title: Central administration of a cytochrome P450-7B product 7 alpha-hydroxypregnenolone improves spatial memory retention in cognitively impaired aged rats.
abstract: Pregnenolone (PREG) and dehydroepiandrosterone (DHEA) have been reported to improve memory in aged rodents. In brain, these neurosteroids are transformed predominantly into 7alpha-hydroxylated metabolites by the cytochrome P450-7B1 (CYP7B). The biological role of steroid B-ring hydroxylation is unclear. It has been proposed to generate bioactive derivatives that enhance cognition, immune, and other physiological processes. In support, 7alpha-hydroxylated DHEA increases the immune response in mice with greater potency than the parent steroid. Whether the memory-enhancing effects of PREG in rats is mediated via its 7alpha-hydroxylated metabolite 7alpha-hydroxyPREG is not known. We investigated this by treating memory-impaired aged rats (identified by their spatial memory performances in the Morris water maze task compared with young controls) with 7alpha-hydroxyPREG or PREG administered intracerebroventricularly using osmotic minipumps and then tested the rats during week 2 of steroid treatment in the eight-arm radial-arm version of the water maze (RAWM) that allows repeated assessment of learning. CYP7B bioactivity in hippocampal tissue (percentage conversion of [14C]DHEA to [14C]7alpha-hydroxyDHEA) was decreased selectively in memory-impaired aged rats compared with both young and memory-intact aged rats. 7alpha-hydroxyPREG (100 ng/h) but not PREG (100 ng/h) administration to memory-impaired aged rats for 11 d enhanced spatial memory retention (after a 30 min delay between an exposure trial 1 and test trial 2) in the RAWM. These data provide evidence for a biologically active enzyme product 7alpha-hydroxyPREG and suggests that reduced CYP7B function in the hippocampus of memory-impaired aged rats may, in part, be overcome by administration of 7alpha-hydroxyPREG.
authors.affiliation: Endocrinology Unit, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom. joyce.yau@ed.ac.uk
authors.forename: Joyce L W
authors.initials: JL
authors.lastname: Yau
authors.forename: June
authors.initials: J
authors.lastname: Noble
authors.forename: Mags
authors.initials: M
authors.lastname: Graham
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
mesh_terms: D006907:17-alpha-Hydroxypregnenolone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000375:Aging / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000008:administration & dosage*; D000072474:Cytochrome P450 Family 7; D007276:Injections, Intraventricular; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051381:Rats; D012153:Retention, Psychology / Q000187:drug effects* / Q000502:physiology; D013037:Spatial Behavior / Q000187:drug effects* / Q000502:physiology; D013250:Steroid Hydroxylases / Q000008:administration & dosage*
chemical_list: C495856:7-hydroxypregnenolone; D006907:17-alpha-Hydroxypregnenolone; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D000072474:Cytochrome P450 Family 7; C490784:Cyp7b1 protein, rat