Combination treatment with U0126 and rt-PA prevents adverse effects of the delayed rt-PA treatment after acute ischemic stroke

Abstract In acute ischemic stroke, the only FDA-approved drug; recombinant tissue plasminogen activator (rt-PA) is limited by restricted time-window due to an enhanced risk of hemorrhagic transformation which is thought to be caused by metalloproteinase (MMP). In experimental stroke inhibitors of th...

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Autores principales:	Cyrille Orset, Kajsa Arkelius, Antoine Anfray, Karin Warfvinge, Denis Vivien, Saema Ansar
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/49c1907db9404eb5a063005ab022e9b9
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spelling	oai:doaj.org-article:49c1907db9404eb5a063005ab022e9b92021-12-02T17:52:11ZCombination treatment with U0126 and rt-PA prevents adverse effects of the delayed rt-PA treatment after acute ischemic stroke10.1038/s41598-021-91469-92045-2322https://doaj.org/article/49c1907db9404eb5a063005ab022e9b92021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91469-9https://doaj.org/toc/2045-2322Abstract In acute ischemic stroke, the only FDA-approved drug; recombinant tissue plasminogen activator (rt-PA) is limited by restricted time-window due to an enhanced risk of hemorrhagic transformation which is thought to be caused by metalloproteinase (MMP). In experimental stroke inhibitors of the mitogen–activated protein kinase kinase extracellular signal–regulated kinase kinase (MEK) 1/2 pathways reduce the MMPs. This study evaluated whether a MEK1/2 inhibitor in combination with rt-PA can prevent the detrimental effects of delayed rt-PA therapy in stroke. Thromboembolic stroke was induced in C57 black/6J mice and the MEK1/2 inhibitor U0126 was administrated 3.5 h and rt-PA 4 h post stroke-onset. Treatment with rt-PA demonstrated enhanced MMP-9 protein levels and hemorrhagic transformation which was prevented when U0126 was given in conjunction with rt-PA. By blocking the MMP-9 with U0126 the safety of rt-PA administration was improved and demonstrates a promising adjuvant strategy to reduce the harmful effects of delayed rt-PA treatment in acute ischemic stroke.Cyrille OrsetKajsa ArkeliusAntoine AnfrayKarin WarfvingeDenis VivienSaema AnsarNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Cyrille Orset Kajsa Arkelius Antoine Anfray Karin Warfvinge Denis Vivien Saema Ansar Combination treatment with U0126 and rt-PA prevents adverse effects of the delayed rt-PA treatment after acute ischemic stroke
description	Abstract In acute ischemic stroke, the only FDA-approved drug; recombinant tissue plasminogen activator (rt-PA) is limited by restricted time-window due to an enhanced risk of hemorrhagic transformation which is thought to be caused by metalloproteinase (MMP). In experimental stroke inhibitors of the mitogen–activated protein kinase kinase extracellular signal–regulated kinase kinase (MEK) 1/2 pathways reduce the MMPs. This study evaluated whether a MEK1/2 inhibitor in combination with rt-PA can prevent the detrimental effects of delayed rt-PA therapy in stroke. Thromboembolic stroke was induced in C57 black/6J mice and the MEK1/2 inhibitor U0126 was administrated 3.5 h and rt-PA 4 h post stroke-onset. Treatment with rt-PA demonstrated enhanced MMP-9 protein levels and hemorrhagic transformation which was prevented when U0126 was given in conjunction with rt-PA. By blocking the MMP-9 with U0126 the safety of rt-PA administration was improved and demonstrates a promising adjuvant strategy to reduce the harmful effects of delayed rt-PA treatment in acute ischemic stroke.
format	article
author	Cyrille Orset Kajsa Arkelius Antoine Anfray Karin Warfvinge Denis Vivien Saema Ansar
author_facet	Cyrille Orset Kajsa Arkelius Antoine Anfray Karin Warfvinge Denis Vivien Saema Ansar
author_sort	Cyrille Orset
title	Combination treatment with U0126 and rt-PA prevents adverse effects of the delayed rt-PA treatment after acute ischemic stroke
title_short	Combination treatment with U0126 and rt-PA prevents adverse effects of the delayed rt-PA treatment after acute ischemic stroke
title_full	Combination treatment with U0126 and rt-PA prevents adverse effects of the delayed rt-PA treatment after acute ischemic stroke
title_fullStr	Combination treatment with U0126 and rt-PA prevents adverse effects of the delayed rt-PA treatment after acute ischemic stroke
title_full_unstemmed	Combination treatment with U0126 and rt-PA prevents adverse effects of the delayed rt-PA treatment after acute ischemic stroke
title_sort	combination treatment with u0126 and rt-pa prevents adverse effects of the delayed rt-pa treatment after acute ischemic stroke
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/49c1907db9404eb5a063005ab022e9b9
work_keys_str_mv	AT cyrilleorset combinationtreatmentwithu0126andrtpapreventsadverseeffectsofthedelayedrtpatreatmentafteracuteischemicstroke AT kajsaarkelius combinationtreatmentwithu0126andrtpapreventsadverseeffectsofthedelayedrtpatreatmentafteracuteischemicstroke AT antoineanfray combinationtreatmentwithu0126andrtpapreventsadverseeffectsofthedelayedrtpatreatmentafteracuteischemicstroke AT karinwarfvinge combinationtreatmentwithu0126andrtpapreventsadverseeffectsofthedelayedrtpatreatmentafteracuteischemicstroke AT denisvivien combinationtreatmentwithu0126andrtpapreventsadverseeffectsofthedelayedrtpatreatmentafteracuteischemicstroke AT saemaansar combinationtreatmentwithu0126andrtpapreventsadverseeffectsofthedelayedrtpatreatmentafteracuteischemicstroke
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Combination treatment with U0126 and rt-PA prevents adverse effects of the delayed rt-PA treatment after acute ischemic stroke

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