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

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 delta8,9-dehydroestrone (∆8E1) and equilin showing the strongest neuroprotective profiles. It has not been evaluated whether ∆8E1 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 ∆8E1 and equilin treatments on a cognitive battery and cholinergic nicotinic receptors (nAChR). Specifically, we used 125I-labeled epibatidine binding to assay brain nicotinic receptor containing 4α and 2β subunits (α4β2-nAChR), since this nicotinic receptor subtype has been shown previously to be sensitive to other estrogens. ∆8E1 enhanced spatial working, recent and reference memory. ∆8E1 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, and neither estrogen impacted 86Rb+ 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 ∆8E1-induced benefits on several dimensions of health-related concerns associated with menopause, this body of research identifies ∆8E1 as a new avenue to be investigated as a potential component of HT that may benefit brain health and function during aging.

Research Highlights
► The Premarin® components Δ8,9-dehydroestrone (∆8E1) and equilin are neuroprotective in vitro.
► ∆8E1 enhanced memory and altered nicotinic acetylcholine receptors (nAChRs) in cognitive brain regions.
► Equilin treatment did not affect memory nor α4β2-nAChR expression.
► Prior research in women showed ∆8E1 benefited multiple parameters negatively impacted by menopause.
► ∆8E1 should be further evaluated as a hormone therapy that benefits cognition in women.