Abstract 128: Amelioration of Ischemic Stroke Damage Through Inhibition of Interleukin-6 Signaling With Tocilizumab Requires Sex Specific Dosing

Abstract

Introduction: Interleukin 6 (IL-6) is a proinflammatory cytokine. Higher plasma IL-6 levels in stroke patients are correlated with increased stroke severity and poor prognosis. Our work has shown that tocilizumab, an FDA approved drug that blocks the IL-6 receptor (IL-6R) significantly reduced acute and long-term brain infarct and atrophy in aged male mice after stroke. At the same dose, tocilizumab had no significant effect on stroke outcome in aged females. Methods: We utilized aged (18-20 month) C57BL/6J male (N= 27) and female (N= 30) mice to examine neuroprotection and behavioral deficits with treatment. Mice were randomly assigned into 4 groups of either stroke or sham and drug or IgG control treatment. Stroke was induced by 1 hour of transient right middle cerebral artery occlusion followed by reperfusion for 35 days. Four hours after the onset of ischemia mice were given an intraperitoneal injection of either tocilizumab (20mg/1kg) or an IgG control. Tests were conducted to evaluate motor, sensory and cognitive deficits. Another aged female cohort (N= 15) was used to assess tocilizumab efficacy at reducing infarct 3 days post stroke with a higher dose (100mg/1kg). Results: Soluble IL-6R expression, while equivalent at baseline, is significantly higher after stroke in aged female mice compared to males (P= 0.0070). Tocilizumab treatment reduced brain atrophy (P= 0.0120), mortality (P= 0.0239) and behavioral deficits in aged males on multiple behavior tests (P< 0.05). Females did not show similar benefits at the same dose (20mg/1kg). A higher dose of tocilizumab (100mg/1kg) reduced brain infarct acutely in aged females 3 days post stroke (P= 0.0005). This affect at only the higher dose in females is likely related to the higher level of soluble IL-6R seen post stroke compared to males. Testing in human stroke patient plasma revealed that women, as in mice, had significantly higher soluble IL-6R level compared to men after stroke (P= 0.0047). Conclusion: These results support our hypothesis that inhibition of the IL-6 receptor can be a novel therapeutic approach for stroke treatment. The neuroprotective dose of tocilizumab is different in males and females, which helps to emphasize the importance of determining dosage efficacy in a sex-specific manner.