmann, C
    Rose, C
    Leibfritz, D
    Butterworth, RF
    [J]. GASTROENTEROLOGY, 2003, 125 (03) : 815 - 824
  • [7] Mild hypothermia prevents cerebral edema and CSF lactate accumulation in acute liver failure
    Chatauret, N
    Rose, C
    Therrien, G
    Butterworth, RF
    [J]. METABOLIC BRAIN DISEASE, 2001, 16 (1-2) : 95 - 102
  • [8] Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration
    Clemmesen, JO
    Larsen, FS
    Kondrup, J
    Hansen, BA
    Ott, P
    [J]. HEPATOLOGY, 1999, 29 (03) : 648 - 653
  • [9] Increased expression of the peripheral-type benzodiazepine receptor isoquinoline carboxamide binding protein mRNA in brain following portacaval anastomosis
    Desjardins, P
    Bandeira, P
    Rao, VLR
    Ledoux, S
    Butterworth, RF
    [J]. BRAIN RESEARCH, 1997, 758 (1-2) : 255 - 258
  • [10] Alterations in expression of genes coding for key astrocytic proteins in acute liver failure
    Desjardins, P
    Bélanger, M
    Butterworth, RF
    [J]. JOURNAL OF NEUROSCIENCE RESEARCH, 2001, 66 (05) : 967 - 971