Chronic Oral Administration of a Novel Estrogen Receptor Beta Agonist Enhances Memory Consolidation and Alleviates Vasomotor Symptoms in a Mouse Model of Menopause

Authors

Aaron W. Fleischer, University of Wisconsin - Milwaukee
Jayson C. Schalk, University of Wisconsin - Milwaukee
Edward Edward Wetzel, Marquette University
Alicia M. Hanson, Concordia University - Wisconsin
Daniel S. Sem, Marquette UniversityFollow
William A. Donaldson, Marquette UniversityFollow
Karyn M. Frick, University of Wisconsin - Milwaukee

Document Type

Article

Publication Date

12-2020

Publisher

Wiley

Source Publication

Alzheimer's & Dementia

Source ISSN

1552-5260

Original Item ID

DOI: 10.1002/alz.047645

Abstract

Background

Women are at greater risk of Alzheimer’s Disease (AD) than men, and symptoms associated with the menopausal loss of circulating estrogens, including hot flashes, exacerbate cognitive decline and AD risk. Although estrogen-based therapies reduce hot flashes and mitigate AD risk early in the menopausal transition, these treatments can increase risks of cancer, among other health issues. These adverse effects are mediated by the alpha (ERα), but not beta (ERβ), estrogen receptor isoform. Moreover, activation of ERβ facilitates memory formation and reduces hot flashes. Thus, ERβ-selective therapies may promote memory function, reduce hot flashes, and diminish AD risk without complications associated with ERa. Our goal here was to determine whether chronic treatment with EGX358, a novel highly selective ERβ agonist developed by our group, could enhance memory and reduce hot flash-like symptoms in a mouse model of menopause.

Methods

Eight-week-old ovariectomized C57BL/6 mice were orally gavaged each day for 10 weeks with vehicle, the highly potent estrogen 17β-estradiol (E₂; equal affinity for ERα and ERβ), the commercially available ERβ agonist diarylpropionitrile (DPN), or EGX358 (∼10x greater selectivity for ERβ than DPN). Compounds were administered at doses that enhance memory when delivered acutely. After two weeks of treatment, hot flash-like symptoms were tested after subcutaneous injection of vehicle or senktide, a tachykinin receptor 3 agonist that induces hot flash-like symptoms. Tail skin temperature was then recorded using a thermal camera for 30 minutes as a proxy for vasodilation. Six weeks later, mice were trained in object recognition (OR) and object placement (OP) tasks to test object and spatial memory, respectively. Memory in the OR and OP tasks was tested 48 and 24 hours later, respectively.

Results

E₂, DPN, or EGX358 treatment reduced the senktide-mediated increase in tail skin temperature. Furthermore, treatment with E₂, DPN, or EGX358, but not vehicle, enhanced memory in the OR and OP tasks.

Conclusions

These data suggest that chronic EGX358 treatment can reduce hot flash-like symptoms and improve spatial and object recognition memories. Therefore, ERβ activation may be a promising avenue for reducing menopause-related hot flashes, memory dysfunction, and AD risk.

Comments

Alzheimer's & Dementia, Vol. 16, No. S9 (December 2020): e047645. DOI.

Daniel S. Sem was affiliated with Concordia University Wisconsin at the time of publication.

Recommended Citation

Fleischer, Aaron W.; Schalk, Jayson C.; Wetzel, Edward Edward; Hanson, Alicia M.; Sem, Daniel S.; Donaldson, William A.; and Frick, Karyn M., "Chronic Oral Administration of a Novel Estrogen Receptor Beta Agonist Enhances Memory Consolidation and Alleviates Vasomotor Symptoms in a Mouse Model of Menopause" (2020). Chemistry Faculty Research and Publications. 1057.
https://epublications.marquette.edu/chem_fac/1057