HEPATIC COMA--GLIAL BENZODIAZEPINE RECEPTORS &STEROIDS

Project: Research project

Project Details

Description

DESCRIPTION (Adapted from Applicant's Abstract): The investigator proposes,
in this revised competitive renewal, to study the pathogenic mechanisms of
hepatic encephalopathy. The mechanism which lead to hepatic encephalopathy
are not well understood but in recent years there has been substantial
evidence which implicates ammonia, astrocytes, and excessive GABAergic
activity mediated by elevated levels of endogenous benzodiazepines. During
the prior funding period, the investigator studied the role of astrocytes,
ammonia and benzodiazepines in hepatic encephalopathy and in their prior
studies they found that 1) ammonia upregulates the peripheral benzodiazepine
receptor in cultured astrocytes an in animal models of hepatic
encephalopathy and 2) peripheral benzodiazepine receptor (PBR) blockers
ameliorate ammonia toxicity in vivo. They also found that neurosteroids
(which are products of PBR activation) are elevated in animal models of
hepatic encephalopathy and in ammonia treated astrocyte cultures, and that
some of these neurosteroids exert behavioral and neuropathologic changes
similar to hepatic encephalopathy. Their hypothesis is that neurosteroids
that positively modulate the GABAA receptor contribute to the pathogenesis
of HE. They further propose that the elevation of neurosteroids result from
an upregulation of astrocytic PBR by the hyperammonemia associated with
liver failure. To test the hypothesis, they plan to investigate the profile
of neurosteroids in animal models of HE and ammonia treated astrocyte
cultures. They plan to determine whether neurosteroids are elevated in HE
and are able to reproduce the clinical, pathological, and neurochemical
features of HE. They will also examine whether inhibiting the synthesis or
action of neurosteroids that have a positive modulatory effect on the GABAA
receptor will improve the outcome of the experimental HE. They plan to
study the role of astrocytic PBRs in the generation of neurosteroids from
brains of animal models of HE by investigating PBR binding parameters.
Measuring PBR mRNA steady-state levels, and localizing changes in the PBR by
in situ hybridization. The functional integrity of the PBR will be examined
by measuring the rate of pregnenolone synthesis. To establish the role of
ammonia in the PBR-dependent production of neurosteroids by astrocytes,
similar studies will be carried out in cultured astrocytes. Their proposed
mechanism, whereby ammonia upregulates the astrocytic PBR resulting in
elevated levels of neurosteroids that act on the neuronal GABAA receptor
synthesizes current pathogenic views and more importantly, provides the
potential for novel therapeutic approaches through intervention of
neurosteroid effects.
StatusFinished
Effective start/end date8/15/967/31/02

Funding

  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke: $163,242.00
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke

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