Abstract
Early reperfusion of occluded arteries via recombinant tissue plasminogen activator (rtPA) administration is considered to be an effective strategy for the treatment of acute ischemic stroke. However, delayed administration of rtPA may cause severe hemorrhagic transformation (HT) and undesirable neurological outcomes. The current study aims to establish a canine HT model using rtPA administration and to investigate the potential mechanisms underlying HT. Following anesthesia, two autologous clots were injected into the middle cerebral artery (MCA) to induce ischemic stroke. To induce reperfusion, rtPA (2 mg/kg) was administrated intravenously 4.5 h after the establishment of stroke. The occurrence of HT was determined by computed tomography (CT) and by pathological assessment. Transmission electron microscopy was utilized to assess blood-brain barrier (BBB) damage. The expression of matrix metalloprotein 9 (MMP-9) was analyzed by enzyme linked immunosorbent assay (ELISA), immunofluorescence (IF), and western blot. Administration of rtPA 4.5 h after stroke induced reperfusion in 73.9% of the canines, caused evident HT, and did not improve neurological outcomes compared to canines that did not receive rtPA. There was a significant increase in expression of MMP-9 after rtPA administration, accompanied by BBB disruption. We have established a canine HT model that closely mimics human HT by using rtPA administration after the induction of middle cerebral artery occlusion (MCAO) with autologous clots. Our data suggest that a potential mechanism underlying rtPA-caused HT may be related to BBB dysfunction induced by an increase in MMP-9 expression.
Highlights
Acute ischemic stroke is a leading cause of death and disability worldwide [1]
We recently described an endovascular canine stroke model based on middle cerebral artery occlusion (MCAO) with autologous clots that is highly suitable for the study of ischemic stroke [11]
There were no significant difference in the mortality rate between the MCAO (2/11) and MCAO + recombinant tissue plasminogen activator (rtPA) groups (4/27)
Summary
Administration of the thrombolytic agent recombinant tissue plasminogen activator (rtPA) is the primary strategy for the treatment of ischemic stroke [2, 3]. In addition to its narrow therapeutic time window (within 4.5 h for intravenous administration after stroke onset), rtPA may induce. It has been reported that HT occurs in 20–40% of patients that receive rtPA treatment [4, 5]. Due to these limitations, few stroke patients can truly benefit from rtPAmediated thrombolysis. There is an urgent need to analyze the molecular mechanisms underlying rtPA-induced HT in order to improve the safety of rtPA administration and advance its clinical application
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