In women, the disruption of the endocrine environment during menopause amplifies the risk for stroke and neuro-inflammatory disease. Using acyclic female rats to model the postmenopausal state, our studies indicate that these animals sustain greater tissue damage following experimental ischemic stroke as compared to mature (cyclic) adult females. Furthermore, while estrogen treatment is protective to mature adult females, it paradoxically increases tissue damage in older acyclic females. These data are congruent with the WHI study, where the risk for stroke was elevated in older women receiving hormone therapy, and underscores the need for novel therapeutic approaches for this group. Based on our recent studies, we hypothesize that estrogens neuroprotective actions require the cooperative action of insulin-like growth factor (IGF)-1, a neuroprotective peptide hormone, and that age-related decline in IGF-1, which occurs in virtually all species, destabilizes the neuroprotective actions of estrogen. This hypothesis is supported by our studies in that (1) IGF-1 levels are reduced in the middle aged (reproductive senescent) female rat, and (2) in a stroke model, IGF-1 infusion to older females overcomes the neurotoxic effects of estrogen in this group. Here we will examine the cooperative interaction of estrogen and IGF-1 on stroke recovery and infarct volume and the extent to which this interaction is altered in reproductive senescence. Secondly, we will examine the extent that estrogen/IGF-1 can improve astrocyte function post stroke in reproductive senescent females. Astrocytes are responsive to both IGF-1 and estrogen and play a crucial role in detoxification of the ischemic environment. Finally we will determine if stroke outcomes can be improved in older females by manipulating epigenetic regulators of IGF-1 namely, microRNA. MiRNA, a type of small non-coding RNA, regulate large gene networks, and play a central role in cell senescence, proliferation (cancer) and injury (stroke). Specifically, we will identify and manipulate miRNA that regulate IGF-1 to improve stroke recovery on older females. Collectively these studies will provide an understanding of estrogen's age-delimited neuroprotective effects and form the foundation for pre-clinical studies of stroke therapy tailored to older females.

Public Health Relevance

Women are at a greater risk for stroke than men after menopause and estrogen therapy to this group unfortunately increases the risk and severity of this disease. In this application we will use an animal model of acyclic older female rats to develop a new therapeutic approach for stroke recovery that involves increasing the availability of a small protein IGF-1, either by directly infusing this peptide or via a class of bio-molecules called microRNA that regulate IGF-1.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS074895-01A1
Application #
8244886
Study Section
Special Emphasis Panel (ZRG1-IFCN-A (03))
Program Officer
Bosetti, Francesca
Project Start
2011-09-01
Project End
2016-05-31
Budget Start
2011-09-01
Budget End
2012-05-31
Support Year
1
Fiscal Year
2011
Total Cost
$317,031
Indirect Cost
Name
Texas A&M University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
Bake, Shameena; Okoreeh, Andre K; Alaniz, Robert C et al. (2016) Insulin-Like Growth Factor (IGF)-I Modulates Endothelial Blood-Brain Barrier Function in Ischemic Middle-Aged Female Rats. Endocrinology 157:61-9
Earnest, David J; Neuendorff, Nichole; Coffman, Jason et al. (2016) Sex Differences in the Impact of Shift Work Schedules on Pathological Outcomes in an Animal Model of Ischemic Stroke. Endocrinology 157:2836-43
Park, Min Jung; Sohrabji, Farida (2016) The histone deacetylase inhibitor, sodium butyrate, exhibits neuroprotective effects for ischemic stroke in middle-aged female rats. J Neuroinflammation 13:300
Selvamani, Amutha; Sohrabji, Farida (2016) Mir363-3p improves ischemic stroke outcomes in female but not male rats. Neurochem Int :
Galea, Liisa A M; Frick, Karyn M; Hampson, Elizabeth et al. (2016) Why estrogens matter for behavior and brain health. Neurosci Biobehav Rev :
Sohrabji, Farida (2015) Estrogen-IGF-1 interactions in neuroprotection: ischemic stroke as a case study. Front Neuroendocrinol 36:1-14
Bake, Shameena; Selvamani, Amutha; Cherry, Jessica et al. (2014) Blood brain barrier and neuroinflammation are critical targets of IGF-1-mediated neuroprotection in stroke for middle-aged female rats. PLoS One 9:e91427
Selvamani, Amutha; Williams, Madison H; Miranda, Rajesh C et al. (2014) Circulating miRNA profiles provide a biomarker for severity of stroke outcomes associated with age and sex in a rat model. Clin Sci (Lond) 127:77-89
Sohrabji, F; Williams, M (2013) Stroke neuroprotection: oestrogen and insulin-like growth factor-1 interactions and the role of microglia. J Neuroendocrinol 25:1173-81
Sohrabji, Farida; Selvamani, Amutha; Balden, Robyn (2013) Revisiting the timing hypothesis: biomarkers that define the therapeutic window of estrogen for stroke. Horm Behav 63:222-30

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