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

Croci, Davide Marco; Wanderer, Stefan; Strange, Fabio; Grüter, Basil E.; Sivanrupan, Sivani; Andereggen, Lukas; Casoni, Daniela; Gunten, Michael von; Widmer, Hans Rudolf; Fandiño, Javier; Mariani, Luigi; Marbacher, Serge

doi:10.1007/s12975-020-00880-3

Cited by 18 publications

(17 citation statements)

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“…Human autopsy studies on SAH patients also demonstrated the presence of microclots and a correlation with location and severity of ischemia [48,50,51]. We previously demonstrated in a rabbit SAH model how the IL-6 receptor antagonist tocilizumab significantly reduced microclot formation, neuronal cell death, and DCVS [14].…”

Section: Il-6 In Relation To Microclot Formationmentioning

confidence: 81%

“…These endothelial and hemostatic dysfunctions with development of microclots are highly involved in the pathophysiology of EBI and the development of DCI [14,61,62]. Different preclinical SAH models in mice and rabbits have confirmed microclot formations after SAH [14,61,63]. Human autopsy studies on SAH patients also demonstrated the presence of microclots and a correlation with location and severity of ischemia [48,50,51].…”

Section: Il-6 In Relation To Microclot Formationmentioning

confidence: 95%

“…IL-6 inhibits the cleavage of ultralarge von Willebrand factor, resulting in platelet aggregation and adhesion of the vascular endothelium, thus possibly causing thrombosis in the microvessels [60]. These endothelial and hemostatic dysfunctions with development of microclots are highly involved in the pathophysiology of EBI and the development of DCI [14,61,62]. Different preclinical SAH models in mice and rabbits have confirmed microclot formations after SAH [14,61,63].…”

Section: Il-6 In Relation To Microclot Formationmentioning

confidence: 99%

“…Overall, 52 studies (85.2%) aimed their research on a possible therapeutic substance after SAH and their effect on IL-6 as well (Supplementary Table 1); however, only two studies (3.2%) analyzed the direct inhibition of IL-6 through a receptor antagonist. The first of these analyzed the effect of a direct IL-6 antagonist in vivo with the IL-6 receptor antagonist tocilizumab, which resulted in decreased DCVS, neuronal cell death, and microclot formation [14]. In the second study, an IL-6 antagonist was applied only vitro, with blockade of the membranous IL-6 receptor with a goat polyclonal IL-6R-neutralizing antibody (IL-6R nAb), and resulted in an inhibition of brain endothelial cell barrier disruption after SAH [15].…”

Section: Animal Studiesmentioning

confidence: 99%

“…Therefore, it seems reasonable to develop new therapies against neuroinflammation to prevent the aggravation of EBI and improve outcome of patients with SAH. Given that animal models have shown that use of an IL-6 antagonist led to a decrease of DCVS, DCI, and microclot formation [14,15,17] and considering the availability of medications such as the IL-6 receptor antagonist tocilizumab, which is widely used in the treatment of rheumatoid arthritis [64][65][66] and was recently used in clinical studies for treatment of patients affected by COVID-19 [67][68][69], new doors have opened for possible future clinical trials using an IL-6 receptor antagonist in an effort to decrease DCVS and DCI after SAH to improve patient outcomes.…”

Section: Il-6 In Relation To Microclot Formationmentioning

confidence: 99%

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Preclinical and clinical role of interleukin-6 in the development of delayed cerebral vasospasm and neuronal cell death after subarachnoid hemorrhage: towards a potential target therapy?

et al. 2021

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Delayed cerebral vasospasm (DCVS), early brain injury (EBI), and delayed cerebral ischemia (DCI) are devastating complications after aneurysmal subarachnoid hemorrhage (SAH). Interleukin (IL)-6 seems to be an important interleukin in the inflammatory response after SAH, and many studies describe a strong correlation between IL-6 and worse outcome. The aim of this study was to systematically review preclinical and clinical studies that evaluated systemic and cerebral IL-6 levels after SAH and their relation to DCVS, neuronal cell death, and DCI. We conducted two systematic literature searches using Pub-Med to identify preclinical and clinical studies evaluating the role of IL-6 after SAH. Suitable articles were selected based on predefined eligibility criteria following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 61 and 30 preclinical and clinical articles, respectively, were included in the systematic reviews. Of the preclinical studies in which IL-6 was measured in cerebrospinal fluid (CSF), parenchyma, and systemically, 100%, 94.4%, and 81.3%, respectively, showed increased expression of IL-6 after SAH. Preclinical results were mirrored by clinical findings in which elevated levels of IL-6 in CSF and plasma were found after SAH, correlating with DCVS, DCI, and worse outcome. Only two preclinical studies analyzed the direct inhibition of IL-6, which resulted in reduced DCVS and neuronal cell death. IL-6 is a marker of intracranial inflammation and plays a role in the pathophysiology of DCVS and DCI after SAH in preclinical animal models and clinical studies. Its inhibition might have therapeutic potential to improve the outcome of SAH patients.

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