Edaravone, a free radical scavenger, inhibits MMP-9-related brain hemorrhage in rats treated with tissue plasminogen activator.
OBJECTIVE
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.
Yagi
Kenji
K
Department of Neurosurgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan. kenji-yagi@mail.goo.ne.jp
Kitazato
Keiko T
KT
Uno
Masaaki
M
Tada
Yoshiteru
Y
Kinouchi
Tomoya
T
Shimada
Kenji
K
Nagahiro
Shinji
S
D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001794:Blood Pressure / Q000502:physiology; D015153:Blotting, Western; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology; D002478:Cells, Cultured; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D000077553:Edaravone; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology*; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020768:Middle Cerebral Artery / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
D016166:Free Radical Scavengers; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D012333:RNA, Messenger; D010959:Tissue Plasminogen Activator; D000077553:Edaravone; D000983:Antipyrine