Reduced brain levels of DHEAS in hepatic coma patients: Significance for increased GABAergic tone in hepatic encephalopathy

► We demonstrated decreased brain level of DHEAS in patients died with HE. ► We demonstrated that reducing DHEAS increases GABAergic tonic currents. ► Decreased DHEAS and increased AP stimulate GABAergic currents synergistically. ► We suggest that reduced brain DHEAS further increase GABAergic tone in human HE. Increased neurosteroids with allosteric modulatory activity on GABAA receptors such as 3α–5α tertrahydroprogesterone; allopregnanolone (ALLO), are candidates to explain the phenomenon of “increased GABAergic tone” in hepatic encephalopathy (HE). However, it is not known how changes of other GABAA receptor modulators such as dehydroepiandrosterone sulfate (DHEAS) contribute to altered GABAergic tone in HE. Concentrations of DHEAS were measured by radioimmunoassay in frontal cortex samples obtained at autopsy from 11 cirrhotic patients who died in hepatic coma and from an equal number of controls matched for age, gender, and autopsy delay intervals free from hepatic or neurological diseases. To assess whether reduced brain DHEAS contributes to increased GABAergic tone, in vitro patch clamp recordings in rat prefrontal cortex neurons were performed. A significant reduction of DHEAS (5.81±0.88ng/g tissue) compared to control values (9.70±0.79ng/g, p