Cerebral ischemia is a potentially life-threatening consequence of neurological injury in patients of both sexes. Although stroke incidence increases in women following menopause, the influence of exogenous estrogen on risk and outcomes of cerebrovascular disease in females is highly controversial. It is unclear if endogenous or exogenous estrogens mediate recovery after brain injury, or how nursing therapeutics should incorporate actual hormone status into stroke prevention/treatment plans. Using an animal model of middle cerebral artery occlusion that simulates clinical, human stroke, we have found striking neuroprotection in the female rat relative to the male when confronted with an ischemic episode. Further, the protection is eliminated by removal of endogenous estrogen but can be restored by chronic treatment with 17beta estradiol. This proposal will determine how estrogen availability is critical to brain salvage in female animals and if the benefits conferred by estrogen are important in postmenopausal females, as well as in young adults. As life expectancy increases in our population, women will soon be postmenopausal for approximately one third of their lives. Our general hypothesis is that estrogen acts via classical estrogen receptors in a trophic manner during brain injury, promoting neuronal integrity and return of function through upregulation of neurotrophic growth factors such as basic fibroblast growth factor (bFGF).
The aims are to: 1) determine if acute and chronic estrogen treatment provides equivalent neuroprotection in the postmenopausal female rat (16 month) as compared to the adult, ovariectomized female (3 month); 2) determine if endogenous and exogenous estrogens produce neuroprotection via classical estrogen receptor mediated mechanisms in young and postmenopausal females; 3) distinguish the importance of estrogen receptor subtype alpha vs beta (ERalpha vs ERbeta) in estrogen's neuroprotective mechanisms and 4) determine if estrogen promotes stroke recovery by bFGF mediated mechanisms. Findings from this study will provide a physiological rationale for nursing care of women, both pre- and postmenopausal, who sustain brain injury from stroke, circulatory arrest or invasive neurosurgical procedures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Nursing Research (NINR)
Type
Research Project (R01)
Project #
5R01NR003521-09
Application #
6477260
Study Section
Nursing Research Study Section (NURS)
Program Officer
Wasserman, Joan
Project Start
1993-12-10
Project End
2003-11-30
Budget Start
2001-12-01
Budget End
2002-11-30
Support Year
9
Fiscal Year
2002
Total Cost
$242,342
Indirect Cost
Name
Johns Hopkins University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Palmateer, Julie; Pan, Jie; Pandya, Arushi et al. (2016) Ultrasonic vocalization in murine experimental stroke: A mechanistic model of aphasia. Restor Neurol Neurosci 34:287-95
Mittal, Nitish; Pan, Jie; Palmateer, Julie et al. (2015) So you think you can jump? A novel long jump assessment to detect deficits in stroked mice. J Neurosci Methods 256:212-9
Hurn, Patricia D (2014) 2014 Thomas Willis Award Lecture: sex, stroke, and innovation. Stroke 45:3725-9
Nobile, Cameron W; Palmateer, Julie M; Kane, Jackie et al. (2014) Impaired limb reaction to displacement of center of gravity in rats with unilateral striatal ischemic injury. Transl Stroke Res 5:562-8
Herson, Paco S; Palmateer, Julie; Hurn, Patricia D (2013) Biological sex and mechanisms of ischemic brain injury. Transl Stroke Res 4:413-9
Ren, Xuefang; Akiyoshi, Kozaburo; Grafe, Marjorie R et al. (2012) Myelin specific cells infiltrate MCAO lesions and exacerbate stroke severity. Metab Brain Dis 27:7-15
Offner, Halina; Hurn, Patricia D (2012) A novel hypothesis: regulatory B lymphocytes shape outcome from experimental stroke. Transl Stroke Res 3:324-30
Kosaka, Y; Quillinan, N; Bond, Ct et al. (2012) GPER1/GPR30 activation improves neuronal survival following global cerebral ischemia induced by cardiac arrest in mice. Transl Stroke Res 3:500-507
Jia, Jia; Verma, Saurabh; Nakayama, Shin et al. (2011) Sex differences in neuroprotection provided by inhibition of TRPM2 channels following experimental stroke. J Cereb Blood Flow Metab 31:2160-8
Dziennis, Suzan; Akiyoshi, Kozaburo; Subramanian, Sandhya et al. (2011) Role of dihydrotestosterone in post-stroke peripheral immunosuppression after cerebral ischemia. Brain Behav Immun 25:685-95

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