Edaravone, a free radical scavenger, Inhibits MMP-9-Related brain hemorrhage in rats treated with tissue plasminogen activator

Abstract

Cerebral infarction 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-κb) 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-κb 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-κb activation in hbecs. Edaravone may render thrombolytic therapy safer for the administration of rtpa in patients with ischemic stroke. © 2009 american heart association, inc.