Clinically, ischemic stroke is recognized as a sexually dimorphic disease. Most international databases consistently demonstrate that women have lower stroke incidence relative to men until advanced age. However, elderly women have higher morbidity and mortality compared to age-matched men once a stroke occurs. Aging enhances the inflammatory response to stroke, and recent data demonstrate that this effect is significantly more pronounced in females. Reproductive hormones clearly contribute to such differences in male and female pathobiology, however, the hormonal environment does not fully account for ischemic sexual dimorphism as tissue damage and functional outcome after an induced stroke are influenced by biologic sex in addition to the hormonal milieu. Emerging data has shown that the mechanisms that trigger cell death differ in males and females. We will utilize genetically manipulated (""""""""Four Core Genotype"""""""") mice to dissociate the effects of chromosomal sex from that of gonadal hormones on stroke outcome in young animals (Aim 1);determine the effect of manipulating neonatal hormone levels on adult infarct damage (Aim 2);and investigate sex and hormone contributions to post-stroke inflammation in the 4CG mice (Aim 3) using a well established middle cerebral artery occlusion (MCAO) model of stroke. The overall goal of this proposal is to determine the genetic and hormonal (organizational and activational effects) contributions to stroke sensitivity across the lifespan. Identification of sex selective cell death mechanisms has significant translational relevance, as neuroprotective agents that are efficacious in one sex may exacerbate injury in the other. As recent clinical trials have shown variable efficacy of drugs in male and female patients, developing """"""""sex- specific"""""""" therapeutic targets may improve our ability to treat stroke patients of both sexes.

Public Health Relevance

There is considerable evidence from both clinical and experimental studies that outcomes after stroke differ in males and females. New experimental data has shown that brain cells die differently in the male versus the female brain, and each sex responds differently to neuroprotective strategies. As stroke is now the number one cause of disability, new treatments are urgently needed.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Koenig, James I
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University of Connecticut
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United States
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Verma, Rajkumar; Cronin, Chunxia G; Hudobenko, Jacob et al. (2017) Deletion of the P2X4 receptor is neuroprotective acutely, but induces a depressive phenotype during recovery from ischemic stroke. Brain Behav Immun 66:302-312
Ritzel, Rodney M; Patel, Anita R; Spychala, Monica et al. (2017) Multiparity improves outcomes after cerebral ischemia in female mice despite features of increased metabovascular risk. Proc Natl Acad Sci U S A 114:E5673-E5682
Spychala, Monica S; Honarpisheh, Pedram; McCullough, Louise D (2017) Sex differences in neuroinflammation and neuroprotection in ischemic stroke. J Neurosci Res 95:462-471
Bravo-Alegria, Javiera; McCullough, Louise D; Liu, Fudong (2017) Sex differences in stroke across the lifespan: The role of T lymphocytes. Neurochem Int 107:127-137
Ritzel, Rodney M; Crapser, Joshua; Patel, Anita R et al. (2016) Age-Associated Resident Memory CD8 T Cells in the Central Nervous System Are Primed To Potentiate Inflammation after Ischemic Brain Injury. J Immunol 196:3318-30
Verma, Rajkumar; Harris, Nia M; Friedler, Brett D et al. (2016) Reversal of the Detrimental Effects of Post-Stroke Social Isolation by Pair-Housing is Mediated by Activation of BDNF-MAPK/ERK in Aged Mice. Sci Rep 6:25176
McCullough, Louise D; Mirza, Mehwish A; Xu, Yan et al. (2016) Stroke sensitivity in the aged: sex chromosome complement vs. gonadal hormones. Aging (Albany NY) 8:1432-41
Manwani, Bharti; Bentivegna, Kathryn; Benashski, Sharon E et al. (2015) Sex differences in ischemic stroke sensitivity are influenced by gonadal hormones, not by sex chromosome complement. J Cereb Blood Flow Metab 35:221-9
Venna, Venugopal Reddy; McCullough, Louise D (2015) Role of social factors on cell death, cerebral plasticity and recovery after stroke. Metab Brain Dis 30:497-506
Friedler, Brett; Crapser, Joshua; McCullough, Louise (2015) One is the deadliest number: the detrimental effects of social isolation on cerebrovascular diseases and cognition. Acta Neuropathol 129:493-509

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