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Effects of angiopoietin-1 on hemorrhagic transformation and cerebral edema after tissue plasminogen activator treatment for ischemic stroke in rats.

ABSTRACT: 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.

SUBMITTER: Kawamura K

PROVIDER: S-EPMC4045756 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Effects of angiopoietin-1 on hemorrhagic transformation and cerebral edema after tissue plasminogen activator treatment for ischemic stroke in rats.

Kawamura Kunio K Takahashi Tetsuya T Kanazawa Masato M Igarashi Hironaka H Nakada Tsutomu T Nishizawa Masatoyo M Shimohata Takayoshi T

PloS one 20140604 6

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 hyperpe ...[more]

PMID: 24896569

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Project description:Background: Thrombolysis with tissue plasminogen activator (tPA) remains the only approved drug therapy for acute ischemic stroke. However, delayed tPA treatment is associated with an increased risk of brain hemorrhage. In this study, we assessed whether QiShenYiQi (QSYQ), a compound Chinese medicine, can attenuate tPA-induced brain edema and hemorrhage in an experimental stroke model. Methods: Male mice were subjected to ferric chloride-induced carotid artery thrombosis followed by mechanical detachment of thrombi. Then mice were treated with QSYQ at 2.5 h followed by administration of tPA (10 mg/kg) at 4.5 h. Hemorrhage, infarct size, neurological score, cerebral blood flow, Evans blue extravasation, FITC-labeled albumin leakage, tight and adherens junction proteins expression, basement membrane proteins expression, matrix metalloproteinases (MMPs) expression, leukocyte adhesion, and leukocyte infiltration were assessed 24 h after tPA administration. Results: Compared with tPA alone treatments, the combination therapy of QSYQ and tPA significantly reduced hemorrhage, infarction, brain edema, Evans blue extravasation, albumin leakage, leukocyte adhesion, MMP-9 expression, and leukocyte infiltration at 28.5 h after stroke. The combination also significantly improved the survival rate, cerebral blood flow, tight and adherens junction proteins (occludin, claudin-5, junctional adhesion molecule-1, zonula occludens-1, VE-cadherin, α-catenin, β-catenin) expression, and basement membrane proteins (collagen IV, laminin) expression. Addition of QSYQ protected the downregulated ATP 5D and upregulated p-Src and Caveolin-1 after tPA treatment. Conclusion: Our results show that QSYQ inhibits tPA-induced brain edema and hemorrhage by protecting the blood-brain barrier integrity, which was partly attributable to restoration of energy metabolism, protection of inflammation and Src/Caveolin signaling activation. The present study supports QSYQ as an effective adjunctive therapy to increase the safety of delayed tPA thrombolysis for ischemic stroke.

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.

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Effects of angiopoietin-1 on hemorrhagic transformation and cerebral edema after tissue plasminogen activator treatment for ischemic stroke in rats.

Publications

Effects of angiopoietin-1 on hemorrhagic transformation and cerebral edema after tissue plasminogen activator treatment for ischemic stroke in rats.

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