Enhanced plasma DHEAS, brain acetylcholine and memory mediated by steroid sulfatase inhibition.
Steroid sulfatase inhibitors can alter the metabolism of neurosteroids which modulate brain function. Administration of the non-steroidal steroid sulfatase inhibitor (p-O-sulfamoyl)-N-tetradecanoyl tyramine (DU-14) to rats for 15 days increased plasma dehydroepiandrosterone sulfate (DHEAS) concentrations by 88.2%, decreased plasma dehydroepiandrosterone (DHEA) concentrations by 84.6%, increased hippocampal acetylcholine (ACh) release determined via in vivo microdialysis by almost 3-fold, and produced a significant blockade of scopolamine-induced amnesia as measured by a passive avoidance test. These results suggest DHEAS rather than DHEA enhances brain cholinergic function and that steroid sulfatase inhibition may become an important tool for enhancing neuronal functions, such as memory, mediated by excitatory neurosteroids.
Rhodes
M E
ME
Division of Pharmacology-Toxicology, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA.
Li
P K
PK
Burke
A M
AM
Johnson
D A
DA
D000109:Acetylcholine / Q000378:metabolism*; D000647:Amnesia; D000818:Animals; D001192:Arylsulfatases / Q000037:antagonists & inhibitors*; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D003687:Dehydroepiandrosterone / Q000097:blood; D019314:Dehydroepiandrosterone Sulfate / Q000097:blood*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012601:Scopolamine / Q000494:pharmacology; D043266:Steryl-Sulfatase; D014439:Tyramine / Q000031:analogs & derivatives* / Q000494:pharmacology
C103321:4-O-(sulfamoyl)-N-tetradecanoyltyramine; D004791:Enzyme Inhibitors; D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate; D012601:Scopolamine; D001192:Arylsulfatases; D043266:Steryl-Sulfatase; D000109:Acetylcholine; D014439:Tyramine