CHRONIC STEROID SULFATASE INHIBITION BY (P-O-SULFAMOYL)-N-TETRADECANOYL TYRAMINE INCREASES DEHYDROEPIANDROSTERONE-SULFATE IN WHOLE-BRAIN

Dehydroepiandrosterone sulfate (DHEAS) is a neurosteroid which functio ns as a negative allosteric modulator of the GABA(A) receptor-gated ch loride channel. Steroid sulfatase inhibitors including (p-O-sulfamoyl) -N-tetradecanoyl tyramine (DU-14), can potentiate the blockade of the amnestic effects of scopolamine by exogenously administered DHEAS. Mor eover, when administered over a 15 day period, DU-14 can block scopola mine amnesia without the concurrent administration of DHEAS. Since the enzyme, steroid sulfatase, facilitates the hydrolysis of the sulfate moiety from DHEAS, the intent of this study was to determine whether c hronic administration of DU-14 could increase whole brain concentratio ns of endogenous DHEAS. Rats were administered DU-14 or corn oil vehic le for 15 days. Following the last day the animals were sacrificed and the brains were removed and analyzed for DHEAS content. DU-14 increas ed the whole brain concentration of DHEAS 77.6%, from 0.65 +/- 0.06 to 1.15 +/- 0.12 mu g/g (mean +/- SEM). This result suggests that steroi d sulfatase inhibitors may enhance cognitive function following chroni c treatment by increasing the concentration of excitatory neurosteroid s such as DHEAS in the brain. Steroid sulfatase inhibitors, therefore, may provide a novel mechanism for facilitating central nervous system function. (C) 1997 Elsevier Science Inc.