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

Abstract

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<0.01) was found. Brain levels of DHEAS in patients with liver disease who died without HE (11.43±1.74ng/g tissue), and in a patient who died in uremic coma (12.56ng/g tissue) were within the control range. Increasing ALLO enhances GABAergic tonic currents concentration-dependently, but increasing DHEAS reduces these currents. High concentrations of DHEAS (50μM) reduce GABAergic tonic currents in the presence of ALLO, whereas reduced concentrations of DHEAS (1μM) further stimulate these currents. These findings demonstrate that decreased concentrations of DHEAS together with increased brain concentrations of ALLO increase GABAergic tonic currents synergistically; suggesting that reduced brain DHEAS could further increase GABAergic tone in human HE.