Timing-Dependent Cleavage of Interleukin-1 Receptor Antagonist by Alteplase Impairs Neuroprotection in Ischemic Stroke

 Will your competent? doctor and hospital do anything with this? Or is head in the sand their response? I'd start asking now so enough time is available to get some competency in your hospital!

Timing-Dependent Cleavage of Interleukin-1 Receptor Antagonist by Alteplase Impairs Neuroprotection in Ischemic Stroke

Ioana-Emilia Mosneag, PhD https://orcid.org/0000-0003-0993-8583 ioana-emilia.mosneag@manchester.ac.uk, 

Marina Rubio, PhD https://orcid.org/0000-0002-6120-4053, 

Eloïse Lemarchand, PhD, 

Yolanda Ohene, PhD https://orcid.org/0000-0002-0213-6302, 

Ben R. Dickie, PhD https://orcid.org/0000-0001-5018-2111, 

Rachel Jones, PhD https://orcid.org/0009-0001-2935-7586, 

Graham Coutts, PhD https://orcid.org/0000-0002-5865-9495, 

Eleanor Ritchie, BSc https://orcid.org/0009-0004-1594-5282, 

Daniela Martins Borges, BSc, 

Denis Vivien, PhD https://orcid.org/0000-0002-7636-2185, 

Craig J. Smith, MD https://orcid.org/0000-0002-9078-9919, and 

Stuart M. Allan, PhD https://orcid.org/0000-0001-9646-4456Author Info & Affiliations

Stroke

New online

https://doi.org/10.1161/STROKEAHA.125.054941

Abstract

BACKGROUND:

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.

METHODS:

A retrospective analysis of SCIL-STROKE trial data was performed. Next, we used a thromboembolic model of stroke in male wild-type mice (25–35 g; n=10–13), treated with tPA (10 mg/kg, 20–60 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.

RESULTS:

Reanalysis of SCIL-STROKE data revealed a 35.8% 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.

CONCLUSIONS:

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.

Graphical Abstract

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