Chronic oral administration of a novel estrogen receptor beta agonist enhances memory consolidation and alleviates vasomotor symptoms in a mouse model of menopause

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.

Male violence disrupts estrogen receptor β signaling in the female hippocampus

“…Unfortunately, cancer diagnoses are increasing in IPV-victimized women 37 . Moreover, studies suggest ERβ activation may be a promising avenue for reducing menopause-related hot flashes, and memory dysfunction, and also to lessen the risk of neurodegenerative disorders, such as Alzheimer’s disease 38 .…”

On the role of sex steroids in biological functions by classical and non-classical pathways. An update

“…Administration of the selective agonist of ERβ - EGX358, reduced the senktide-mediated increase in tail skin temperature and enhanced memory in the object recognition and object placement tasks in ovariectomized mice. Thus, this ERβ agonist seems to be a promising in research of drugs for reducing menopause-related hot flashes or memory dysfunction ( Fleischer et al, 2020 ). The possible signaling pathways of intracellular and membrane-associated ERs are summarized in Fig.…”