Dataset Information

A Canine Model of Hemorrhagic Transformation Using Recombinant Tissue Plasminogen Activator Administration After Acute Ischemic Stroke.

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.

SUBMITTER: Jiang RH

PROVIDER: S-EPMC6603151 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A Canine Model of Hemorrhagic Transformation Using Recombinant Tissue Plasminogen Activator Administration After Acute Ischemic Stroke.

Jiang Run-Hao RH Zu Qing-Quan QQ Xu Xiao-Quan XQ Wang Bin B Ding Ye Y Wang Jun J Liu Sheng S Shi Hai-Bin HB

Frontiers in neurology 20190625

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 clot ...[more]

PMID: 31293509

Similar Datasets

Project description:An angiogenesis factor, angiopoietin-1 (Ang1), is associated with the blood-brain barrier (BBB) disruption after focal cerebral ischemia. However, whether hemorrhagic transformation and cerebral edema after tissue plasminogen activator (tPA) treatment are related to the decrease in Ang1 expression in the BBB remains unknown. We hypothesized that administering Ang1 might attenuate hemorrhagic transformation and cerebral edema after tPA treatment by stabilizing blood vessels and inhibiting hyperpermeability. Sprague-Dawley rats subjected to thromboembolic focal cerebral ischemia were assigned to a permanent ischemia group (permanent middle cerebral artery occlusion; PMCAO) and groups treated with tPA at 1 h or 4 h after ischemia. Endogenous Ang1 expression was observed in pericytes, astrocytes, and neuronal cells. Western blot analyses revealed that Ang1 expression levels on the ischemic side of the cerebral cortex were decreased in the tPA-1h, tPA-4h, and PMCAO groups as compared to those in the control group (P = 0.014, 0.003, and 0.014, respectively). Ang1-positive vessel densities in the tPA-4h and PMCAO groups were less than that in the control group (p = 0.002 and <0.001, respectively) as well as that in the tPA-1h group (p = 0.047 and 0.005, respectively). These results suggest that Ang1-positive vessel density was maintained when tPA was administered within the therapeutic time window (1 h), while it was decreased when tPA treatment was given after the therapeutic time window (4 h). Administering Ang1 fused with cartilage oligomeric protein (COMP) to supplement this decrease has the potential to suppress hemorrhagic transformation as measured by hemoglobin content in a whole cerebral homogenate (p = 0.007) and cerebral edema due to BBB damage (p = 0.038), as compared to administering COMP protein alone. In conclusion, Ang1 might be a promising target molecule for developing vasoprotective therapies for controlling hemorrhagic transformation and cerebral edema after tPA treatment.

Project description:BackgroundHemorrhagic transformation (HT) is a critical issue in thrombolytic therapy in acute ischemic stroke. Damage-associated molecular pattern (DAMP)-stimulated sterile neuroinflammation plays a crucial role in the development of thrombolysis-associated HT. Our previous study showed that the phthalide derivative CD21 attenuated neuroinflammation and brain injury in rodent models of ischemic stroke. The present study explored the effects and underlying mechanism of action of CD21 on tissue plasminogen activator (tPA)-induced HT in a mouse model of transient middle cerebral artery occlusion (tMCAO) and cultured primary microglial cells.MethodsThe tMCAO model was induced by 2 h occlusion of the left middle cerebral artery with polylysine-coated sutures in wildtype (WT) mice and macrophage scavenger receptor 1 knockout (MSR1-/-) mice. At the onset of reperfusion, tPA (10 mg/kg) was intravenously administered within 30 min, followed by an intravenous injection of CD21 (13.79 mg/kg/day). Neuropathological changes were detected in mice 3 days after surgery. The effect of CD21 on phagocytosis of the DAMP peroxiredoxin 1 (Prx1) in lysosomes was observed in cultured primary microglial cells from brain tissues of WT and MSR1-/- mice.ResultsSeventy-two hours after brain ischemia, CD21 significantly attenuated neurobehavioral dysfunction and infarct volume. The tPA-infused group exhibited more severe brain dysfunction and hemorrhage. Compared with tPA alone, combined treatment with tPA and CD21 significantly attenuated ischemic brain injury and hemorrhage. Combined treatment significantly decreased Evans blue extravasation, matrix metalloproteinase 9 expression and activity, extracellular Prx1 content, proinflammatory cytokine mRNA levels, glial cells, and Toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB) pathway activation and increased the expression of tight junction proteins (zonula occludens-1 and claudin-5), V-maf musculoaponeurotic fibrosarcoma oncogene homolog B, and MSR1. MSR1 knockout significantly abolished the protective effect of CD21 against tPA-induced HT in tMCAO mice. Moreover, the CD21-induced phagocytosis of Prx1 was MSR1-dependent in cultured primary microglial cells from WT and MSR1-/- mice, respectively.ConclusionThe phthalide derivative CD21 attenuated tPA-induced HT in acute ischemic stroke by promoting MSR1-induced DAMP (Prx1) clearance and inhibition of the TLR4/NF-κB pathway and neuroinflammation.

Dataset Information

A Canine Model of Hemorrhagic Transformation Using Recombinant Tissue Plasminogen Activator Administration After Acute Ischemic Stroke.

Publications

A Canine Model of Hemorrhagic Transformation Using Recombinant Tissue Plasminogen Activator Administration After Acute Ischemic Stroke.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets