Sex-specific reperfusion dynamics uncouple from outcome following ischemic stroke in elderly mice
Line Mathilde Brostrup Hansen, Jane Holbæk Rønn, Tina Myhre Pedersen, Şefik Evren Erdener, Dmitry D. Postnov, Vladimir V. MatchkovAbstract:
INTRODUCTION:
The prevalence and severity of ischemic stroke increase with age and are influenced by sex. Despite this, most preclinical stroke studies are performed in young male subjects, potentially obscuring the detrimental impact of female sex in aging. Therefore, a robust translational model for ischemic stroke-reperfusion is essential for addressing this difference and to improve the clinical relevance of preclinical findings.
AIM:
The study investigated the differences in ischemic stroke-reperfusion outcomes in elderly mice that may be critical for effective, physiologically tailored treatment of patients of both sexes.
MATERIALS AND METHODS:
Utilizing 19-month-old C57BL/6JRj mice of both sexes, we modeled ischemia–reperfusion with distal middle cerebral artery occlusion for 1 h. Cortex perfusion was assessed with laser speckle contrast imaging of both hemispheres in anesthetized mice during cerebral artery occlusion and in awake mice over 72 h post-reperfusion. Ischemia–reperfusion outcomes were assessed with cylinder behavior tests, FITC–dextran assay for blood–brain barrier permeability, and postmortal brain immuno staining.
RESULTS:
Blood flow in male mice recovered in poststroke reperfusion to baseline, whereas females developed hyperperfusion that was unrelated to infarct size, FITC–dextran leakage, and brain edema. However, among elderly females only, the blood–brain barrier disruption was correlated with larger infarct size and severe motor deficits. Female-specific reperfusion changes were associated with a reduced abundance of glial fibrillary acidic protein-positive astrocytes at the ischemic core.
CONCLUSIONS:
While ischemic stroke outcomes did not differ by sex, variation in blood flow recovery highlighted a mismatch between perfusion and functional outcomes, warranting further research of this relationship in elderly populations.