Combination treatment with U0126 and rt-PA prevents adverse effects of the delayed rt-PA treatment after acute ischemic stroke
Orset, Cyrille ; Arkelius, Kajsa LU ; Anfray, Antoine ; Warfvinge, Karin LU
; Vivien, Denis
and Ansar, Saema
LU
(2021)
In Scientific Reports
11.
- 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... (More)
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.
(Less)
- author
- Orset, Cyrille
; Arkelius, Kajsa
LU
; Anfray, Antoine
; Warfvinge, Karin
LU
; Vivien, Denis
and Ansar, Saema
LU
- organization
- publishing date
- 2021-12
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Scientific Reports
- volume
- 11
- article number
- 11993
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:34099834
- scopus:85107547364
- ISSN
- 2045-2322
- DOI
- 10.1038/s41598-021-91469-9
- language
- English
- LU publication?
- yes
- id
- 2278b442-cd24-4e47-bf9e-ab68919fd8f7
- date added to LUP
- 2021-07-01 14:15:40
- date last changed
- 2025-01-26 12:20:44
@article{2278b442-cd24-4e47-bf9e-ab68919fd8f7,
abstract = {{<p>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.</p>}},
author = {{Orset, Cyrille and Arkelius, Kajsa and Anfray, Antoine and Warfvinge, Karin and Vivien, Denis and Ansar, Saema}},
issn = {{2045-2322}},
language = {{eng}},
publisher = {{Nature Publishing Group}},
series = {{Scientific Reports}},
title = {{Combination treatment with U0126 and rt-PA prevents adverse effects of the delayed rt-PA treatment after acute ischemic stroke}},
url = {{http://dx.doi.org/10.1038/s41598-021-91469-9}},
doi = {{10.1038/s41598-021-91469-9}},
volume = {{11}},
year = {{2021}},
}