Investigation and Modulation of Interleukin 6 following Subarachnoid Hemorrhage: Targeting Inflammatory Activation for Cerebral Vasospasm

Abstract

Background: Cerebral vasospasm (CV) can contribute signi cant morbidity for subarachnoid hemorrhage (SAH) patients. A key unknown is how CV induction is triggered following SAH. Methods: human aneurysmal blood was collected for evaluation. To con rm mechanism, c57/bl6 wild type and c57/bl6 IL-6 female knockout (KO) mice were utilized with groups: saline injected, SAH, SAH + IL-6 blockade, SAH IL-6 KO, SAH IL-6 KO + IL-6 administration. For SAH, 50mm blood was collected from tail puncture and administered into basal cisterns. IL-6 blockade was given at various time points. Various markers of neuroin ammation were measured with western blot and immunohistochemistry.Cerebral blood ow was also measured. Vasospasm was measured via cardiac injection of indiaink/gelatin. Turning test and Garcia's modi ed SAH score were utilized. P<0.05 was considered signi cant.Results: IL-6 expression peaked 3 days following SAH (p<0.05). Human IL-6 was increased in aneurysmal blood (p<0.05). Receptor upregulation was periventricular and perivascular. A signi cant increase in BBB markers endothelin 1 and occludin were noted following SAH but reduced with IL-6 blockade (p<0.01). CV occurred 5 days post SAH but was absent in IL-6 KO mice and mitigated with IL-6 blockade (p<0.05). IL-6 blockade, and IL-6 KO mitigated effects of SAH on cerebral blood ow (p<0.05). SAH mice had impaired performance on turn test and poor Modi ed Garcia Scores compared to saline and IL-6 blockade. A distinct microglia phenotype was noted day 5 in the SAH group (overlap coe cients r=0.96 and r=0.94) for Arg1 and iNOS, which was altered by IL-6 blockade. Day 7, a signi cant increase in toll-like receptor 4 and Stat3 were noted. This was mitigated by IL-6 blockade and IL-6 KO, which also reduced Caspase 3 (p<0.05). Ventricular dilation and increased tunel positivity were noted day 9 but resolved by IL-6 blockade (p<0.05).Conclusion: correlation between IL-6 and CV has been well documented. We show that a mechanistic connection exists via the in ammatory response, and IL-6 blockade provides bene t in reducing CV and its consequences.