Effect of tocilizumab in subarachnoid hemorrhage-induced cerebral vasospasm of experimental rats
Effect of tocilizumab in subarachnoid hemorrhage-induced cerebral vasospasm of experimental rats
Aim: This study aimed to evaluate the effects of tocilizumab (TCZ), a recombinant humanized, anti-human monoclonal antibody of the immunoglobulin G1k subclass, on vascular morphological changes, endothelial apoptosis, and the levels of pro-inflammatory and apoptotic cytokines, such as IL-6, tumor necrosis factor-alpha (TNF-α), caspase-3, Bcl-2 associated X-protein (BAX), and vascular endothelial growth factor (VEGF) in a rat SAH model.
Material and Method: The rats were randomly assigned (animal study) to 4 groups KONÜDAM Experimental Animal Research Center, Necmettin Erbakan University, Meram Faculty of Medicine, Konya, Turkey; 15/03/2019): (1) normal control (without SAH); (2) SAH (without treatment); (3) SAH treated with saline (SAH + Sal.); and (4) SAH treated with TCZ (SAH + Toc.). The tissues were measured using enzyme-linked immunosorbent assay (ELISA) kits. A series of brain and basilar artery sections were categorized into several subgroups for hematoxylin and eosin (H&E) staining, immunohistochemistry, and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining.
Results: The levels of caspase, BAX, and IL-6 in the SAH + TOC group were significantly lower than in other groups. TCZ treatment significantly increased the lumen of the basilar artery compared with that in the SAH and SAH + SAL groups without treatment (p=0.002 and p=0.004 respectively). SAH increased the apoptotic index in the endothelium compared with TCZ treatment (p=0.027) groups.
Conclusion: It can be concluded that TCZ is safe and effective for treating experimental SAH. The results reveal clearly experimental evidence for the potential clinical application of TCZ in SAH patients.
___
- Simon M, Grote A. Interleukin 6 and aneurysmal subarachnoid hemorrhage. a narrative review. Int J Mol Sci 2021; 22: 4133
- Etminan N, Chang HS, Hackenberg K, et al. Worldwide incidence of aneurysmal subarachnoid hemorrhage according to region, time period, blood pressure, and smoking prevalence in the population: a systematic review and meta-analysis. JAMA Neurol 2019; 76(5): 588-97.
- Bederson JB, Connolly ES, Jr., Batjer HH, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 2009; 40: 994-1025
- Vergouwen MD, Vermeulen M, van Gijn J, et al. Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke 2010; 41: 2391-5
- Bakker MK, van der Spek RA, van Rheenen W, et al. Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors. Nat Genet 2020; 52: 1303-13
- Masato Naraoka M, Matsuda N, Shimamura N, Ohkuma H. Role of microcirculatory impairment in delayed cerebral ischemia and outcome after aneurysmal subarachnoid hemorrhage. J Cerebral Blood Flow Metab 2022; 42: 186–96.
- Lucke-Wold BP, Logsdon AF, Manoranjan B, et al. Aneurysmal subarachnoid hemorrhage and neuroinflammation: a comprehensive review. Int J Mol Sci 2016; 17: 497
- Singh N, Hopkins SJ, Hulme S, et al. The effect of intravenous interleukin-1 receptor antagonist on inflammatory mediators in cerebrospinal fluid after subarachnoid hemorrhage: a phase II randomized controlled trial. J Neuroinflamm 2014; 11: 1-8.
- Rothaug M, Becker-Pauly C, Rose-John S. The role of interleukin-6 signaling in nervous tissue. Biochimica et Biophysica Acta -Molecul Cell Res 2016; 1863: 1218-27.
- Sheppard M, Laskou F, Stapleton PP, Hadavi S, Dasgupta B. Tocilizumab (Actemra). Hum Vaccin Immunother 2017; 13: 1972-88.
- Deng HJ, Deji Q, Zhaba W, et al. A20 establishes negative feedback with TRAF6/NF-κB and attenuates early brain injury after experimental subarachnoid hemorrhage. Front Immunol 2021; 12: 623256.
- Dabus G, Nogueira RG. Current options for the management of aneurysmal subarachnoid hemorrhage-induced cerebral vasospasm: a comprehensive review of the literature. Interv Neurol 2013; 2: 30-51.
- Yeo N, Terrett L, Gupta AKJ, Care C. Contemporary management of aneurysmal subarachnoid hemorrhage: a literature review. J Neuroanaesthesiol Crit Care 2019; 6: 131-9
- Kaur S, Bansal Y, Kumar R, Bansal G. A panoramic review of IL-6: structure, pathophysiological roles, and inhibitors. Bioorganic Medicinal Chemistry 2020; 28: 115327.
- Le RQ, Li L, Yuan W, et al. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell‐induced severe or life‐threatening cytokine release syndrome. Oncologist 2018; 23: 943.
- Weil MH & Whigham H: Head-Down (Tredelenburg) Position for Treatment of Irreversible Hemorrhagic Shock: Experimental Study in Rats. Ann Surg 1965; 162: 905-9.
- Erdi F, Keskin F, Esen H, et al. Telmisartan ameliorates oxidative stress and subarachnoid haemorrhage-induced cerebral vasospasm. Neurol Res 2016; 38: 224-31.
- Graetz D, Nagel A, Schlenk F, Sakowitz O, Vajkoczy P, Sarrafzadeh A. High ICP as trigger of proinflammatory IL-6 cytokine activation in aneurysmal subarachnoid hemorrhage. Neurologic Res 2010; 32: 728-35.
- Kang S, Tanaka T, Kishimoto T. Therapeutic uses of anti-interleukin-6 receptor antibody. Int Immunol 2015; 27: 21-9.
- Pers Y-M, Schaub R, Constant E, et al. Efficacy and safety of tocilizumab in elderly patients with rheumatoid arthritis. Joint Bone Spine 2015; 82: 25-30.
- Savvatis K, Müller I, Fröhlich M, et al. Interleukin-6 receptor inhibition modulates the immune reaction and restores titin phosphorylation in experimental myocarditis. Basic Res Cardiol 2014; 109: 1-14.
- Pang Y, Tien LT, Zhu H, et al. Interleukin-1 receptor antagonist reduces neonatal lipopolysaccharide-induced long-lasting neurobehavioral deficits and dopaminergic neuronal injury in adult rats. Int J Mol Sci 2015; 16: 8635-54
- Rock KL, Latz E, Ontiveros F, Kono H. The sterile inflammatory response. Ann Rev Immunol 2009; 28: 321-42
- Greenhalgh AD, Brough D, Robinson EM, Girard S, Rothwell NJ, Allan SM. Interleukin-1 receptor antagonist is beneficial after subarachnoid haemorrhage in rat by blocking haem-driven inflammatory pathology. Dis Models Mechanisms 2012; 5: 823-33
- Hanafy KA, Grobelny B, Fernandez L, et al. Brain interstitial fluid TNF-α after subarachnoid hemorrhage. J Neurol Sci 2010; 291: 69-73.
- Wu W, Guan Y, Zhao G, et al. Elevated IL-6 and TNF-alpha levels in cerebrospinal fluid of subarachnoid hemorrhage patients. Mol Neurobiol 2016; 53: 3277-85
- Wu CH, Tsai YC, Tsai TH, et al. Valproic acid reduces vasospasm through modulation of akt phosphorylation and attenuates neuronal apoptosis in subarachnoid hemorrhage rats. Int J Mol Sci 2021; 22: 5975.
- Croci DM, Wanderer S, Strange F, et al. Tocilizumab reduces vasospasms, neuronal celle death, and microclot formation in a rabbit model of subarachnoid hemorrhage. Transl Stroke Res 2021; 12: 894-904.
- Xu L, Wu J, Liu Y, Chen G, Ma C, Zhang H. Peroxisome proliferator activated receptor β/δ regulates cerebral vasospasm after subarachnoid hemorrhage via modulating vascular smooth muscle cells phenotypic conversion. Mol Med Rep 2021; 24: 860.
- Hasegawa Y, Suzuki H, Sozen T, Altay O, Zhang JH. Apoptotic mechanisms for neuronal cells in early brain injury after subarachnoid hemorrhage. Early Brain Injury or Cerebral Vasospasm 2011; 110: 43-8
- Heinsberg LW, Weeks DE, Alexander SA, et al. Iron homeostasis pathway DNA methylation trajectories reveal a role for STEAP3 metalloreductase in patient outcomes after aneurysmal subarachnoid hemorrhage. Epigenetics Commun 2021; 1: 4.
- Fragata I, Bustamante A, Penalba A, et al. TNF-R1 correlates with cerebral perfusion and acute ischemia following subarachnoid hemorrhage. Neurocrit Care 2020; 33: 679-87.
- Wu F, Liu Z, Li G, et al. Inflammation and oxidative stress: potential targets for improving prognosis after subarachnoid hemorrhage. Front Cell Neurosci 2021; 15: 739506.
- Barry C, Turner RJ, Corrigan F, Vink R. New therapeutic approaches to subarachnoid hemorrhage. Expert Opin Investig Drugs 2012; 21: 845-59.
- Marsal Barril S, Martin-Martinez MA, Blanco-Garcia FJ, et al. Effectiveness and safety of tocilizumab in monotherapy in biologic-naïve and non-naïve patients with rheumatoid arthritis in a real-world setting. Reumatol Clin (Engl Ed) 2022; 18: 567-73.