Tonic Premarin dose-dependently enhances memory, affects neurotrophin protein levels and alters gene expression in middle-aged rats

Abstract

Premarin™ is the most commonly prescribed estrogenic component of hormone therapy, given since 1942. The current study is the first examining cognitive effects of tonic Premarin treatment in an animal model. Middle-aged ovariectomized (Ovx) rats received vehicle or one of three doses of Premarin (12, 24 or 36 μg daily). Rats were tested on a spatial working and reference memory maze battery. Both Medium- and High- dose Premarin enhanced memory retention, while Low-dose Premarin impaired learning and memory retention. Correlations with serum hormone levels showed that as the ratio of estrone:17β-estradiol increased, animals tended to show better working memory performance. Taken together with the dissociation of dose-specific estrogenic profiles, results suggest that higher levels of estrone, in the presence of 17β-estradiol concentrations higher than that of Ovx levels, may be beneficial for memory. Moreover, Premarin exerted dose and brain-region specific effects on BDNF and NGF protein levels, with most marked changes in cingulate and perirhinal cortices. Hippocampal gene expression profiling demonstrated significant Premarin-induced transcriptional changes in genes linked to plasticity and cognition. These findings indicate that Premarin can impact memory and the brain, and that dosing should be recognized as a clinically relevant factor possibly affecting the direction and efficacy of cognitive outcome.

Sex Hormones and Cognition: Neuroendocrine Influences on Memory and Learning

“…Partly consistent with these findings, low-dose daily Premarin impaired spatial reference and working memory compared to ovariectomized controls in the working/reference memory version of the radial arm maze (45). High doses of tonic Premarin reduced the number of errors in a delayed matching to sample plus maze when a 6 h delay was introduced between trials 2 and 3 (153). Medium and high tonic Premarin doses also improved performance in the reference Morris Water Maze task (154).…”

“…Engler-Chiurrazzi et al [2011] gave tonic Premarin at levels analogous to low, medium, or high (time levels of the usual dose given to women (153). Low-dose tonic Premarin treatment impaired learning the Morris Water Maze (spatial reference memory) and the delayed-match-to-sample plus maze (spatial working memory), but had no significant effect in the working/reference memory version of a water radial arm maze (153). Partly consistent with these findings, low-dose daily Premarin impaired spatial reference and working memory compared to ovariectomized controls in the working/reference memory version of the radial arm maze (45).…”

Learning to remember: cognitive training-induced attenuation of age-related memory decline depends on sex and cognitive demand, and can transfer to untrained cognitive domains

“…NGF protein concentrations were assessed via enzyme-linked immunosorbent assay (ELISA) using commercially available kits from Promega (Madison, Wisconsin). NGF assay procedures were conducted as previously described (Engler-Chiurazzi, et al, 2009). Briefly, tissue lysates were made, processed, and read in flat-bottom 96 well plates according to the kit's instructions.…”

Modeling menopause: The utility of rodents in translational behavioral endocrinology research

“…This effect occurred specifically at the highest working memory load, where animals have the most items of information to remember; Ovx animals treated with MPA in middle-age also had impaired overnight forgetting on the MM, a measure of memory retention [124–125]. Related research utilizing the Ovx model showed that, depending on dose, CEE benefited spatial working and reference memory after a delay in the WRAM and a delayed match-to-sample task (DMS), another common water escape task used to evaluate spatial working and recent memory [126]. …”