While numerous pre-clinical studies have supported the benefit of hormone therapy in reducing the incidence of age-associated brain dysfunction (including reducing the risk for Alzheimer's disease (AD)), results from the Women's Health Initiative (WHl) have suggested the contrary and left the field unsettled as to the future of hormone therapy. However, important caveats of the WHl include the possibility that the duration of postmenopausal hormone deprivation diminish the protective brain response to steroid hormones, suggesting the concept of a finite therapeutic window of opportunity for estrogens and/or progestins. During the first period (4 years) of funding, this Program Project sought to identify and characterize new and alternative mechanistic targets through which estrogens and progestins affect the brain. The intent was to achieve a broader perspective on the neurobiology of steroid hormones and a better conceptual understanding of how these hormones protect the brain from insults relevant to age and age-associated diseases such as AD. These studies were successful and showed that membrane progesterone receptors, a mitochondria localized estrogen receptor, and intracellular Ca2+ channels (IP3 receptors and Ryanodine receptors) are key targets for estrogens and/or progesterone (P4), particularly within the context of brain protection. In this competitive renewal, we propose to apply our findings from the first period of funding to test our overall hypothesis that the expression and/or function of these novel targets dictate the sensitivity of the brain to the protective effects of estrogens and P4, and therefore define the "critical window" of therapeutic opportunity. Our team of researchers will address the overall hypothesis by integrating their respective Project-specific analyses (which themselves have common themes, such as hormone-induced cell signaling) into a common animal model (the OVXed rat, enabled by Core B), and then translating the results into human samples (brain samples from surgically menopausal women and their respective controls - enabled by Core A). Successful completion of the studies proposed will serve as the framework for defining strategies to expand the therapeutic window. That is, interventions that help maintain the expression and/or function of progesterone receptors, mitochondrial ER? and intracellular calcium channels may help maintain the brain's capacity to respond to estrogen and P4. Together, these strategies will lead to the development of safer and more effective therapeutic strategies for treating the menopause and reducing the risk for various brain disorders (including AD) whose risk increases during the post'-menopausal period.

Public Health Relevance

With increasing numbers of women reaching the menopause, more women will be faced with the decision to consider hormone therapy, an option that may treat not only menopausal symptoms, but potentially, help maintain a healthy brain. Through the studies proposed here, we expect to not only advance our understanding of the neurobiology of hormones, but to establish the framework by which to expand the therapeutic window of opportunity for estrogens and progesterone.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9 (O2))
Program Officer
Wise, Bradley C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Texas
Other Domestic Higher Education
Fort Worth
United States
Zip Code
Kaja, Simon; Sumien, Nathalie; Shah, Vidhi V et al. (2015) Loss of Spatial Memory, Learning, and Motor Function During Normal Aging Is Accompanied by Changes in Brain Presenilin 1 and 2 Expression Levels. Mol Neurobiol 52:545-54
Petrone, Ashley B; Simpkins, James W; Barr, Taura L (2014) 17?-estradiol and inflammation: implications for ischemic stroke. Aging Dis 5:340-5
Li, W; Huang, R; Chen, Z et al. (2014) PTEN degradation after ischemic stroke: a double-edged sword. Neuroscience 274:153-61
Chen, Fangfang; Qi, Wen; Sun, Jiahong et al. (2014) Urinary metabolites of isorhynchophylline in rats and their neuroprotective activities in the HT22 cell assay. Fitoterapia 97:156-63
Payne, Andrew J; Kaja, Simon; Naumchuk, Yuliya et al. (2014) Antioxidant drug therapy approaches for neuroprotection in chronic diseases of the retina. Int J Mol Sci 15:1865-86
Cunningham, Rebecca L; Singh, Meharvan; O'Bryant, Sid E et al. (2014) Oxidative stress, testosterone, and cognition among Caucasian and Mexican-American men with and without Alzheimer's disease. J Alzheimers Dis 40:563-73
Kaja, Simon; Naumchuk, Yuliya; Grillo, Stephanie L et al. (2014) Differential up-regulation of Vesl-1/Homer 1 protein isoforms associated with decline in visual performance in a preclinical glaucoma model. Vision Res 94:16-23
Petrone, Ashley B; Gatson, Joshua W; Simpkins, James W et al. (2014) Non-feminizing estrogens: a novel neuroprotective therapy. Mol Cell Endocrinol 389:40-7
Xie, Luokun; Sun, Fen; Wang, Jixian et al. (2014) mTOR signaling inhibition modulates macrophage/microglia-mediated neuroinflammation and secondary injury via regulatory T cells after focal ischemia. J Immunol 192:6009-19
Faure, Lionel; Nagarajan, Subbiah; Hwang, Hyeondo et al. (2014) Synthesis of phenoxyacyl-ethanolamides and their effects on fatty acid amide hydrolase activity. J Biol Chem 289:9340-51

Showing the most recent 10 out of 58 publications