Neurosteroids in hepatic encephalopathy: Novel insights and new therapeutic opportunities

• Published in: The Journal of steroid biochemistry and molecular biology 2016-06, Vol.160, p.94-97
• Main Author: Butterworth, Roger F.
• Format: Article
• Language: English
• Subjects: Allopregnanolone; Animals; Brain - drug effects; Brain - metabolism; Brain - pathology; Cirrhosis; Desoxycorticosterone - analogs & derivatives; Desoxycorticosterone - metabolism; Drug Discovery - methods; GABA; GAMSA; Hepatic encephalopathy; Hepatic Encephalopathy - drug therapy; Hepatic Encephalopathy - metabolism; Hepatic Encephalopathy - pathology; Humans; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver failure; Molecular Targeted Therapy - methods; Neurosteroids; Neurotransmitter Agents - metabolism; Pregnanolone - metabolism; Receptors, GABA-A - metabolism; Translocator protein
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2015.11.006

•GABAergic neurotransmission (GABAergic tone) is increased in hepatic encephalopathy (HE).•The intrinsic GABA system of brain, however, is not modified in HE.•Certain neurosteroids (NS) are potent agonists of a modulatory site on the GABA-A receptor.•Concentrations of the NS allopregnanolone are increased in brains of HE patients.•Studies reveal that NS antagonists have potential as novel therapeutic agents in HE. Hepatic encephalopathy (HE) is a serious neuropsychiatric disorder resulting from liver failure. Symptoms of HE include mild cognitive impairment, stupor and coma. Morphological changes to neuroglia (both astrocytes and microglia) occur in HE consisting of cytotoxic brain edema (astrocyte swelling) in acute liver failure and Alzheimer type-2 astrocytosis in cirrhosis. Visual-evoked responses in animals with liver failure and HE manifest striking similarities to those in animals treated with agonists of the GABA-A receptor complex. Neurosteroids are synthesized in brain following activation of translocator protein (TSPO), a mitochondrial neuroglial cholesterol-transporter protein. TSPO sites are activated in both animal models of HE as well as in autopsied brain tissue from HE patients. Activation of TSPO sites results in increased cholesterol transport into the mitochondrion followed by stimulation of a metabolic pathway culminating in the synthesis of allopregnanolone (ALLO) and tetrahydrodeoxycorticosterone (THDOC), neurosteroids with potent positive allosteric modulatory action on the GABA-A receptor complex. Concentrations of ALLO and THDOC in brain tissue from mice with HE resulting from toxic liver injury are sufficient to induce sedation in animals of the same species and significant increases in concentrations of ALLO have been reported in autopsied brain tissue from cirrhotic patients with HE leading to the proposal that “increased GABAergic tone” in HE results from that increased brain concentrations of this neurosteroid. Agents with the potential to decrease neurosteroid synthesis and/or prevent their modulatory actions on the GABA-A receptor complex may provide novel approaches to the management and treatment of HE. Such agents include indomethacin, benzodiazepine receptor inverse agonists and a novel series of compounds known as GABA-A receptor-modulating steroid antagonists (GAMSA).