Loss of noradrenaline transporter sites in frontal cortex of rats with acute (ischemic) liver failure

Abstract

There is increasing evidence that central noradrenaline (NA) transport mechanisms are implicated in the central nervous system complications of acute liver failure. In order to assess this possibility, binding sites for the high affinity NA transporter ligand [3 H]-nisoxetine were measured by quantitative receptor autoradiography in the brains of rats with acute liver failure resulting from hepatic devascularization and in appropriate controls. In vivo microdialysis was used to measure extracellular brain concentrations of NA. Severe encephalopathy resulted in a significant loss of [ 3 H]-nisoxetine sites in frontal cortex and a concomitant increase in extracellular brain concentrations of NA in rats with acute liver failure. A loss of transporter sites was also observed in thalamus of rats with acute liver failure. This loss of NA transporter sites could result from depletion of central NA stores due to a reserpine-like effect of ammonia which is known to accumulate to millimolar concentrations in brain in ischemic liver failure. Impaired NA transport and the consequent increase in synaptic concentrations and increased stimulation of neuronal and astrocytic noradrenergic receptors could be implicated in the pathogenesis of the encephalopathy and brain edema characteristic of acute liver failure.

The Use of Microdialysis in the Study of Encephalopathies

“…Michalak et al (1998) showed that there is an increase of extracellular brain concentrations of noradrenalin (NA), from the extracellular compartment of frontal cortex and thalamus in rats with acute liver failure (Michalak et al, 1998), and this is associated to the loss of NA transporter sites resulting from depletion of central NA stores due to a reserpine-like effect of ammonia which is known to accumulate in brain in ischemic liver failure (Michalak et al, 2010). These experimental data suggested that noradrenergic neurotransmission may play a role in this pathology.…”

Miscellanea on Encephalopathies

“…Like other systems affected in HE, there is an experimental evidence suggesting that noradrenergic system is affected and describes that central noradrenergic mechanisms may contribute to the central nervous system manifestations of HE. Michalak et al (1998) showed that there is an increase of extracellular brain concentrations of noradrenalin (NA), from the extracellular compartment of frontal cortex and thalamus in rats with acute liver failure (Michalak et al, 1998), and this is associated to the loss of NA transporter sites resulting from depletion of central NA stores due to a reserpine-like effect of ammonia which is known to accumulate in brain in ischemic liver failure (Michalak et al, 2010). These experimental data suggested that noradrenergic neurotransmission may play a role in this pathology.…”

Molecular Neurobiology of Acute Liver Failure

“…Hepatic devascularization also results in reductions in the density of sites for serotonin 43 and noradrenaline 44 transporters. However, in contrast to EAAT-2 and GLYT-1, the loss of these monoamine transporters occurs via posttranslational mechanisms.…”