Abstract

There is growing evidence that estrogen (E2) and SERMs may have beneficial effects upon the CNS in neurodegenerative diseases. This application would study the potential mechanisms of E2/SERM neuroprotection in cerebral ischemia, and would follow up on exciting preliminary work by our lab which suggests that E2/SERMs enhance neurogenesis following cerebral ischemia. With regards to neuroprotection, our preliminary studies suggest that E2 and the SERM, tamoxifen (TMX) inhibit activation of putative prodeath factors (ROS, ERKs, INK, c-Jun), with an increase in activation of the prosurvival factor, Akt. To confirm these preliminary findings and clarify the underlying mechanisms, Aim 1 would determine the temporal pattern and cell type of ERK/JNK/Akt activation following cerebral ischemia in female animals (which is currently lacking), establish the onset and duration of E2/SERM regulatory effects upon these key kinases, and determine the role of estrogen receptors in the regulatory effects.
Aim 2 would determine whether reactive oxygen species (ROS) function as the major upstream activator of ERKs/JNK following cerebral ischemia, and establish whether E2 and TMX can suppress ROS production as a mechanism for suppression of ERK/JNK activation. Causation between ROS and ERK/JNK activation would be determined through the use of the antioxidant SOD mimetic compound, tempol (which scavenges/reduces ROS production).
Aim 3 would determine whether AP-1 transcription complex and proapoptotic BH-3 proteins act downstream of ERKs/JNK to induce apoptosis in the penumbra region, and establish whether E2 and TMX suppress AP-1 activation and induction of BH-3 proteins as a means of neuroprotection.
Aim 4 would characterize the temporal pattern of E2/SERM effects on neurogenesis, and characterize the migration, differentiation and long-term survival of newly generated cells into the injured regions of the brain following cerebral ischemia. Correlation to functional neurological outcomes will also be determined. As a whole, the proposed studies would significantly advance our understanding of the neuroprotective and neurogenic actions of E2 and SERMs in the injured brain.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050730-04
Application #
7414740
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Golanov, Eugene V
Project Start
2005-05-24
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
4
Fiscal Year
2008
Total Cost
$313,552
Indirect Cost

  Institution

Name
Georgia Regents University
Department
Neurology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912

  Publications

Thakkar, Roshni; Wang, Ruimin; Wang, Jing et al. (2018) 17?-Estradiol Regulates Microglia Activation and Polarization in the Hippocampus Following Global Cerebral Ischemia. Oxid Med Cell Longev 2018:4248526
Thakkar, R; Sareddy, G R; Zhang, Q et al. (2018) PELP1: a key mediator of oestrogen signalling and actions in the brain. J Neuroendocrinol 30:
Ma, Merry W; Wang, Jing; Zhang, Quanguang et al. (2017) NADPH oxidase in brain injury and neurodegenerative disorders. Mol Neurodegener 12:7
Thakkar, Roshni; Wang, Ruimin; Sareddy, Gangadhara et al. (2016) NLRP3 Inflammasome Activation in the Brain after Global Cerebral Ischemia and Regulation by 17?-Estradiol. Oxid Med Cell Longev 2016:8309031
Tu, Jingyi; Zhang, Xi; Zhu, Ying et al. (2015) Cell-Permeable Peptide Targeting the Nrf2-Keap1 Interaction: A Potential Novel Therapy for Global Cerebral Ischemia. J Neurosci 35:14727-39
Khan, Mohammad M; Wakade, Chandramohan; de Sevilla, Liesl et al. (2015) Selective estrogen receptor modulators (SERMs) enhance neurogenesis and spine density following focal cerebral ischemia. J Steroid Biochem Mol Biol 146:38-47
Sareddy, Gangadhara R; Zhang, Quanguang; Wang, Ruimin et al. (2015) Proline-, glutamic acid-, and leucine-rich protein 1 mediates estrogen rapid signaling and neuroprotection in the brain. Proc Natl Acad Sci U S A 112:E6673-82
Mann, Monica; Zou, Yi; Chen, Yidong et al. (2014) PELP1 oncogenic functions involve alternative splicing via PRMT6. Mol Oncol 8:389-400
Nair, B C; Krishnan, S R; Sareddy, G R et al. (2014) Proline, glutamic acid and leucine-rich protein-1 is essential for optimal p53-mediated DNA damage response. Cell Death Differ 21:1409-18
Scott, Erin L; Zhang, Quan-Guang; Vadlamudi, Ratna K et al. (2014) Premature menopause and risk of neurological disease: basic mechanisms and clinical implications. Mol Cell Endocrinol 389:2-6

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