Abstract T P324: Sex Differences in Ischemic Outcomes and Inflammatory Responses in Neonatal Stroke

Abstract

Background and Purpose: Neonatal arterial ischemic stroke (NAIS) is an important cause of motor and cognitive impairment in children. Clinically, male infants are more vulnerable to ischemic insult and suffer more long-term deficits than female infants though the mechanisms remain elusive. Inflammatory processes are fundamental in the pathophysiology of ischemia as microglial activation initiates the inflammatory response after ischemia. Recent studies report a sexual dimorphism in microglia numbers and expression of activation markers in neonatal brains under normal conditions. How these basal sex differences in microglia affect NAIS remains largely unexplored. This study investigated sex differences in stroke phenotypes and inflammation triggered by NAIS. We hypothesize that ischemia induces sex-specific tissue injury in male and female neonates, which is related to differences in microglial activation and inflammatory responses. Methods: Male and female C57BL6 mice were subjected to 60-minute Rice-Vanucci Modeling at post-natal day 10 (P10) to induce NAIS. Stroke outcomes were measured at 24 hours, 72 hours and 7 days after stroke. Microglial activation and inflammatory responses were evaluated by flow cytometry, immunohistochemistry, and multiplex cytokine analysis. Results: At 24 hours no difference in infarct volumes (total infarct: male vs. female 46.6±7.2% vs. 43.2±9.3%, n=6/gp) and in Iba-1 staining of the ischemic brain were seen between male and female neonates. However, at 72 hours female neonates exhibited significantly smaller infarct size and improved behavior outcomes compared to males (total infarct: male vs. female 43.1±9.9% vs. 27.1±8.8%, n=6/gp, p <.05). Male animals demonstrated increased microglial activation and up-regulated inflammatory response compared to females at 72 hours. This male-specific phenotype was also seen at 7 days after injury. There was no difference in hormone levels at any of the three time points after stroke. Conclusions: Acute ischemia leads to an equivalent primary brain injury in male and female P10 mice. However, infarct damage worsens in males at sub-acute time points vs. females, as does the immune response. This sex difference independent of hormone levels exists in NAIS.