Baicalin reduces hemorrhagic transformation of rat ischemic stroke with delayed T-PA treatment

Abstract

Hemorrhagic transformation (HT) is the severe complication of delayed tissue plasminogen activator (t-PA) treatment in ischemic stroke. Previously we showed that targeting peroxynitrite attenuated HT and improved neurological outcomes in ischemic stroke with thrombolytic therapy. Here we test the hypothesis that baicalin, a natural compound capable of scavenging peroxynitrite, could reduce HT in a rat cerebral ischemia-reperfusion model with delayed t-PA treatment, through targeting peroxynitrite-MMP-9 signaling. Male Sprague-Dawley (SD) rats were subjected to middle cerebral artery occlusion (MCAO) 5 hours plus reperfusion 19 hours. T-PA (10 mg/kg) or t-PA plus baicalin (50, 100, 150 mg/kg) was administrated via femoral vein at 4.5 hours after MCAO. Delayed t-PA treatment increased the mortality rates and further exacerbated blood brain barrier (BBB) permeability in surviving rats, leading to HT, increasement of brain edema, and exacerbation of neurological outcomes. Such deleterious effects of t-PA were dose-dependently and significantly attenuated by baicalin co-treatment. Delayed t-PA treatment increased 3-NT (a biomarker of peroxynitrite) formation, leading to MMP-9 overproduction and tight junction ZO-1 reduction, which were also significantly reversed by baicalin co-treatment. Taken together, baicalin could be a potential combination compound to reduce HT and other complications induced by delayed t-PA treatment, possibly via inhibiting peroxynitrite mediated MMP-9 production. Copyright © 2016 Published by Elsevier Inc.