{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T20:57:24Z","timestamp":1781125044965,"version":"3.54.1"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Inflammation contributes significantly to neuronal damage in ischemic stroke, with IL (interleukin)-1 being a key mediator. IL-1Ra (IL-1 receptor antagonist) inhibits IL-1 signaling, successfully reducing inflammation in preclinical and clinical stroke studies. However, in the latest phase II trial of IL-1Ra in ischemic stroke (SCIL-STROKE [Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke]), a secondary mediation analysis uncovered an alternative pathway leading to no overall functional benefit. This was the first IL-1Ra trial where participants (73%) received preceding tPA (tissue-type plasminogen activator), raising the possibility that IL-1Ra and tPA interact negatively in ischemic stroke. We aim to explore this postulated negative interaction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>A retrospective analysis of SCIL-STROKE trial data was performed. Next, we used a thromboembolic model of stroke in male wild-type mice (25\u201335 g; n=10\u201313), treated with tPA (10 mg\/kg, 20\u201360 minutes poststroke), followed by IL-1Ra (100 mg\/kg) either 6 doses, twice daily (after tPA), or 2 doses at 30 minutes (during tPA) and 3 hours poststroke. The primary outcome was lesion volume at 72 hours, measured by T2-magnetic resonance imaging.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>Reanalysis of SCIL-STROKE data revealed a 36.7% reduction in plasma IL-1Ra in patients cotreated with preceding tPA, suggesting IL-1Ra degradation. Biochemical assays confirmed IL-1Ra cleavage by plasmin. While replicating the SCIL-STROKE dosing regimen preclinically, no negative interactions were noted. However, when IL-1Ra was administered during thrombolysis, it impaired the beneficial effect of tPA, reducing lesion volume by only 15%, compared with 68% with tPA alone. Acute cotreatment of IL-1Ra and tPA also led to reduced tissue perfusion and increased leukocyte infiltration and neutrophil extracellular traps.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>We show that IL-1Ra is cleaved by plasmin, and its administration during thrombolysis worsens outcomes poststroke. These studies confirm a negative interaction between the 2 drugs, which can be prevented by tPA preceding IL-1Ra treatment. The findings raise broader concerns about how tPA may interfere with other neuroprotective treatments.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/strokeaha.125.054941","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T09:00:52Z","timestamp":1773824452000},"page":"1777-1791","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Timing-Dependent Cleavage of Interleukin-1 Receptor Antagonist by Alteplase Impairs Neuroprotection in Ischemic Stroke"],"prefix":"10.1161","volume":"57","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0993-8583","authenticated-orcid":true,"given":"Ioana-Emilia","family":"Mosneag","sequence":"first","affiliation":[{"name":"Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance NHS Foundation Trust (I.-E.M., Y.O., B.R.D., R.J., G.C., E.R., D.M.B., C.J.S., S.M.A.), The University of Manchester, 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Recherche M\u00e9dicale (INSERM), Unit\u00e9 Mixte de Recherche Scientifique (UMR-S) U1237 Caen Normandie, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Blood and Brain Institute @ Caen-Normandie (BB@C), Caen, France (M.R., E.L., D.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0213-6302","authenticated-orcid":true,"given":"Yolanda","family":"Ohene","sequence":"additional","affiliation":[{"name":"Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance NHS Foundation Trust (I.-E.M., Y.O., B.R.D., R.J., G.C., E.R., D.M.B., C.J.S., S.M.A.), The University of Manchester, United Kingdom"},{"name":"Division of Psychology, Communication and Human Neuroscience, School of Health Sciences (Y.O.), The University of Manchester, United 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