{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T16:59:15Z","timestamp":1780505955938,"version":"3.54.1"},"reference-count":31,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T00:00:00Z","timestamp":1739491200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Subarachnoid hemorrhage (SAH) is a severe neurological condition with high mortality and morbidity rates, often exacerbated by secondary complications such as inflammation, cerebral vasospasm, and apoptosis. Proinflammatory cytokines, including interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-\u03b1), and interleukin-6 (IL-6), play critical roles in these pathological processes. Anakinra, an IL-1 receptor antagonist, has demonstrated significant anti-inflammatory effects in various disease models. This study aimed to evaluate the efficacy of anakinra in mitigating inflammation, vasospasm, and apoptosis in an experimental rat model of SAH. Methods: Thirty-two male Sprague Dawley rats were divided into four groups: Control (healthy), SAH (no treatment), Saline (0.2 mL saline subcutaneously), and Anakinra (50 mg\/kg subcutaneously, twice daily). Proinflammatory markers (CRP, TNF-\u03b1, IL-1, IL-6, and fibrinogen) were measured in serum and cerebrospinal fluid (CSF) at 3, 7, and 10 days post-SAH. Basilar artery diameter was evaluated histopathologically, and Caspase-3 expression was assessed immunohistochemically to determine apoptotic activity. Results: SAH significantly increased levels of CRP, TNF-\u03b1, IL-1, IL-6, and fibrinogen in both serum and CSF, reduced basilar artery diameter, and elevated Caspase-3 expression compared to the Control group. Saline treatment provided limited improvements, with inflammatory markers and histopathological parameters remaining elevated. Anakinra treatment significantly reduced inflammatory markers, restored basilar artery diameter, and lowered Caspase-3 expression, highlighting its efficacy in mitigating inflammation, vasospasm, and apoptosis. Conclusions: Anakinra effectively suppresses inflammation, alleviates cerebral vasospasm, and inhibits apoptosis in an experimental model of SAH. These findings suggest its potential as a therapeutic agent for managing SAH and its complications. Further research is needed to explore its clinical applicability and long-term effects.<\/jats:p>","DOI":"10.3390\/jcm14041253","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T03:20:52Z","timestamp":1739503252000},"page":"1253","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Mitigating Post-Subarachnoid Hemorrhage Complications: Anti-Inflammatory and Anti-Apoptotic Effects of Anakinra in an Experimental Study"],"prefix":"10.3390","volume":"14","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, 81620 Duzce, 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, 81620 Duzce, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9896-6097","authenticated-orcid":false,"given":"Amir","family":"Halabi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Faculty of Medicine, Duzce University, 81620 Duzce, 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, 81620 Duzce, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehmet Ali","family":"Sungur","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Faculty of Medicine, Duzce University, 81620 Duzce, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8782-9561","authenticated-orcid":false,"given":"Merve","family":"Alpay","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Medicine, Duzce University, 81620 Duzce, 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, 81620 Duzce, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1177-2351","authenticated-orcid":false,"given":"Hakan","family":"Soylu","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Faculty of Medicine, Duzce University, 81620 Duzce, 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, 81620 Duzce, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d6mer","family":"Polat","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Cagsu Hospital, 81600 Bolu, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2708","DOI":"10.1161\/STROKEAHA.123.043541","article-title":"Comment on the 2023 Guidelines for the Management of Patients With Aneurysmal Subarachnoid Hemorrhage","volume":"54","author":"Spears","year":"2023","journal-title":"Stroke"},{"key":"ref_2","first-page":"110939","article-title":"Hyperoxia and unfavourable outcome in patients with non-traumatic subarachnoid haemorrhage: A systematic review and meta-analysis","volume":"131","author":"Catalano","year":"2025","journal-title":"J. Clin. Neurosci. Off. J. Neurosurg. Soc. Australas."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/s12987-023-00483-8","article-title":"Pathogenic mechanisms and therapeutic implications of extracellular matrix remodelling in cerebral vasospasm","volume":"20","author":"Hu","year":"2023","journal-title":"Fluids Barriers CNS"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"K\u0131l\u0131\u00e7, G., Engin, B.E., Halabi, A., Tuncer, C., Sungur, M.A., Alpay, M., Kurtulu\u015f, A., Soylu, H., and G\u00f6k, A. (2024). The Comparative Effects of Anakinra and Tocilizumab on Inflammation and Cerebral Vasospasm in an Experimental Subarachnoid Hemorrhage Model. Medicina, 60.","DOI":"10.3390\/medicina60122025"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Miller, B.A., and Turan, N. (2014). Inflammation, vasospasm, and brain injury after subarachnoid hemorrhage. BioMed Res. Int., 2014.","DOI":"10.1155\/2014\/384342"},{"key":"ref_6","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_7","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1136\/ard.61.11.960","article-title":"Potential therapeutic uses of interleukin 1 receptor antagonists in human diseases","volume":"61","author":"Hallegua","year":"2002","journal-title":"Ann. Rheum. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1038\/nrd3800","article-title":"Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases","volume":"11","author":"Dinarello","year":"2012","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.6061\/clinics\/2012(12)18","article-title":"Hypertonic saline solution reduces the inflammatory response in endotoxemic rats","volume":"67","author":"Theobaldo","year":"2012","journal-title":"Clinics"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Menzel, A., Samouda, H., Dohet, F., and Loap, S. (2021). Common and Novel Markers for Measuring Inflammation and Oxidative Stress Ex Vivo in Research and Clinical Practice-Which to Use Regarding Disease Outcomes?. Antioxidants, 10.","DOI":"10.3390\/antiox10030414"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"He, Q., Su, G., and Liu, K. (2017). Sex-specific reference intervals of hematologic and biochemical analytes in Sprague-Dawley rats using the nonparametric rank percentile method. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0189837"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/S0165-0270(00)00156-4","article-title":"Experimental models of subarachnoid hemorrhage in the rat: A refinement of the endovascular filament model","volume":"96","author":"Schwartz","year":"2000","journal-title":"J. Neurosci. Methods"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"515","DOI":"10.3171\/2016.9.JNS16615","article-title":"Reduction of inflammation after administration of interleukin-1 receptor antagonist following aneurysmal subarachnoid hemorrhage: Results of the Subcutaneous Interleukin-1Ra in SAH (SCIL-SAH) study","volume":"128","author":"Galea","year":"2018","journal-title":"J. Neurosurg."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1293\/tox.2017-0046","article-title":"Quality assessment of long-term stored formalin-fixed paraffin embedded tissues for histopathological evaluation","volume":"31","author":"Ono","year":"2018","journal-title":"J. Toxicol. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/978-1-59745-324-0_14","article-title":"Heat-induced antigen retrieval for immunohistochemical reactions in routinely processed paraffin sections","volume":"588","author":"Krenacs","year":"2010","journal-title":"Methods Mol. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Romoli, M., and Giammello, F. (2023). Immunological Profile of Vasospasm after Subarachnoid Hemorrhage. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24108856"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1186\/s12974-019-1629-7","article-title":"Innate immunity activation in the early brain injury period following subarachnoid hemorrhage","volume":"16","author":"Gris","year":"2019","journal-title":"J. Neuroinflammation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1097\/01.TA.0000119686.33487.65","article-title":"Hypertonic saline prevents inflammation, injury, and impaired intestinal transit after gut ischemia\/reperfusion by inducing heme oxygenase 1 enzyme","volume":"56","author":"Attuwaybi","year":"2004","journal-title":"J. Trauma"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.jaci.2014.07.039","article-title":"IL-1 receptor antagonist reduces endotoxin-induced airway inflammation in healthy volunteers","volume":"135","author":"Hernandez","year":"2015","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Thelin, E.P., Tajsic, T., Zeiler, F.A., Menon, D.K., Hutchinson, P.J.A., Carpenter, K.L.H., Morganti-Kossmann, M.C., and Helmy, A. (2017). Monitoring the Neuroinflammatory Response Following Acute Brain Injury. Front. Neurol., 8.","DOI":"10.3389\/fneur.2017.00351"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"420","DOI":"10.3390\/pathophysiology30030032","article-title":"Pathophysiology, Management, and Therapeutics in Subarachnoid Hemorrhage and Delayed Cerebral Ischemia: An Overview","volume":"30","author":"Sanicola","year":"2023","journal-title":"Pathophysiology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.wneu.2023.11.122","article-title":"Stellate Ganglion Block in Subarachnoid Hemorrhage: A Promising Protective Measure Against Vasospasm?","volume":"182","author":"Oliveira","year":"2024","journal-title":"World Neurosurg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.2174\/1570159X16666180412110919","article-title":"Inflammatory Events Following Subarachnoid Hemorrhage (SAH)","volume":"16","author":"Schneider","year":"2018","journal-title":"Curr. Neuropharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"767","DOI":"10.3171\/jns.1990.72.5.0767","article-title":"The role of inflammation in experimental cerebral vasospasm","volume":"72","author":"Peterson","year":"1990","journal-title":"J. Neurosurg."},{"key":"ref_25","first-page":"699","article-title":"Effect of tocilizumab in subarachnoid hemorrhage-induced cerebral vasospasm of experimental rats","volume":"6","author":"Keskin","year":"2022","journal-title":"J. Health Sci. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"25","DOI":"10.3171\/jns.2005.103.1.0025","article-title":"Effect of normal saline bolus on cerebral blood flow in regions with low baseline flow in patients with vasospasm following subarachnoid hemorrhage","volume":"103","author":"Jost","year":"2005","journal-title":"J. Neurosurg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.3390\/encyclopedia2040111","article-title":"Apoptosis regulators bcl-2 and caspase-3","volume":"2","author":"Hussar","year":"2022","journal-title":"Encyclopedia"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.3906\/sag-2008-258","article-title":"The role of anakinra in the modulation of intestinal cell apoptosis and inflammatory response during ischemia\/reperfusion","volume":"51","author":"Kandemir","year":"2021","journal-title":"Turk. J. Med Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1523\/JNEUROSCI.22-05-01738.2002","article-title":"Caspase-3-dependent proteolytic cleavage of protein kinase Cdelta is essential for oxidative stress-mediated dopaminergic cell death after exposure to methylcyclopentadienyl manganese tricarbonyl","volume":"22","author":"Anantharam","year":"2002","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.2174\/1570159X19666211111121146","article-title":"The Role of Caspase Family in Acute Brain Injury: The Potential Therapeutic Targets in the Future","volume":"20","author":"Zhang","year":"2022","journal-title":"Curr. Neuropharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Jacquens, A., Needham, E.J., and Zanier, E.R. (2022). Neuro-Inflammation Modulation and Post-Traumatic Brain Injury Lesions: From Bench to Bed-Side. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911193"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/4\/1253\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:34:01Z","timestamp":1760027641000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/4\/1253"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,14]]},"references-count":31,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["jcm14041253"],"URL":"https:\/\/doi.org\/10.3390\/jcm14041253","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,14]]}}}