Progesterone is protective against insults relevant to the aging process and neurodegenerative disease. However, the impact of age,and whether mechanisms implicated in progesterone's protective effects translate to the ability of progesterone to preserve cognitive function is still unclear. In the first period of funding, we determined that progesterone is neuroprotective and that this protection was dependent on the ERK/MAPK pathway and neurotrophin signaling. In addition, our data suggested that the NMDA receptor may be a relevant downstream target of progesterone's protective effects. The NMDA receptor is an important mediator of hippocampal long term potentiation (LTP). Since the ERK pathway and neurotrophin signaling are also implicated in the regulation of cognitive function, we hypothesized that progesterone by itself protects against age-associated cognitive impairment by regulating the function and/or expression of NMDA receptors and associated hippocampal LTP. Further, we predict that the intactness of progesterone- induced signaling, NMDA receptor phosphorylation and/or expression, and LTP will predict successful cognitive aging in old mice. These hypotheses will be tested through the completion of the following 4 aims: 1) To determine if progesterone prevents against ovariectomy-induced cognitive deficits in young adult, middle aged and old C57BI/6 mice, and if such effects are associated with effects of progesterone on hippocampal LTP;2) To determine if progesterone regulates NMDA receptor expression and/or phosphorylation as a potential mechanism underyling its effects on LTP and cognition;3) To determine if signaling mediators of progesterone-induced neuroprotection (such as ERK)mediate the effects of progesterone on NMDA receptor phosphorylation and hippcampal LTP;and 4) To determine if the """"""""intactness"""""""" of progesterone-induced signaling, NMDA receptor phosphorylation (or expression) and regulation of LTP,predicts successful aging. The successful completion of this project will fill an important gap in our understanding of how progesterone alone regulates cognitive function, and will be achieved through extensive utilization of the the 3 Cores and substantial interaction with the other Projects. In addition to greatly expanding our understanding of progesterone neurobiology, the results may also impact how we consider hormones in treating such neurodegenerative diseases as Alzheimer's disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Texas
Fort Worth
United States
Zip Code
Sun, Jiahong; Ren, Xuefang; Qi, Wen et al. (2016) Geissoschizine methyl ether protects oxidative stress-mediated cytotoxicity in neurons through the 'Neuronal Warburg Effect'. J Ethnopharmacol 187:249-58
Engler-Chiurazzi, E B; Singh, M; Simpkins, J W (2016) From the 90's to now: A brief historical perspective on more than two decades of estrogen neuroprotection. Brain Res 1633:96-100
Engler-Chiurazzi, E B; Brown, C M; Povroznik, J M et al. (2016) Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury. Prog Neurobiol :
Engler-Chiurazzi, Elizabeth B; Covey, Douglas F; Simpkins, James W (2016) A novel mechanism of non-feminizing estrogens in neuroprotection. Exp Gerontol :
Sarkar, S; Jun, S; Rellick, S et al. (2016) Expression of microRNA-34a in Alzheimer's disease brain targets genes linked to synaptic plasticity, energy metabolism, and resting state network activity. Brain Res 1646:139-51
Richter, Frank; Koulen, Peter; Kaja, Simon (2016) N-Palmitoylethanolamine Prevents the Run-down of Amplitudes in Cortical Spreading Depression Possibly Implicating Proinflammatory Cytokine Release. Sci Rep 6:23481
Engler-Chiurazzi, Elizabeth B; Stapleton, Phoebe A; Stalnaker, Jessica J et al. (2016) Impacts of prenatal nanomaterial exposure on male adult Sprague-Dawley rat behavior and cognition. J Toxicol Environ Health A 79:447-52
Sun, Fen; Nguyen, Trinh; Jin, Xin et al. (2016) Pgrmc1/BDNF Signaling Plays a Critical Role in Mediating Glia-Neuron Cross Talk. Endocrinology 157:2067-79
Sun, Jiahong; Hu, Heng; Ren, Xuefang et al. (2016) Tert-butylhydroquinone compromises survival in murine experimental stroke. Neurotoxicol Teratol 54:15-21
Shetty, Ritu A; Rutledge, Margaret A; Forster, Michael J (2016) Retrograde conditioning of place preference and motor activity with cocaine in mice. Psychopharmacology (Berl) :

Showing the most recent 10 out of 162 publications