Experimental Pediatric Arterial Ischemic Stroke Model Reveals Sex-specific Estrogen Signaling

Abstract

Background and Purpose— Pediatric stroke, birth to 18 years, is a significant cause of long-term disability in the United States; however, there is currently little experimental data on the pathophysiology of childhood stroke owing to lack of animal models. We developed a novel mouse model of experimental childhood-onset arterial ischemic stroke to characterize the sex-specific response of the adolescent brain to cerebral ischemia and assess the neuroprotective effect of estrogen at this developmental stage. Methods— Postnatal day 20 to 25 mice were subjected to 90 minutes experimental stroke via the intraluminal filament middle cerebral artery occlusion model and ischemic damage assessed 22 hours after reperfusion. Real-time quantitative real-time polymerase chain reaction was performed 22 hours after middle cerebral artery occlusion to determine the effects of ischemia and estrogen treatment on the proapoptotic gene Bax . Results— Ischemic injury did not differ between male and female juvenile (postnatal day 20–25) mice after middle cerebral artery occlusion. However, estrogen reduced ischemic injury in female mice, whereas having no effect in juvenile males. No differences in estrogen receptor expression were observed on postnatal day between 20 males and females. In contrast, estrogen minimized the ischemia-induced increase in the proapoptotic gene Bax in female mice, whereas having no effect on Bax induction in the male brain. Conclusions— Focal ischemia has fundamentally different effects in the juvenile brain compared with the adult, as evidenced by the lack of sex difference in ischemic injury in the murine postnatal day 20 to 25 middle cerebral artery occlusion model and the sexually dimorphic response to estrogen neuroprotection.