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The Differences in Neuroprotective Efficacy of Progesterone and Medroxyprogesterone Acetate Correlate with Their Effects on Brain-Derived Neurotrophic Factor Expression

Department of Pharmacology and Neuroscience (P.K.J., P.K., W.U., M.S.), Center Focused on Resources for Her Health, Education, and Research, the Institute for Aging and Alzheimer’s Disease Research, University of North Texas Health Science Center, Fort Worth, Texas 76107-2699; and Department of Cell Biology (J.P.L.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Meharvan Singh, Ph.D., Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, 3400 Camp Bowie Boulevard, Fort Worth, Texas 76107-2699. E-mail: msingh{at}hsc.unt.edu.

Whereas hormone therapy is used for the treatment of menopausal symptoms, its efficacy in helping reduce the risk of other diseases such as Alzheimer’s disease has been questioned in view of the results of recent clinical trials that appeared inconsistent with numerous basic research studies that supported the beneficial effects of hormones. One possible explanation of this discrepancy may lie in the choice of hormone used. For example, we and others found that progesterone is neuroprotective whereas medroxyprogesterone acetate (MPA), the synthetic progestin used in hormone therapy, is not. Because our data suggest that progesterone-induced protection is associated with the induction of brain-derived neurotrophic factor (BDNF) levels and, importantly, can be blocked by inhibiting the neurotrophin signaling, we determined whether progesterone and medroxyprogesterone acetate differed in their ability to regulate BDNF levels in the explants of the cerebral cortex. We found that progesterone elicited an increase in both BDNF mRNA and protein levels, whereas medroxyprogesterone acetate did not. Furthermore, using both a pharmacological inhibitor of the progesterone receptor (PR) and PR knockout mice, we determined that the effects of progesterone were mediated by the classical PR. Our results underscore the fact that not all progestins have equivalent effects on the brain and suggest that the selection of the appropriate progestin may influence the success of hormone therapy formulations used in treating the menopause and/or reducing the risk for diseases associated with the postmenopausal period.