NEURAL MECHANISMS OF HEPATIC ENCEPHALOPATHY

The experiments described in this proposal were designed to examine the
pathophysiologic sequence of events which results in the generalized
neuroinhibition of hepatic encephalopathy. Evidence is presented from
preliminary studies that gamma-amino-butyric acid (GABA), the principal
inhibitory neurotransmitter of the mammalian brain, and its
neurotransmitter system may play an important role in hepatic coma in man.
The proposed studies involve four broad areas: 1) Evaluating the source
and metabolic economy of serum GABA in healthy and diseased humans; 2)
Exploring new methods which may shed light on control of the blood-brain
barrier; 3) Examining the anatomic distribution of GABA-ergic effects with
36Cl- autoradiography in animal models of hepatic coma and; 4) Measuring
neurotransmitter receptor density and affinity in human autopsy specimens.
All of these experiments make use of recently developed neurobiologic
principles and methods to explore an old and tantalizing problem in
clinical medicine. The goals of this research are several. The first
would be to gain sufficient understanding of the pathophysiology of hepatic
coma so that therapy might be rational rather than empiric. Second,
increased understanding of blood-brain barrier permeability control in
hepatic coma may lead to new therapeutic options. Third, insights into the
pharmacodynamics of such widely used drugs as benzodiazepines and
barbiturates would assist in rational therapy of patients with liver
disease.