Estrogen receptor β as a therapeutic target for promoting neurogenesis and preventing neurodegeneration

Both estrogen receptor (ER) subtypes, ERα and ERβ, are expressed throughout the brain of both rodents and humans. Analyses from our laboratory and others reveal that both ERα and ERβ can contribute to estrogen-induced protection against neu rodegenerative insults. ERβ plays a key role in regulating brain development and estrogen-induced promotion of neurogenesis and memory. These findings suggest that targeting ERβ could generate safe and effective therapeutics to promote neuronal defense mechanisms and to maintain cognitive function, while simultaneously reducing adverse effects in reproductive organs such as breast and uterus. A number of naturally occurring ERβ selective phytoestrogens have been identified and multiple structurally diverse ERβ selective ligands have been synthesized. A comparison of the models of complexes between selective agonists and either ERα or ERβ reveals that two variant amino acid residues in the ligand binding site, Leu384 and Met421 in ERα, which are replaced with Met336 and Ile373, respectively, in ERβ, are the key molecular constituents underlying the binding of selective ligands to either ER subtype. Development of an ERβ brain-selective estrogen receptor modulator, in particular a natural source formulation, has great potential benefit for peri- and post-menopausal women who face age-associated cognitive decline and neurodegeneration. In addition, an ERβ selective formulation might promote neuronal defense mechanisms and cognition in men, while reducing the risk of prostate cancer.