Edaravone, a free radical scavenger, inhibits MMP-9-related brain hemorrhage in rats treated with tissue plasminogen activator.

Abstract

BACKGROUND AND PURPOSE:

Intracerebral hemorrhage, induced by recombinant tissue plasminogen activator (rtPA) in ischemic stroke, is attributable to the increased activity of matrix metalloproteinase-9 (MMP-9). Patients with acute infarct benefit from the neuroprotective drug edaravone, a free radical scavenger. We examined the mechanisms by which edaravone may help to suppress rtPA-induced brain hemorrhage.

METHODS:

Male Wistar rats weighing 250 to 280 g were subjected to 3-hour transient middle cerebral artery occlusion (MCAO) and divided randomly into 3 groups. Immediately after reperfusion, 1 group was intravenously injected with 10 mg/kg rtPA, another with rtPA plus 3 mg/kg edaravone, and the 3rd group received no treatment. We assessed the hemorrhage volume and the activity of MMP-9 in the brain 24 hours postischemia. We also studied the activity of MMP-9, its mRNA expression, and nuclear factor-kappa B (NF-kappaB) activity in rtPA-stimulated human microvascular endothelial cells (HBECs).

RESULTS:

The degree of hemorrhage and the level of endothelial cell-derived MMP-9 were elevated in rats treated with rtPA alone and attenuated in rats treated with rtPA plus edaravone. In rtPA-stimulated HBECs, edaravone suppressed the activity and mRNA expression of MMP-9 in a dose-dependent manner. Edaravone also inhibited NF-kappaB activation.

CONCLUSIONS:

We demonstrate that edaravone inhibits rtPA-induced cerebral hemorrhage in the ischemic brain of rats via the inhibition of MMP-9 expression in vivo, which is substantiated by inhibition of MMP-9 expression and NF-kappaB activation in HBECs. Edaravone may render thrombolytic therapy safer for the administration of rtPA in patients with ischemic stroke.

• Authors: Kenji Yagi, Keiko T Kitazato, Masaaki Uno, Yoshiteru Tada, Tomoya Kinouchi, Kenji Shimada, Shinji Nagahiro
• Journal: Stroke (Stroke) Vol. 40 Issue 2 Pg. 626-31 (Feb 2009) ISSN: 1524-4628 [Electronic] United States
• PMID: 19095969 (Publication Type: Journal Article)

Chemical References

• Free Radical Scavengers
• Matrix Metalloproteinase Inhibitors
• NF-kappa B
• RNA, Messenger
• Tissue Plasminogen Activator
• Edaravone
• Antipyrine

Topics

• Animals
• Antipyrine (analogs & derivatives, pharmacology)
• Blood Pressure (physiology)
• Blotting, Western
• Brain Ischemia (drug therapy, pathology)
• Cells, Cultured
• Cerebral Hemorrhage (drug therapy, enzymology)
• Dose-Response Relationship, Drug
• Edaravone
• Endothelial Cells (drug effects, metabolism)
• Free Radical Scavengers (pharmacology)
• Immunohistochemistry
• Infarction, Middle Cerebral Artery (pathology)
• Male
• Matrix Metalloproteinase Inhibitors
• Middle Cerebral Artery (physiology)
• NF-kappa B (metabolism)
• RNA, Messenger (biosynthesis, genetics)
• Rats
• Rats, Wistar
• Reperfusion Injury (drug therapy, pathology)
• Reverse Transcriptase Polymerase Chain Reaction
• Tissue Plasminogen Activator (pharmacology)