ASTROCYTE BENZODIAZEPINE RECEPTOR IN HEPATIC COMA

Project: Research project

Project Details

Description

The pathogenetic mechanisms involved in acute and chronic liver failure are
still poorly understood. Currently, abnormalities in the benzodiazepine
(BZD) receptor system are widely considered as a mechanism of hepatic
encephalopathy (HE). Recent studies in our laboratory suggest that the
peripheral-type BZD receptor, which is predominantly localized in
astrocytes, may be preferentially involved in HE. This in keeping with
substantial evidence indicating that astrocytes are the target cells in HE.

Our hypothesis is that toxin-induced abnormalities in the astrocyte BZD
receptor are a key factor in the pathogenesis of HE. Since little is known
about the significance of the astrocytic BZD receptor, our aim is to
investigate its properties and functions in cultured astrocytes. We will
determine its intracellular location as this would provide important clues
to its function. We anticipate that a major portion will be located on
mitochondria an accordingly, we will evaluate the action of BZD on energy
metabolism by measuring levels of key energy metabolites and establishing
the effect on cellular respiration. Basic cellular effects of BZD on
astrocytes including morphology, proliferative capacity, and the status of
key astrocytic markers (eg, glial fibrillary acidic protein, glutamine
synthetase, pyruvate carboxylase) will be established. As the BZD receptor
is also likely to be located in the plasma membrane, the ability of BZD to
affect the uptake of cations and neuromodulators will be studied as changes
in these properties may affect CNS excitability. The identification of
possible second messengers will be done and the effect of BZD on other
membrane receptors will be evaluated. The regulatory role of protein
phosphorylation in BZD receptor activity, as well as the effect of agents
known to modify the BZD receptor in other systems eg, taurine, melatonin
and diazepam-binding inhibitor, will be performed on cultures that head
been exposed to HE-related toxins and serum form rabbit with fulminant
hepatic failure (FHF). Observed differences between toxin-treated and
untreated cultures will support our hypothesis. The last phase of our
project density of the peripheral BZD receptor will be determined in
various models of HE (thioacetamide-induced FHF, ammonia intoxication,
portocaval-shunted rats and portocaval-shunted rats challenged with
ammonia). The effect of peripheral BZD receptor blockers on the clinical
course of experimental HE will also be carried out. We anticipate that
these studies on cultured astrocytes and in vivo models will provide a
better understanding of the role of the astrocyte receptor in the
pathogenesis of HE and may furthermore provide therapeutic measures which
may be useful int he management of patients with this disorder.
StatusFinished
Effective start/end date12/31/893/31/95

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases

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