Review
Selective estrogen receptor modulators (SERMs) for the brain: Current
status and remaining challenges for developing NeuroSERMs
Liqin Zhao, Kathleen OTNeill, Roberta Diaz Brinton
T
Department of Molecular Pharmacology and Toxicology and the Program in Neuroscience, School of Pharmacy, University of Southern California,
Pharmaceutical Sciences Center, Los Angeles, CA 90089, USA
Accepted 19 January 2005
Available online 23 March 2005
Abstract
Multiple issues regarding the efficacy of estrogen action in the brain remain unresolved. These include the timing, formulation and
duration of the therapy intervention. Moreover, issues of thrombotic and neoplastic risks must be factored into the design of estrogen
alternatives developed to prevent age-associated neurodegenerative disorders, as well as other climacteric symptoms such as hot flush and
sleep dysfunction. One strategy to address these issues is to develop molecules that selectively target and activate estrogen mechanisms of
action in the brain while avoiding activation of estrogen receptors peripheral to the brain, particularly in reproductive organs. An overview of
recent advances in our understanding of the molecular mechanisms of estrogen action is discussed in the context of designing an efficacious
NeuroSERM that will activate cellular, biochemical and genomic events required for the promotion of memory function and neuronal
survival. Pharmacological analyses of estrogen receptor subtypes and the case for a membrane-associated estrogen receptor splice variant in
mediating these mechanisms are provided along with a summary of the activation profiles of existing clinically relevant estrogen alternatives
or SERMs in neurons. Results of these endeavors have yielded insights into strategies for developing novel molecules with NeuroSERM
potential in order to prevent brain related climacteric symptoms and neurodegenerative diseases.
D 2005 Elsevier B.V. All rights reserved.
Theme: Endocrine and autonomic regulation
Topic: Neuroendocrine regulation: other
Keywords: Estrogen; ET; SERM; Cognition; Neuroprotection; Alzheimer’s disease
Contents
1. Introduction .......................................................... 473
1.1. Aging and Alzheimer’s disease: a societal health issue ................................. 473
1.2. Gender demographics of Alzheimer’s disease: a women’s health issue ......................... 473
2. Estrogen therapy and clinical characteristics in the CNS ................................... 473
3. Brain estrogen receptors: structural and functional requirements for a NeuroSERM...................... 474
3.1. An estrogen receptor splice variant as a potential membrane ER . . .......................... 475
3.2. ERa and/or ERh in estrogen-inducible promotion of cognitive function and neuronal survival ............ 476
4. Estrogen-activated signaling cascades in neurons: mechanistic requirements for a NueroSERM ............... 477
0165-0173/$ - see front matter D 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.brainresrev.2005.01.009
Brain Research Reviews 49 (2005) 472– 493
www.elsevier.com/locate/brainresrev
T Corresponding author. Fax: +1 323 442 1489.
E-mail address: rbrinton@hsc.usc.edu (R. Diaz Brinton).
URL: http://www.pharmweb.usc.edu/brinton-lab (R. Diaz Brinton).