Synaptic Plasma Membrane Composition and Fluidity in the Pathogenesis of Hepatic Encephalopathy

Abstract

The precise pathogenesis of hepatic encephalopathy (HE) remains unclear. The last decade has witnessed a change in the conceptual thinking regarding the neuromechanisms that might be operative in producing this disorder. While historically attention has focused on the role of actual or potential neurotoxins such as ammonia, short chain fatty acids (SCFA), and methylmercaptans, attention has more recently come to be focused on the role of endogenous neurotransmitter substances, chiefly gamma-aminobutyric acid (GABA) and as yet uncharacterized endogenous benzodiazepine (BZDP) receptor ligands (1). While these new thoughts have created considerable excitement in the area of HE research, much work remains to be done. Surprisingly, the concept that a fundamental alteration in synaptic plasma membrane (SPM) composition and fluidity may be important in the pathogenesis of HE has received little attention (2). This is even more surprising when one considers that hypotheses of the mechanisms of general anaesthesia (3), hibernation (4) and cerebral ethanol effects (3), all situations resembling in some aspects the syndrome of HE, have involved the potential or actual role for altered plasma membrane fluidity as being very important. Fundamental changes in membrane composition are known to affect important membrane functions, particularly membrane enzyme and receptor modulation. Studies of membrane fluidity and composition have attracted considerable attention in other areas of hepatology (for example, the pathogenesis of bile acid-induced cholestasis and the effect of drugs on bile cannalicular functions (5)).