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.
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.
|Venna, Venugopal Reddy; Verma, Rajkumar; O'Keefe, Lena M et al. (2014) Inhibition of mitochondrial p53 abolishes the detrimental effects of social isolation on ischemic brain injury. Stroke 45:3101-4|
|Roy-O'Reilly, Meaghan; McCullough, Louise D (2014) Sex differences in stroke: the contribution of coagulation. Exp Neurol 259:16-27|
|Manwani, Bharti; Friedler, Brett; Verma, Rajkumar et al. (2014) Perfusion of ischemic brain in young and aged animals: a laser speckle flowmetry study. Stroke 45:571-8|
|Liu, Fudong; McCullough, Louise D (2014) The middle cerebral artery occlusion model of transient focal cerebral ischemia. Methods Mol Biol 1135:81-93|
|Verma, Rajkumar; Friedler, Brett D; Harris, Nia M et al. (2014) Pair housing reverses post-stroke depressive behavior in mice. Behav Brain Res 269:155-63|
|Bushnell, Cheryl; McCullough, Louise (2014) Stroke prevention in women: synopsis of the 2014 American Heart Association/American Stroke Association guideline. Ann Intern Med 160:853-7|
|Liu, Fudong; McCullough, Louise D (2013) Inflammatory responses in hypoxic ischemic encephalopathy. Acta Pharmacol Sin 34:1121-30|
|Ritzel, Rodney M; Capozzi, Lori A; McCullough, Louise D (2013) Sex, stroke, and inflammation: the potential for estrogen-mediated immunoprotection in stroke. Horm Behav 63:238-53|
|Mirza, Mehwish A; Capozzi, Lori A; Xu, Yan et al. (2013) Knockout of vascular early response gene worsens chronic stroke outcomes in neonatal mice. Brain Res Bull 98:111-21|
|Manwani, Bharti; Liu, Fudong; Scranton, Victoria et al. (2013) Differential effects of aging and sex on stroke induced inflammation across the lifespan. Exp Neurol 249:120-31|
Showing the most recent 10 out of 47 publications