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 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.

• Authors: Cyrille Orset, Kajsa Arkelius, Antoine Anfray, Karin Warfvinge, Denis Vivien, Saema Ansar
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 11993 (06 07 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 34099834 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Butadienes
• Nitriles
• U 0126
• Mitogen-Activated Protein Kinase Kinases
• Tissue Plasminogen Activator
• Matrix Metalloproteinase 9

Topics

• Animals
• Butadienes (pharmacokinetics, therapeutic use)
• Disease Models, Animal
• Drug Discovery
• Drug Therapy, Combination
• Drug-Related Side Effects and Adverse Reactions (prevention & control)
• Hemorrhage (prevention & control)
• Humans
• Ischemic Stroke (drug therapy)
• Male
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Nitriles (pharmacokinetics, therapeutic use)
• Signal Transduction
• Tissue Plasminogen Activator (pharmacology, therapeutic use)
• Treatment Outcome