Selective loss of binding sites for the glutamate receptor ligands [3H]kainate and (S)-[3H]5-fluorowillardiine in the brains of rats with acute liver failure.

Abstract

There is increasing evidence that alterations of glutamatergic function are implicated in the pathogenesis of central nervous system consequences of acute liver failure. The aim of the study was to assess the integrity of glutamate receptors in the brain in experimental ischemic liver failure using quantitative receptor autoradiography and the selective ligands [3H]MK801 (for N-methyl-D-aspartate [NMDA] sites), [3H]5-fluorowillardiine (for non-NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA] subclass sites), and [3H]kainate (for non-NMDA, kainate subclass sites). At coma stages of encephalopathy, a selective loss of up to 60% of binding sites for the kainate- and AMPA-receptor ligands was observed in cerebral cortical and hippocampal structures as well as in the hypothalamus and cerebellum. The finding of a selective loss of AMPA sites at coma stages of encephalopathy in this model of acute liver failure is consistent with previous electrophysiological reports of inhibition of AMPA-mediated neuronal depolarization resulting from exposure of hippocampal neurons to millimolar concentrations of ammonia. On the other hand, the present study showed that binding sites for the NMDA-receptor ligand [3H]MK801 at coma stages of encephalopathy in acute liver failure were within normal limits in all brain structures examined. NMDA sites are uniquely neuronal, whereas kainate and AMPA sites are localized on both neurons and astrocytes. Therefore, the selective loss of non-NMDA sites in acute liver failure may also reflect astrocytic changes in this condition. Because astrocytic glutamate receptors are implicated in K+ and neurotransmitter reuptake, alterations in their density could result in altered neuronal excitability and thus be responsible for the neurological dysfunction characteristic of hepatic encephalopathy in acute liver failure.