A component of Premarin® enhances multiple cognitive functions and influences nicotinic receptor expression

Abstract

In women, ovarian hormone loss at menopause has been related to cognitive decline, and some studies suggest that estrogen-containing hormone therapy (HT) can mitigate these effects. Recently, the Women's Health Initiative study found that conjugated equine estrogens, the most commonly prescribed HT, do not benefit cognition. Isolated components of conjugated equine estrogens (tradename Premarin ® ) have been evaluated in vitro, with Δ 8,9 -dehydroestrone (Δ 8 E1) and equilin showing the strongest neuroprotective profiles. It has not been evaluated whether Δ 8 E1 or equilin impact cognition or the cholinergic system, which is affected by other estrogens and known to modulate cognition. Here, in middle-aged, ovariectomized rats, we evaluated the effects of Δ 8 E1 and equilin treatments on a cognitive battery and cholinergic nicotinic receptors (nAChR). Specifically, we used 125 I-labeled epibatidine binding to assay the neuronal nicotinic receptor containing 4α and 2β subunits (α4β2-nAChR), since this nicotinic receptor subtype has been shown previously to be sensitive to other estrogens. Δ 8 E1 enhanced spatial working, recent and reference memory. Δ 8 E1 also decreased hippocampal and entorhinal cortex α4β2-nAChR expression, which was related to spatial reference memory performance. Equilin treatment did not affect spatial memory or rat α4β2-nAChR expression. Neither estrogen impacted 86 Rb + efflux, indicating lack of direct action on human α4β2 nAChR function. Both estrogens influenced vaginal smear profiles, uterine weights, and serum luteinizing hormone levels, analogous to classic estrogens. The findings indicate that specific isolated Premarin ® components differ in their ability to affect cognition and nAChR expression. Taken with the works of others showing Δ 8 E1-induced benefits on several dimensions of health-related concerns associated with menopause, this identifies Δ 8 E1 as a new avenue to be investigated as a potential component of HT that may benefit brain health and function during aging.

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

“…After the completion of all training sessions, just prior to the initiation of the final maze battery, all females received vaginal smears once a day in the morning for several consecutive days following previously published methods (Acosta, et al, 2009b, Talboom, et al, 2010). Vaginal cytology was classified as proestrus, estrous, metestrus, or diestrus (Goldman, et al, 2007).…”

Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury

“…In an in vivo behaving rodent, detrimental effects are observed. Indeed, unlike 17βE2 or another CEE component, delta 8,9 -dehydroestrone, E1 dose-dependently failed to impact, and at some doses even impaired, aversive memory in the contextual fear conditioning task and spatial working memory among adult and middle-aged Ovx rats (Barha et al, 2009a; Engler-Chiurazzi et al, 2012; Talboom et al, 2010). Further, while chronic 17βE2 increased basal forebrain ChAT-immunoreactive neurons and number of bromodeoxyuridine (BrdU)-labeled neurons in the DG, substrates underlying memory performance, chronic E1 does not impart these same changes (Engler-Chiurazzi et al, 2012; McClure et al, 2013).…”

Estradiol and cognitive function: Past, present and future

“…These three metabolites are hypothesized to be primarily responsible for the estrogenic effects of CEE (Sitruk-Ware, 2002), although there are other estrogens and related metabolites that could also exert effects (Kuhl, 2005). Most of these estrogenic compounds have not been extensively investigated in animals or humans, but effects of individual components as compared to CEE appear to differ as estrone impaired (Engler-Cjoirazzo, 2012), dehydroestrone enhanced and equiline had no effect on memory tasks in middle aged rats (Talboom et al, 2010) while low dose Premarin impaired learning and memory retention but medium and high doses enhanced it in middle aged rats (Engler-Ehiurazzi, 2011; see Acosta et al, 2013 for further discussion). In women with a uterus, Premarin (as well as estradiol) must be given with a progestin, such as Medroxyprogesterone acetate, because uterine cancer can develop with chronic estrogen treatment.…”