Neuroactive amino acids and glutamate (NMDA) receptors in frontal cortex of rats with experimental acute liver failure.
It has been proposed that alterations of excitatory and inhibitory amino acids play a role in the pathogenesis of hepatic encephalopathy in acute liver failure. To evaluate this possibility, in vivo cerebral microdialysis was used to sample extracellular concentrations of amino acids in the frontal cortex of unanesthetized rats at various times during the progression of encephalopathy resulting from acute liver failure. Liver failure was induced by portacaval anastomosis followed 24 hours later by hepatic artery ligation. Dialysate concentrations of amino acids were measured by high-performance liquid chromatography (HPLC) with fluorescence detection. Deterioration of neurological status was accompanied by two- to four-fold increases in extracellular glutamate, glutamine, and glycine; concentrations of gamma-aminobutyric acid (GABA) and taurine were unchanged. Densities of binding sites for the glutamate (N-methyl-D-aspartate [NMDA]) receptor ligand 3H-MK801, assessed using quantitative receptor autoradiography, however, were unchanged in the frontal cortex of rats at coma stages of ischemic liver failure. Increased extracellular glutamate concentrations were positively correlated with the severity of encephalopathy and with arterial ammonia concentrations. Such changes may result from an ammonia-induced reduction in the capacity for astrocytes to uptake glutamate. Increased extracellular glutamate in brain, together with increases in concentrations of glycine, a positive allosteric modulator of glutamate (NMDA) receptors, are consistent with increased NMDA-related glutamatergic neurotransmission in this model of acute liver failure. Increased extracellular glutamate, therefore, could contribute to the pathogenesis of hepatic encephalopathy and brain edema in acute liver failure.
Michalak
A
A
Neuroscience Research Unit, Hôpital Saint-Luc (University of Montreal), Quebec, Canada.
Rose
C
C
Butterworth
J
J
Butterworth
R F
RF
D000818:Animals; D001224:Aspartic Acid / Q000032:analysis; D001923:Brain Chemistry; D018846:Excitatory Amino Acids / Q000032:analysis*; D005110:Extracellular Space / Q000737:chemistry*; D018698:Glutamic Acid / Q000032:analysis; D006501:Hepatic Encephalopathy; D008297:Male; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000032:analysis
D018846:Excitatory Amino Acids; D001224:Aspartic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid