Okubo S, Igarashi H, Kanamatsu T, Hasegawa D, Orima H, Katayama YFK-506 extended the therapeutic time window for thrombolysis without increasing the risk of hemorrhagic transformation in an embolic rat stroke model. Brain Res 1143:221-227
Division of Neurology, Nephrology and Rheumatology, Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Brain Research
(Impact Factor: 2.84).
05/2007; 1143(1):221-7. DOI: 10.1016/j.brainres.2007.01.050
FK-506 confers a neuroprotective effect and is thought to extend the time window for thrombolytic treatment of cerebral ischemia. These effects have not been assessed in an embolic stroke model. In addition, clinical studies have raised concern that FK-506 may increase the risk of hemorrhagic transformation by damaging vascular endothelial cells. We investigated whether combined administration of recombinant tissue plasminogen activator (rt-PA) and FK-506 would extend the therapeutic time window without increasing the hemorrhagic transformation in a rat embolic stroke model. Male Sprague-Dawley rats (n=66) were subjected to embolic infarction and assigned into eight groups. Six of the groups were treated with or without FK-506 (0.3 mg/kg) administration at 60 min after embolization, together with and all six groups received systemic rt-PA administration (10 mg/kg) at 60, 90, or 120 min. Two permanent ischemia groups were administered saline either with or without FK-506. Infarct and hemorrhagic volume were assessed at 24 h after embolization. Diffusion-weighted and perfusion-weighted magnetic resonance imaging (MRI) were performed in the groups administered rt-PA at 90 min and a vehicle control group to assess whether FK-506 influenced the effectiveness of MRI in revealing ischemic lesion. FK-506 extended the therapeutic time window for systemic thrombolysis compared to rt-PA alone without increasing the risk for hemorrhage. Combined therapy with FK-506 salvaged some of the MRI, revealing ischemic lesions destined to infarction in the animals treated by rt-PA alone. Single low dose of FK-506 alone did not ameliorate the embolic infarction, but it did prove effective in extending the therapeutic time windows for thrombolysis without increasing the risk of hemorrhagic transformation.
Available from: Hironaka Igarashi
- "The hemorrhagic transformation that occurs after tPA treatment is thought to be caused by damage of the blood brain barrier (BBB). We previously demonstrated that tPA treatment after the therapeutic time window promoted expression of an endothelial cell–specific growth factor, vascular endothelial cell growth factor (VEGF), in BBB, MMP-9 activation, degradation of BBB components, and hemorrhagic transformation using a rat model of thromboembolic focal cerebral ischemia ,. Compared with tPA and control antibody, combination treatment with tPA and the anti-VEGF neutralizing antibody significantly attenuated VEGF expression in BBB, MMP-9 activation, degradation of BBB components, and hemorrhagic transformation, and it also improved motor outcome and mortality . "
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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.
PLoS ONE 06/2014; 9(6):e98639. DOI:10.1371/journal.pone.0098639 · 3.23 Impact Factor
Available from: Axel Montagne
- "It enhances thrombus dissolution and prevents microthrombosis. Combination treatment is superior to each treatment performed alone Su et al (2008) Imatinib (PDGFR-a antagonist) Imatinib reduces cerebrovascular permeability and hemorrhagic transformation after late thrombolysis Okubo et al (2007) FK-506 (tacrolimus) FK-506 increases therapeutic window of tPA without increasing the risk of hemorrhagic transformation Romanos et al (2007) Uric acid (UA) UA reduces tyrosine nitration, reduces brain neutrophil infiltration and further increases the benefits of thrombolysis Cheng et al (2006) Activated Protein C (APC) APC inhibits tPA-induced MMP9 pathway and reduces tPA-mediated hemorrhage Armstead et al (2006) EEIIMD (hexapeptide) EEIIMD abolishes tPA-induced increase in infarct size and intracranial bleeding Chen et al (2006) Melatonin Melatonin attenuates BBB permeability and hemorrhagic transformation after thrombolysis NMDA, N-methyl-D-aspartate; tPA, tissue-type plasminogen activator; MMP, metalloproteinase; LRP, lipoprotein receptor-related protein; PPARg, peroxisome proliferator-activated receptor gamma; PDGFR-a, platelet-derived growth factor receptor a; BBB, blood–brain barrier. "
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ABSTRACT: About 15 million strokes occur each year worldwide. As the number one cause of morbidity and acquired disability, stroke is a major drain on public health-care funding, due to long hospital stays followed by ongoing support in the community or nursing-home care. Although during the last 10 years we have witnessed a remarkable progress in the understanding of the pathophysiology of ischemic stroke, reperfusion induced by recombinant tissue-type plasminogen activator (tPA-Actilyse) remains the only approved acute treatment by the health authorities. The objective of the present review is to provide an overview of our present knowledge about the impact of tPA on the neurovascular unit during acute ischemic stroke.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 08/2011; 31(11):2119-34. DOI:10.1038/jcbfm.2011.127 · 5.41 Impact Factor
Available from: Takayoshi Shimohata
- "A catheter was inserted into the tail artery of the rats for blood pressure measurement and blood gas analysis . The level of cerebral cortical blood flow ( CCBF ) was monitored by laser Doppler flowmetry as described previously ( Okubo et al , 2007 ) . Briefly , a Plexiglass tube was mounted onto the skull to aid placement . "
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ABSTRACT: An angiogenic factor, vascular endothelial growth factor (VEGF), might be associated with the blood-brain barrier (BBB) disruption after focal cerebral ischemia; however, it remains unknown whether hemorrhagic transformation (HT) after tissue plasminogen activator (tPA) treatment is related to the activation of VEGF signaling pathway in BBB. Here, we hypothesized that inhibition of VEGF signaling pathway can attenuate HT after tPA treatment. Rats subjected to thromboembolic focal cerebral ischemia were assigned to a permanent ischemia group and groups treated with tPA at 1 or 4 hours after ischemia. Anti-VEGF neutralizing antibody or control antibody was administered simultaneously with tPA. At 24 hours after ischemia, we evaluated the effects of the antibody on the VEGF expression, matrix metalloproteinase-9 (MMP-9) activation, degradation of BBB components, and HT. Delayed tPA treatment at 4 hours after ischemia promoted expression of VEGF in BBB, MMP-9 activation, degradation of BBB components, and HT. Compared with tPA and control antibody, combination treatment with tPA and the anti-VEGF neutralizing antibody significantly attenuated VEGF expression in BBB, MMP-9 activation, degradation of BBB components, and HT. It also improved motor outcome and mortality. Inhibition of VEGF signaling pathway may be a promising therapeutic strategy for attenuating HT after tPA treatment.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 02/2011; 31(6):1461-74. DOI:10.1038/jcbfm.2011.9 · 5.41 Impact Factor
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