Abstract W MP79: The Sex Chromosome Complement Contributes to Ischemic Stroke Sensitivity and Inflammatory Responses in Aged FCG Mice

Abstract

Introduction: Aging is the most important non-modifiable risk factor for ischemic stroke; modeling stroke in aged animals is of clinical relevance and translational value. Stroke is a sexually dimorphic disease. Elderly women not only have higher stroke incidence than age-matched men, but also have poorer recovery, higher morbidity and mortality once a stroke occurs. Much of this has been attributed to the loss of estrogen with menopause. However, stroke incidence does not begin to climb until well after natural menopause, suggesting there are hormone independent effects on ischemic sensitivity. As hormone levels are relatively equivalent between sexes at the age post-menopausal, tissue damage and functional outcomes must be influenced by biologic sex (XX vs. XY) in addition to the hormonal milieu. Hypothesis: We hypothesized that sex differences in ischemic stroke in aged brains are shaped by the sex chromosome complement. Methods: The Four Core Genotype (FCG) mouse model was utilized to dissociate the effects of sex chromosome compliment from hormone exposure on ischemic sensitivity. XXF, XXM, XYF, and XYM aged mice (18-20 months) were subjected to 90-minute middle cerebral artery occlusion (MCAO). Stroke outcomes were examined at 24h and 7d of stroke. Inflammatory responses were also evaluated by flow cytometry, immunohistochemistry, and multiplex cytokine analysis. Results: At 24h and 7d of stroke, more microglial activation and higher levels of pro-inflammatory cytokines (IL-1β and IL-6) were seen in XXF and XXM than in XYF and XYM mice respectively. Accordingly, XXF and XXM mice had significantly larger infarct volumes than XYF and XYM cohorts respectively (XXF vs.XYF: 43.26 ± 5.63% vs. 24.22 ± 3.48%; XXM vs. XYM: 50.44 ± 6.11% vs. 26.24 ± 3.91%; P <0.05, n=7~9/group) at 7d of stroke. There was no significant difference in hormone levels in aged FCG mice. Although no significant difference in neurological deficit scores (NDS) were seen between any two genotypes 24 hours after stroke, XXF and XXM mice exhibited worse NDS than XYF and XYM cohorts respectively at 7 d of stroke. Conclusions: The sex chromosome complement contributes to ischemic sensitivity in aged animals, which is likely mediated in part by innate immune responses.