Central administration of a cytochrome P450-7 alpha product 7 alpha-hydroxypregnenolone improves spatial memory retention in cognitively impaired aged rats

Pregnenolone ( PREG) and dehydroepiandrosterone ( DHEA) have been reported to improve memory in aged rodents. In brain, these neurosteroids are transformed predominantly into 7 alpha-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, 7 alpha-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 7 alpha-hydroxylated metabolite 7 alpha-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 7 alpha-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 [C-14]DHEA to [C-14]7 alpha-hydroxyDHEA) was decreased selectively in memory- impaired aged rats compared with both young and memory- intact aged rats. 7 alpha-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 7 alpha-hydroxyPREG and suggests that reduced CYP7B function in the hippocampus of memory- impaired aged rats may, in part, be overcome by administration of 7 alpha-hydroxyPREG.