ASTROCYTE RECEPTORS IN HEPATIC ENCEPHALOPATHY

Project: Research project

Description

The principal objective of these studies is to investigate the
potential role of astrocytes in the pathogenesis of hepatic
encephalopathy (HE). Since the primary morphological change in
HE is characterized by astrocytic degeneration, a derangement
in astroglia may be a contributing factor to the development of
encephalopathy. Given that astrocytes possess membrane
receptors which influence glial function, as well as provide the
chief mechanism for neuronal-glial communication, we propose
that encephalopathy results from a toxin-induced breakdown in
glial-neuronal interaction. Accordingly, we plan to investigate
the potential involvement of astrocytic receptors and their
second messenger' systems (cAMP, inositol phosphate) in primary
astrocyte cultures. The effect of toxins implicated in HE
(ammonia, short-chain fatty acids, mercaptans, phenol), their
possible synergism and the effects of serum from patients with
HE, on the affinity (Kd) and number (Bmax) of receptors will be
determined. We have chosen to study the adrenergic,
benzodiazepine, serotonin and histamine receptors, as there is
evidence of their specific involvement in HE. These experiments
will consist of saturation studies of specific ligands for each of
the listed receptors. Where appropriate, the ability of the
receptor to form high-agonist affinity complexes will also be
examined. In addition, the effect of toxin exposure on basal and
receptor agonist-stimulated levels of cAMP and inositol
phosphate will be evaluated. Finally, the ability of agonists,
antagonists and agents that act directly on the second messenger
systems to modify toxin-induced changes, will be determined
using light and electron microscopy. These experiments will, for
the first time, delineate the effects of HE-related toxins on
astrocyte receptor systems. It is anticipated that the
characterization of specific receptor systems changes will
elucidate possible mechanisms involved in HE and may lead to
the formulation of new therapeutic strategies.
StatusFinished
Effective start/end date1/1/873/31/95

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $199,747.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $225,707.00
  • National Institutes of Health
  • National Institutes of Health

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Hepatic Encephalopathy
Astrocytes
GABA-A Receptors
Benzodiazepines
Aptitude
Neuroglia
Ammonia
Histamine Receptors
Inositol Phosphates
Volatile Fatty Acids
Serotonin Receptors
Diazepam Binding Inhibitor
Brain Diseases
Phenol
Pyruvate Carboxylase
Thioacetamide
Cell Respiration
Sulfhydryl Compounds
Adrenergic Receptors
End Stage Liver Disease

ASJC

  • Medicine(all)