Baicalin Attenuates Blood-Brain Barrier Disruption and Hemorrhagic Transformation and Improves Neurological Outcome in Ischemic Stroke Rats with Delayed t-PA Treatment: Involvement of ONOO−-MMP-9 Pathway

Abstract

Tissue plasminogen activator (t-PA) has a restrictive therapeutic window within 4.5 h after ischemic stroke with the risk of hemorrhagic transformation (HT) and neurotoxicity when it is used beyond the time window. In the present study, we tested the hypothesis that baicalin, an active compound of medicinal plant, could attenuate HT in cerebral ischemia stroke with delayed t-PA treatment. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 4.5 h and then continuously received t-PA infusion (10 mg/kg) for 0.5 h and followed by 19-h reperfusion. Baicalin (50, 100, 150 mg/kg) was administrated via femoral vein at 4.5 h after MCAO cerebral ischemia. Delayed t-PA infusion significantly increased the mortality rate, induced HT, blood-brain barrier (BBB) damage, and apoptotic cell death in the ischemic brains and exacerbated neurological outcomes in cerebral ischemia-reperfusion rats at 24 h after MCAO cerebral ischemia. Co-treatment of baicalin significantly reduced the mortality rates, ameliorated the t-PA-mediated BBB disruption and HT. Furthermore, baicalin showed to directly scavenge peroxynitrite and inhibit MMP-9 expression and activity in the ischemic brains with the delayed t-PA treatment. Baicalin had no effect on the t-PA fibrinolytic function indicated by t-PA activity assay. Taken together, baicalin could attenuate t-PA-mediated HT and improve the outcomes of ischemic stroke treatment possibly via inhibiting peroxynitrite-mediated MMP-9 activation.

High Neutrophil-to-Platelet Ratio Is Associated With Hemorrhagic Transformation in Patients With Acute Ischemic Stroke

“…Moreover, the increase in matrix metalloproteinase-9 (MMP-9) during the inflammatory phase of ischemic stroke was related to HT, and a 24 h peak of MMP-9 occurred before PH (34). The inhibition of MMP-9 expression with baicalin could maintain the BBB integrity, attenuate thrombolysis-induced HT and improve the prognosis in patients with acute ischemic stroke (35). Several studies have indicated that neutrophil played an important role in the BBB disruption after stroke (22,36).…”

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

“…Despite that some astrocyte-derived factors maintain the BBB function, some astrocyte-derived factors damage the BBB by inducing endothelial cell apoptosis or decreasing the expression of endothelial tight junctionrelated proteins, which include vascular endothelial growth factor (VEGF) [204][205][206][207], glutamate [208][209][210], endothelins (ETs) [21,211,212], MMP [208,213,214], and nitric oxide (NO) [215,216] (Table 1). As zincendopeptidases, MMPs can directly degrade endothelial tight junction-related proteins and ECM molecules, which promotes angiogenesis whereas simultaneously increases BBB permeability [78,217,218]. And it is through the signaling pathway activating or suppressing MMPs that many other factors such as APOE, NO, and ETs get to affect the BBB integrity [201,212,215].…”

Neuroprotective and Cognitive Enhancement Potentials of Baicalin: A Review

“…In a recent study, baicalin administration significantly decreased the mortality rates, and ameliorated BBB disruption and hemorrhagic transformation. In addition, baicalin markedly scavenged peroxynitrite and inhibited MMP-9 expression and activity in MCAO-induced ischemic brains with delayed tissue plasminogen activator treatment [ 86 ]. The effect of baicalin on hyperglycemia-exacerbated cerebral ischemia/reperfusion injury in rats was investigated by Li et al [ 13 ].…”