{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:55:17Z","timestamp":1787028917294,"version":"build-2736575974"},"reference-count":37,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T00:00:00Z","timestamp":1733702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Objective: Subarachnoid hemorrhage (SAH) is a life-threatening cerebrovascular condition that triggers a robust inflammatory response and cerebral vasospasm. This study aimed to evaluate the effects of anakinra, an interleukin-1 receptor antagonist, and tocilizumab, an interleukin-6 receptor antagonist, on inflammation and vasospasm in an experimental rat SAH model. Methods: Forty male Sprague Dawley rats (200\u2013250 g) were randomly assigned to five groups: control, SAH, SAH + anakinra (ANA), SAH + tocilizumab (TCZ), and SAH + anakinra + tocilizumab (ANA+TCZ). SAH was induced by injecting non-heparinized arterial blood into the cisterna magna. Treatment groups received anakinra (50 mg\/kg twice daily), tocilizumab (8 mg\/kg once daily), or their combination for three days. Blood and cerebrospinal fluid (CSF) samples were analyzed for inflammatory markers (IL-1, IL-6, TNF-\u03b1, CRP), and histopathological evaluations were conducted to assess vasospasm and apoptosis. Results: SAH significantly increased pro-inflammatory cytokines (IL-1, IL-6, TNF-\u03b1, CRP) and fibrinogen levels in serum and CSF while reducing the basilar artery lumen diameter (p &lt; 0.001). Anakinra and tocilizumab treatments significantly reduced inflammatory markers and vasospasm severity compared to the SAH group (p &lt; 0.05). Combination therapy was more effective in reducing inflammation and vasospasm than either treatment alone (p &lt; 0.05). Anakinra showed a stronger effect on IL-1 reduction, while tocilizumab was more effective in lowering IL-6 levels. The ANA+TCZ group exhibited a significant decrease in caspase activity, indicating reduced apoptosis (p &lt; 0.05). Conclusions: Anakinra and tocilizumab effectively mitigated inflammation and vasospasm in an experimental SAH model, with combination therapy showing superior efficacy. These findings suggest that targeting both IL-1 and IL-6 pathways may be a promising therapeutic strategy for managing SAH complications. Further studies are warranted to evaluate long-term outcomes and clinical implications.<\/jats:p>","DOI":"10.3390\/medicina60122025","type":"journal-article","created":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T06:16:14Z","timestamp":1733724974000},"page":"2025","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Comparative Effects of Anakinra and Tocilizumab on Inflammation and Cerebral Vasospasm in an Experimental Subarachnoid Hemorrhage Model"],"prefix":"10.3390","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5050-7908","authenticated-orcid":false,"given":"G\u00fcven","family":"K\u0131l\u0131\u00e7","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Faculty of Medicine, Duzce University, Duzce 81100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9422-4975","authenticated-orcid":false,"given":"Berk Enes","family":"Engin","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Faculty of Medicine, Duzce University, Duzce 81100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Halabi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Faculty of Medicine, Duzce University, Duzce 81100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2400-5546","authenticated-orcid":false,"given":"Cengiz","family":"Tuncer","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Faculty of Medicine, Duzce University, Duzce 81100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehmet Ali","family":"Sungur","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Faculty of Medicine, Duzce University, Duzce 81100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merve","family":"Alpay","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Medicine, Duzce University, Duzce 81100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8084-1015","authenticated-orcid":false,"given":"Adem","family":"Kurtulu\u015f","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Faculty of Medicine, Duzce University, Duzce 81100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hakan","family":"Soylu","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Faculty of Medicine, Duzce University, Duzce 81100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4103-9537","authenticated-orcid":false,"given":"Ali","family":"G\u00f6k","sequence":"additional","affiliation":[{"name":"Experimental Animals Application and Research Center, Duzce University, Duzce 81100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.nrl.2012.07.009","article-title":"Clinical management guidelines for subarachnoid haemorrhage. Diagnosis and treatment","volume":"29","author":"Vivancos","year":"2014","journal-title":"Neurologia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"jrm41225","DOI":"10.2340\/jrm.v56.41225","article-title":"Early mobilization in patients with aneurysmal subarachnoid haemorrhage may im-prove functional status and reduce cerebral vasospasm rate: A systematic review with meta-analysis","volume":"56","author":"Foudhaili","year":"2024","journal-title":"J. Rehabil. Med."},{"key":"ref_3","first-page":"46","article-title":"Epidemiological trends of subarachnoid hemorrhage at global, regional, and national level: A trend analysis study from 1990 to 2021","volume":"11","author":"Lv","year":"2024","journal-title":"Mil. Med. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"108084","DOI":"10.1016\/j.jstrokecerebrovasdis.2024.108084","article-title":"The impact of systolic blood pressure reduction on aneurysm re-bleeding in subarachnoid hemorrhage: A systematic review and meta-analysis","volume":"33","author":"Aladawi","year":"2024","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Xiao, Z.K., Wang, B., Liu, J., Yang, Y., Jie, N., Mao, X., Gong, X., Liu, A., and Duan, Y.H. (2024). Risk factors for the development of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis. World Neurosurg., in press.","DOI":"10.1016\/j.wneu.2024.09.104"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.wneu.2024.06.060","article-title":"Clinical Characteristics as Predictors of Early and Delayed Cerebral Infarction in Aneurysmal Subarachnoid Hemorrhage Patients: A Meta-Analysis of 4527 Cases","volume":"189","author":"Gillani","year":"2024","journal-title":"World Neurosurg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1179\/174313209X393564","article-title":"Cerebral vasospasm following subarachnoid hemorrhage: Time for a new world of thought","volume":"31","author":"Pluta","year":"2009","journal-title":"Neurol. Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Lucke-Wold, B.P., Logsdon, A.F., Manoranjan, B., Turner, R.C., McConnell, E., Vates, G.E., Huber, J.D., Rosen, C.L., and Simard, J.M. (2016). Aneurysmal Subarachnoid Hemorrhage and Neuroinflammation: A Comprehensive Review. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17040497"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Qi, X., Chiavaroli, L., Lee, D., Ayoub-Charette, S., Khan, T.A., Au-Yeung, F., Ahmed, A., Cheung, A., Liu, Q., and Blanco Mejia, S. (2022). Effect of Important Food Sources of Fructose-Containing Sugars on Inflammatory Biomarkers: A Systematic Review and Meta-Analysis of Controlled Feeding Trials. Nutrients, 14.","DOI":"10.3390\/nu14193986"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2055","DOI":"10.21037\/tau-24-209","article-title":"NOSTRIN is involved in benign prostatic hyperplasia via inhibition of proliferation, oxidative stress, and inflammation in prostate epithelial cells","volume":"13","author":"Li","year":"2024","journal-title":"Transl. Androl. Urol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Konsman, J.P. (2022). Cytokines in the Brain and Neuroinflammation: We Didn\u2019t Starve the Fire!. Pharmaceuticals, 15.","DOI":"10.3390\/ph15020140"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Wu, F., Liu, Z., Li, G., Zhou, L., Huang, K., Wu, Z., Zhan, R., and Shen, J. (2021). Inflammation and Oxidative Stress: Potential Targets for Improving Prognosis After Subarachnoid Hemorrhage. Front. Cell Neurosci., 15.","DOI":"10.3389\/fncel.2021.739506"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1007\/s10143-021-01628-9","article-title":"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?","volume":"45","author":"Croci","year":"2022","journal-title":"Neurosurg. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1007\/s12975-020-00880-3","article-title":"Tocilizumab Reduces Vasospasms, Neuronal Cell Death, and Microclot Formation in a Rabbit Model of Subarachnoid Hemorrhage","volume":"12","author":"Croci","year":"2021","journal-title":"Transl. Stroke Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"105054","DOI":"10.1016\/j.jstrokecerebrovasdis.2020.105054","article-title":"Changes in the cerebrospinal fluid lipid profile following subarachnoid hemorrhage in a closed cranium model: Correlations to cerebral vasospasm, neuronal cell death and Interleukin-6 synthesis. A pilot study","volume":"29","author":"Croci","year":"2020","journal-title":"J. Stroke Cerebrovasc. Dis. Off. J. Natl. Stroke Assoc."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Cavalli, G., and Dinarello, C.A. (2018). Anakinra Therapy for Non-cancer Inflammatory Diseases. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.01157"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1111\/ejh.14029","article-title":"Intravenous anakinra for the treatment of haemophagocytic lymphohistiocytosis\/macrophage activation syndrome: A systematic review","volume":"111","author":"Charlesworth","year":"2023","journal-title":"Eur. J. Haematol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Lokau, J., Kleinegger, F., Garbers, Y., Waetzig, G.H., Gr\u00f6tzinger, J., Rose-John, S., Haybaeck, J., and Garbers, C. (2020). Tocilizumab does not block interleukin-6 (IL-6) signaling in murine cells. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0232612"},{"key":"ref_19","first-page":"Cd013484","article-title":"Tocilizumab for giant cell arteritis","volume":"5","author":"Antonio","year":"2022","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.5005\/jp-journals-10071-24320","article-title":"Comparison of Anakinra and Tocilizumab in Anticytokine Therapy in the Treatment of Coronavirus Disease-2019","volume":"26","author":"Ozkan","year":"2022","journal-title":"Indian. J. Crit. Care Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.seizure.2022.06.012","article-title":"Anakinra and tocilizumab in the chronic phase of febrile infection-related epilepsy syndrome (FIRES): Effectiveness and safety from a case-series","volume":"100","author":"Hariramani","year":"2022","journal-title":"Seizure"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"368","DOI":"10.54817\/IC.v64n3a09","article-title":"Effect of anakinra, tocilizumab, and the combination thereof on bladder ischemia-reperfusion damage in albino Wistar-type rats","volume":"64","author":"Bicer","year":"2023","journal-title":"Investig. Cl\u00ednica"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Miller, B.A., Turan, N., Chau, M., and Pradilla, G. (2014). Inflammation, vasospasm, and brain injury after subarachnoid hemorrhage. Biomed. Res. Int., 2014.","DOI":"10.1155\/2014\/384342"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e136","DOI":"10.1016\/j.wneu.2020.03.151","article-title":"Blocking VEGF by Bevacizumab Attenuates VEGF-Induced Vasospasm After Experimental Subarachnoid Hemorrhage in Rabbits","volume":"139","author":"Akturk","year":"2020","journal-title":"World Neurosurg."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Wang, L., Geng, G., Zhu, T., Chen, W., Li, X., Gu, J., and Jiang, E. (2022). Progress in Research on TLR4-Mediated Inflammatory Response Mechanisms in Brain Injury after Subarachnoid Hemorrhage. Cells, 11.","DOI":"10.3390\/cells11233781"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Mill\u00e1n Solano, M.V., Salinas Lara, C., S\u00e1nchez-Garibay, C., Soto-Rojas, L.O., Escobedo-\u00c1vila, I., Tena-Suck, M.L., Ort\u00edz-Butr\u00f3n, R., Chore\u00f1o-Parra, J.A., Romero-L\u00f3pez, J.P., and Mel\u00e9ndez Camargo, M.E. (2023). Effect of Systemic Inflammation in the CNS: A Silent History of Neuronal Damage. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241511902"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Romoli, M., Giammello, F., Mosconi, M.G., De Mase, A., De Marco, G., Digiovanni, A., Ciacciarelli, A., Ornello, R., and Storti, B. (2023). Immunological Profile of Vasospasm after Subarachnoid Hemorrhage. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24108856"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1186\/s12974-019-1578-1","article-title":"Inflammation in delayed ischemia and functional outcomes after subarachnoid hemorrhage","volume":"16","author":"Ahn","year":"2019","journal-title":"J. Neuroinflammation"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ku, E.J., Kim, B.R., Lee, J.I., Lee, Y.K., Oh, T.J., Jang, H.C., and Choi, S.H. (2022). The Anti-Atherosclerosis Effect of Anakinra, a Recombinant Human Interleukin-1 Receptor Antagonist, in Apolipoprotein E Knockout Mice. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23094906"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1742-2094-11-1","article-title":"The effect of intravenous interleukin-1 receptor antagonist on inflammatory mediators in cerebrospinal fluid after subarachnoid haemorrhage: A phase II randomised controlled trial","volume":"11","author":"Singh","year":"2014","journal-title":"J. Neuroinflammation"},{"key":"ref_31","first-page":"823","article-title":"Interleukin-1 receptor antagonist is beneficial after subarachnoid haemorrhage in rat by blocking haem-driven inflammatory pathology","volume":"5","author":"Greenhalgh","year":"2012","journal-title":"Dis. Models Mech."},{"key":"ref_32","first-page":"e42494","article-title":"Comparative Roles of IL-1, IL-6, IL-10, IL-17, IL-18, 1L-22, IL-33, and IL-37 in Various Cardiovascular Diseases With Potential Insights for Targeted Immunotherapy","volume":"15","author":"Abubakar","year":"2023","journal-title":"Cureus"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Tanaka, T., Narazaki, M., and Kishimoto, T. (2014). IL-6 in inflammation, immunity, and disease. Cold Spring Harb. Perspect. Biol., 6.","DOI":"10.1101\/cshperspect.a016295"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Rigoard, P., Billot, M., Moens, M., Goudman, L., El-Hajj, H., Ingrand, P., Ounajim, A., Roulaud, M., Page, P., and Babin, E. (2023). Evaluation of External Trigeminal Nerve Stimulation to Prevent Cerebral Vasospasm after Subarachnoid Hemorrhage Due to Aneurysmal Rupture: A Randomized, Double-Blind Proof-of-Concept Pilot Trial (TRIVASOSTIM Study). Int. J. Environ. Res. Public Health, 20.","DOI":"10.3390\/ijerph20105836"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"571328","DOI":"10.1155\/2013\/571328","article-title":"Cerebral vasospasm pharmacological treatment: An update","volume":"2013","author":"Siasios","year":"2013","journal-title":"Neurol. Res. Int."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1186\/s12974-022-02592-x","article-title":"Investigation and modulation of interleukin-6 following subarachnoid hemorrhage: Targeting inflammatory activation for cerebral vasospasm","volume":"19","author":"Dodd","year":"2022","journal-title":"J. Neuroinflammation"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Bonaventura, A., Liberale, L., Vecchi\u00e9, A., Casula, M., Carbone, F., Dallegri, F., and Montecucco, F. (2016). Update on Inflammatory Biomarkers and Treatments in Ischemic Stroke. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17121967"}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/60\/12\/2025\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:50:04Z","timestamp":1760115004000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/60\/12\/2025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,9]]},"references-count":37,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["medicina60122025"],"URL":"https:\/\/doi.org\/10.3390\/medicina60122025","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,9]]}}}