DRUG DEVELOPMENT RESEARCH 66:103–117 (2006) Research Overview Estrogen Receptor b as a Therapeutic Target for Promoting Neurogenesis and Preventing Neurodegeneration Liqin Zhao and Roberta Diaz Brinton 1Ã Department of Molecular Pharmacology and Toxicology, Norris Foundation Laboratory for Neuroscience Research, University of Southern California, Pharmaceutical Sciences Center, Los Angeles, California Strategy, Management and Health Policy Enabling Technology, Genomics, Proteomics Preclinical Research Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics Clinical Development Phases I-III Regulatory, Quality, Manufacturing Postmarketing Phase IV ABSTRACT Both estrogen receptor (ER) subtypes, ERa and ERb, are expressed throughout the brain of both rodents and humans. Analyses from our laboratory and others reveal that both ERa and ERb can contribute to estrogen-induced protection against neurodegenerative insults. ERb plays a key role in regulating brain development and estrogen-induced promotion of neurogenesis and memory. These findings suggest that targeting ERb 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 ERb selective phytoestrogens have been identified and multiple structurally diverse ERb selective ligands have been synthesized. A comparison of the models of complexes between selective agonists and either ERa or ERb reveals that two variant amino acid residues in the ligand binding site, Leu384 and Met421 in ERa, which are replaced with Met336 and Ile373, respectively, in ERb, are the key molecular constituents underlying the binding of selective ligands to either ER subtype. Development of an ERb 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 ERb selective formulation might promote neuronal defense mechanisms and cognition in men, while reducing the risk of prostate cancer. Drug Dev. Res. 66:103–117, 2006.  c 2006 Wiley-Liss, Inc. Key words: estrogen receptor b; estrogen therapy; cognition; neurogenesis; brain development; neurodegeneration; neuron survival; Alzheimer’s disease CLINICAL OUTCOMES OF ESTROGEN THERAPY: THE HEALTHY CELL BIAS OF ESTROGEN BENEFIT IN THE BRAIN The profound disparities between the largely positive basic science findings of estrogen action in the brain [see the recent reviews of Brinton, 2004a,b; Simpkins et al., 2005] and the adverse outcomes of recent estrogen therapy (ET) trials in women who are either postmenopausal and normal [Rapp et al., 2003; Shumaker et al., 2003, 2004; Espeland et al., 2004] or postmenopausal with Alzheimer’s disease DDR Published online in Wiley InterScience (www.interscience.wiley. com). DOI: 10.1002/ddr.20049 Grant sponsor: National Institute of Aging; Grant sponsor: National Institute of Mental Health; Grant sponsor: Kenneth T. and Eileen L. Norris Foundation; Grant sponsor: L.K. Whittier Foundation; Grant sponsor: Stanley Family Trust; Grant sponsor: Alzheimer’s Association. Ã Correspondence to: Roberta Diaz Brinton, Department of Molecular Pharmacology and Toxicology, University of Southern California, Pharmaceutical Sciences Center, 1985 Zonal Avenue, Los Angeles, CA 90089. E-mail: rbrinton@hsc.usc.edu  c 2006 Wiley-Liss, Inc.