Baicalin reduces hemorrhagic transformation in ischemic stroke rats with delayed t-PA treatment: involvement of ONOO–MMP-9 pathway

Abstract

OBJECTIVE: Hemorrhagic transformation (HT) is the severe complication of delayed tissue plasminogen activator (t-PA) treatment in ischemic stroke. Previously we found that peroxynitrite (ONOO-) plays an important role in HT after t-PA treatment. Here we test the CONCLUSIONS: Unerupted permanent incisors could be associated with other dental anomalies. Clinicians should be aware of such an association and thereby should look for presence of any dental anomalies in patients with unerupted incisors. hypothesis that baicalin, a highly-safe natural compound capable of scavenging peroxynitrite, could attenuate HT in a rat cerebral ischemia-reperfusion model with delayed t-PA treatment. METHODS: 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. RESULTS: Delayed t-PA treatment significantly increased the mortality rate, induced hemorrhagic transformation, and exacerbated blood-brain barrier (BBB) permeability, brain edema, and neurological deficit at 24 hours after ischemia. Such deleterious effects of t-PA were dosedependently and significantly attenuated by baicalin cotreatment. Delayed t-PA treatment substantially increased 3-NT (a biomarker of peroxynitrite) formation in ischemic hemispheres, leading to active MMP-9 overproduction, which were also greatly prevented by baicalin cotreatment. CONCLUSION: Baicalin is a potential candidate for combination therapy in ischemic stroke to reduce HT and other complications induced by delayed t-PA treatment, possibly via inhibiting ONOO- mediated active MMP-9 production. REFERENCES [1] Chen, H.S.; Chen, X.M.; Feng, J.H.; Liu, K.J.; Qi, S.H.; Shen, J.G. Peroxynitrite Decomposition Catalyst Reduces Delayed Thrombolysis-induced Hemorrhagic Transformation in Ischemiareperfused Rat Brains. CNS neuroscience & therapeutics, 2015, 21(7), 585–590. [2] Xu, M.; Chen, X.; Gu, Y.; Peng, T.; Yang, D.; Chang, R.C.-C.; So, K.-F.; Liu, K.; Shen, J. Baicalin can scavenge peroxynitrite and ameliorate endogenous peroxynitritemediated neurotoxicity in cerebral ischemia-reperfusion injury. J Ethnopharmacol, 2013, 150(1), 116–124.