Abstract 28: Inhibition of Interleukin-6 Signaling With Tocilizumab Ameliorates Ischemic Stroke Damage in Aged Male and Female Mice

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Introduction: In stroke patients higher plasma IL-6 levels are correlated with increased stroke severity and poor long-term prognosis. Preliminary work in our lab has shown that tocilizumab, an FDA approved drug that blocks IL-6 receptors inhibiting the effects of IL-6, reduced infarct size and behavior deficits in young male mice following MCAO. Due to this promising preliminary data we hypothesized that tocilizumab will ameliorate injury in aged male and female mice. Testing both sexes and aged mice is important because the majority of stroke occurs in patients over 65 in both sexes.

Methods: Aged (18-20month) C57BL/6J male (n=42) and female mice (n=45) were used to examine neuroprotection and behavioral deficits with treatment. Mice were randomly separated into 4 groups, stroke or sham then subdivided into drug or control treatment. Stroke was induced by 1 hour of transient MCAO followed by reperfusion for either 3 or 35 days. Four hours after the onset of ischemia mice were intraperitoneally injected with tocilizumab (20mg/1kg) or an IgG control. Behavior tests evaluated motor/sensory deficits, anxiety and locomotor activity. Depression and memory formation was also tested in the 35 day cohort.

Results: Tocilizumab reduced mortality in aged male mice and significantly reduced anxiety levels in aged female mice 20 days after stroke (p=0.04). Treatment also led to a significant reduction (p=0.04) in infarct size 3 days post-ischemia. The corner test showed improved sensorimotor function in males on all testing days 3, 7 and 14 after stroke but was only significant for females on post stroke day 3 (p<0.05). Direct revisit error on the Y-maze was significantly reduced in tocilizumab treated aged male mice on day 7 after stroke (p=0.04) and aged female mice on day 3 after stroke (p=0.032) showing an improved spatial learning. Time to discover the escape hole in the Barnes maze 31 days post stroke was improved in aged male mice (p=0.05) conveying benefit to new memory formation post stroke by tocilizumab.

Conclusion: This study showed that tocilizumab treatment reduced stroke damage and decreased behavioral deficits in both sexes. Therefore, this study concludes that inhibition of the IL-6 receptor may be a potential therapeutic approach for stroke treatment.

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