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.
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