Luca Liberale1,2, Candela Diaz-Cañestro1, Nicole R Bonetti1,3, Francesco Paneni1, Alexander Akhmedov1, Jürg H Beer1,3, Fabrizio Montecucco1,4,5, Thomas F Lüscher1,6, Giovanni G Camici1,7. 1. Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, Schlieren, Switzerland. 2. Department of Internal Medicine, First Clinic of Internal Medicine, University of Genoa, 6 viale Benedetto XV, Genoa, Italy. 3. Department of Internal Medicine, Cantonal Hospital of Baden, Im Ergel 1, Baden, Switzerland. 4. Ospedale Policlinico San Martino 10 Largo Benzi, Genoa, Italy. 5. Centre of Excellence for Biomedical Research (CEBR), University of Genoa, 9 viale Benedetto XV, Genoa, Italy. 6. Royal Brompton and Harefield Hospitals and Imperial College, London, UK. 7. Zurich Neuroscience Center, University of Zurich, Winterthurer Strasse 190, Zurich, Switzerland.
Abstract
Aims: The CANTOS trial underscored the efficacy of selective antibody-based interleukin (IL)-1β inhibition with Canakinumab in secondary prevention of cardiovascular events. Despite the success of the trial, incidence of stroke was not reduced likely due to the low number of events and the relatively young age of patients enrolled. Given the established role of IL-1β in stroke, we tested the efficacy of the murine Canakinumab-equivalent antibody in a mouse model of ischaemic stroke. To mimic the clinical scenario of modern stroke management, IL-1β inhibition was performed post-ischaemically upon reperfusion as it would be the case in patients presenting to the emergency room and eligible for thrombolytic therapy. Methods and results: Transient middle cerebral artery occlusion (tMCAO) was performed in wild type mice; upon reperfusion, mice were randomly allocated to anti-IL-1β antibody or vehicle treatment. Following tMCAO, cerebral IL-1β levels, unlike tumour necrosis factor-α, were increased underscoring a role for this cytokine. Post-ischaemic treatment with IL-1β antibody reduced infarct size, cerebral oedema and improved neurological performance as assessed by 2,3,5-triphenyltetrazolium chloride staining, Bederson and RotaRod tests. Antibody-treated animals also exhibited a reduced neutrophil and matrix metalloproteinase (MMP)-2 but not MMP-9, activity in ipsilateral hemispheres as compared to vehicle-treated mice. Noteworthy, tMCAO associated vascular endothelial-cadherin reduction was blunted in IL-1β antibody-treated mice compared to vehicle-treated, likely providing the mechanistic explanation for the improved outcome. Conclusion: Our data for the first time demonstrate the efficacy of selective post-ischaemic IL-1β blockade in improving outcome following experimental ischaemia/reperfusion brain injury in the mouse and encourage further focused clinical studies assessing the potential of the approved IL-1β antibody Canakinumab, as an adjuvant therapy to thrombolysis in acute ischaemic stroke patients.
Aims: The CANTOS trial underscored the efficacy of selective antibody-based interleukin (IL)-1β inhibition with Canakinumab in secondary prevention of cardiovascular events. Despite the success of the trial, incidence of stroke was not reduced likely due to the low number of events and the relatively young age of patients enrolled. Given the established role of IL-1β in stroke, we tested the efficacy of the murineCanakinumab-equivalent antibody in a mouse model of ischaemic stroke. To mimic the clinical scenario of modern stroke management, IL-1β inhibition was performed post-ischaemically upon reperfusion as it would be the case in patients presenting to the emergency room and eligible for thrombolytic therapy. Methods and results: Transient middle cerebral artery occlusion (tMCAO) was performed in wild type mice; upon reperfusion, mice were randomly allocated to anti-IL-1β antibody or vehicle treatment. Following tMCAO, cerebral IL-1β levels, unlike tumour necrosis factor-α, were increased underscoring a role for this cytokine. Post-ischaemic treatment with IL-1β antibody reduced infarct size, cerebral oedema and improved neurological performance as assessed by 2,3,5-triphenyltetrazolium chloride staining, Bederson and RotaRod tests. Antibody-treated animals also exhibited a reduced neutrophil and matrix metalloproteinase (MMP)-2 but not MMP-9, activity in ipsilateral hemispheres as compared to vehicle-treated mice. Noteworthy, tMCAO associated vascular endothelial-cadherin reduction was blunted in IL-1β antibody-treated mice compared to vehicle-treated, likely providing the mechanistic explanation for the improved outcome. Conclusion: Our data for the first time demonstrate the efficacy of selective post-ischaemic IL-1β blockade in improving outcome following experimental ischaemia/reperfusion brain injury in the mouse and encourage further focused clinical studies assessing the potential of the approved IL-1β antibody Canakinumab, as an adjuvant therapy to thrombolysis in acute ischaemic strokepatients.
Authors: Nele Hermanns; Viola Wroblewski; Pablo Bascuñana; Bettina Wolf; Andras Polyak; Tobias L Ross; Frank M Bengel; James T Thackeray Journal: Basic Res Cardiol Date: 2022-10-24 Impact factor: 12.416
Authors: Alexander Akhmedov; Nicole R Bonetti; Martin F Reiner; Remo D Spescha; Heidi Amstalden; Mario Merlini; Daniel S Gaul; Candela Diaz-Cañestro; Sylvie Briand-Schumacher; Rebecca S Spescha; Aurora Semerano; Giacomo Giacalone; Gianluigi Savarese; Fabrizio Montecucco; Luka Kulic; Roger M Nitsch; Christian M Matter; Gerd A Kullak-Ublick; Maria Sessa; Thomas F Lüscher; Jürg H Beer; Luca Liberale; Giovanni G Camici Journal: J Cereb Blood Flow Metab Date: 2018-08-03 Impact factor: 6.200
Authors: Tobias Borchert; Annika Hess; Mario Lukačević; Tobias L Ross; Frank M Bengel; James T Thackeray Journal: Eur J Nucl Med Mol Imaging Date: 2020-03-03 Impact factor: 9.236
Authors: Luca Liberale; Erik W Holy; Alexander Akhmedov; Nicole R Bonetti; Fabian Nietlispach; Christian M Matter; François Mach; Fabrizio Montecucco; Jürg H Beer; Francesco Paneni; Frank Ruschitzka; Peter Libby; Thomas F Lüscher; Giovanni G Camici Journal: J Clin Med Date: 2019-11-26 Impact factor: 4.241