Tocilizumab Reduces Vasospasms, Neuronal Cell Death, and Microclot Formation in a Rabbit Model of Subarachnoid Hemorrhage.

Croci, Davide M; Wanderer, Stefan; Strange, Fabio; Grüter, Basil E; Sivanrupan, Sivani; Andereggen, Lukas; Casoni, Daniela; von Gunten, Michael; Widmer, Hans Rudolf; Di Santo, Stefano; Fandino, Javier; Mariani, Luigi; Marbacher, Serge (2021). Tocilizumab Reduces Vasospasms, Neuronal Cell Death, and Microclot Formation in a Rabbit Model of Subarachnoid Hemorrhage. Translational stroke research, 12(5), pp. 894-904. Springer 10.1007/s12975-020-00880-3

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Early brain injury (EBI), delayed cerebral vasospasm (DCVS), and delayed cerebral ischemia (DCI) are common complications of subarachnoid hemorrhage (SAH). Inflammatory processes in the cerebrospinal fluid (CSF) are one of the causes for such complications. Our aim to study the effects of an IL-6 receptor antagonist (Tocilizumab) examines the occurrence of DCVS, neuronal cell death, and microclot formation in an acute SAH rabbit model. Twenty-nine New Zealand white rabbits were randomized into one of three groups as the SAH, SAH + Tocilizumab, and sham groups. In SAH groups, hemorrhage was induced by extracranial-intracranial arterial blood shunting from the subclavian artery into the cisterna magna under intracranial pressure (ICP) monitoring. In the second group, Tocilizumab was given once intravenously 1 h after SAH induction. Digital subtraction angiography was performed, and CSF and blood were sampled before and after (day 3) SAH induction. IL-6 plasma and CSF levels were measured. TUNEL, FJB, NeuN, and caspase-3 immunostaining were used to assess cell apoptosis, neurodegeneration, and neuronal cell death, respectively. Microclot formation was detected by fibrinogen immunostaining. Between baseline and follow-up, there was a significant reduction of angiographic DCVS (p < 0.0001) in the Tocilizumab compared with the SAH group. Tocilizumab treatment resulted in decreased neuronal cell death in the hippocampus (p = 0.006), basal cortex (p = 0.001), and decreased microclot formation (p = 0.02). Tocilizumab reduced DCVS, neuronal cell death, and microclot formation in a rabbit SAH model, and could be a potential treatment to prevent DCVS and DCI in SAH patients.

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