Glycyrrhizin could inhibit HMGB1-MMP-9 signaling and prevent hemorrhagic transformation in ischemic stroke with delayed T-PA treatment

Abstract

Tissue plasminogen activator (t-PA) has restrict therapeutic window for ischemic stroke and hemorrhagic transformation (HT) is the major complications. High mobility group box protein 1 (HMGB1) and MMPs are critical targets for reducing HT. Glycyrrhizin is an antioxidant isolated from Glycyrrhiza glabra. We hypothesize that glycyrrhizin could inhibit HMGB1, MMPs, reduce HT and improve survival rates in ischemic stroke with delayed t-PA tretament. Male SD rats were subjected middle cerebral artery occlusion (MCAO) for 5 hours plus 19 hours of reperfusion. T-PA (10 mg/kg) was intravenously administrated at 4.5 hours after MCAO and continuously injected for 30 min. Glycyrrhizin (30 mg/kg) was administrated at onset of t-PA treatment and saline was used as control. Major discoveries are as below: (1) Delayed t-PA treatment had increased mortality rate, brain swelling, hemorrhagic transformation with the increase of HMGB1 and MMP-9 expression. (2) Glycyrrhizin significantly inhibited HMGB1 and MMP-9, attenuated HT, decreased mortality and improved neurological outcomes. In conclusion, glycyrrhizin could be an adjuvant therapy with t-PA to improve the therapeutic outcome for ischemic stroke. Copyright © 2016 Published by Elsevier Inc.