title: GABAergic neurosteroids: the "endogenous benzodiazepines" of acute liver failure.
abstract: Acute liver failure (ALF) or fulminant hepatic failure represents a serious life-threatening condition. ALF is characterized by a significant liver injury that leads to a rapid onset of hepatic encephalopathy (HE). In ALF, patients manifest rapid deterioration in consciousness leading to hepatic coma together with an onset of brain edema which induces high intracranial pressure that frequently leads to herniation and death. It is well accepted that hyperammonemia is a cardinal, but not the sole, mediator in the pathophysiology of ALF. There is increasing evidence that neurosteroids, including the parent neurosteroid pregnenolone, and the progesterone metabolites tetrahydroprogesterone (allopregnanolone) and tetrahydrodeoxycorticosterone (THDOC) accumulate in brain in experimental models of ALF. Neurosteroids in ALF represent good candidates to explain the phenomenon of "increased GABAergic tone" in chronic and ALF, and the beneficial effects of benzodiazepine drugs. The mechanisms that trigger brain neurosteroid changes in ALF are not yet well known, but could involve partially de novo neurosteroidogenesis following activation of the translocator protein (TSPO). The factors that contribute to TSPO changes in ALF may include ammonia and cytokines. It is possible that increases in brain levels of neurosteroids in ALF may result in auto-regulatory mechanisms where hypothermia may play a significant role. Possible mechanisms that may involve neurosteroids in the pathophysiology of HE, and more speculatively in brain edema, and inflammatory processes in ALF are suggested.
authors: Université Cadi Ayyad, Faculté des Sciences Semlalia, Equipe Neurosciences Pharmacologie et Environnement, BP 2930 Marrakech, Morocco. sahboucha@hotmail.com
authors: Samir
authors: S
authors: Ahboucha
authors: Halima
authors: H
authors: Gamrani
authors: Glen
authors: G
authors: Baker
mesh_terms: D001569:Benzodiazepines / Q000378:metabolism; D001929:Brain Edema / Q000209:etiology / Q000503:physiopathology; D006801:Humans; D007427:Intracranial Pressure; D017114:Liver Failure, Acute / Q000150:complications / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018377:Neurotransmitter Agents; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid