Pathophysiology of hepatic encephalopathy: a new look at GABA from the molecular standpoint.
Hepatic encephalopathy (HE) is a neuropsychiatric disorder associated with either acute or chronic liver failure. More than two decades ago, the role of altered GABAergic neurotransmission was proposed following evidence of "increased GABAergic tone" in HE. Increased GABAergic tone was based on several observations: (i) Similarity of visual evoked response potential patterns between rabbits with galactosamine-induced fulminant hepatic failure and animals treated with various allosteric agonists of the GABA receptor complex (GRC). (ii) Spontaneous activities of isolated Purkinje neurons from rabbits with galactosamine-induced fulminant hepatic failure are more depressed by GRC modulator compounds compared to normal animals. (iii) Flumazenil, a high selective benzodiazepine antagonist at the GRC, ameliorates behavioral symptoms and EEG activity in some HE patients. Pathophysiological mechanisms put forward to explain increased GABAergic tone in HE include (1) increase in brain GABA content due to increased brain GABA uptake through altered permeability of the blood brain barrier, (2) alteration of the integrity of constituents of the GRC, and (3) increase of endogenous GRC modulators such as benzodiazepines (and more recently neurosteroids) with potent agonist properties at the GRC. Studies performed subsequently excluded alterations of either GABA content or GRC integrity in favor of increased brain concentrations of endogenous agonists. While the role of endogenous benzodiazepines remains controversial, the presence of neurosteroids with GABA agonist properties affords a plausible explanation for increased GABAergic tone in HE.
Ahboucha
Samir
S
Neuroscience Research Unit, CHUM (Hopital Saint-Luc), Montreal, Quebec, Canada.
Butterworth
Roger F
RF
D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology*; D018757:GABA Modulators / Q000494:pharmacology; D006501:Hepatic Encephalopathy / Q000378:metabolism* / Q000503:physiopathology*; D006801:Humans; D018079:Receptors, GABA / Q000378:metabolism*; D013256:Steroids / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018757:GABA Modulators; D018079:Receptors, GABA; D013256:Steroids; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid