A broad-spectrum matrix metalloproteinase inhibitor prevents hemorrhagic complications induced by tissue plasminogen activator in mice

Mishiro, Keisuke; Ishiguro, Mitsunori; Suzuki, Yukiya; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Hara, Hideaki

doi:10.1016/j.neuroscience.2011.12.042

Cited by 57 publications

(53 citation statements)

References 38 publications

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“…45 MMP-9 has been implicated in tPA-induced cerebral hemorrhage and BBB disruption in ischemic stroke. 6,46,47 We found that tPA infusion increases Evans blue dye extravasation in the ischemic hemisphere and PPK deficiency reduced this leakage. In addition, we also showed that PKal inhibition reversed the MMP-9 activity caused by tPA treatment.…”

Section: Discussionmentioning

confidence: 74%

Plasma kallikrein mediates brain hemorrhage and edema caused by tissue plasminogen activator therapy in mice after stroke

Simão

Üstünkaya

Clermont

et al. 2017

Blood

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Section: Discussionmentioning

confidence: 74%

Plasma kallikrein mediates brain hemorrhage and edema caused by tissue plasminogen activator therapy in mice after stroke

Simão

Üstünkaya

Clermont

et al. 2017

Blood

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“…We know that after cerebral ischemia, matrix metalloproteinases, a family of zinc-binding proteolytic enzymes, participate in the disruption of the BBB by degrading the major components of basal lamina surrounding the microvessels. 11 Several studies suggest a strong relationship between metalloproteinase-9 (MMP-9) induction and tPA-induced hemorrhage both in animal models of ischemic injury 12,13 and in stroke patients, 14 suggesting that MMP-9 inhibition may be an important strategy to prevent hemorrhagic complications induced by delayed tPA treatment after ischemia.…”

Section: Introductionmentioning

confidence: 99%

Progesterone Attenuates Hemorrhagic Transformation after Delayed tPA Treatment in an Experimental Model of Stroke in Rats: Involvement of the VEGF–MMP Pathway

Won

Lee

Wali

et al. 2013

J Cereb Blood Flow Metab

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Tissue plasminogen activator (tPA) is the only FDA-approved treatment for acute stroke, but its use remains limited. Progesterone (PROG) has shown neuroprotection in ischemia, but before clinical testing, we must determine how it affects hemorrhagic transformation in tPA-treated ischemic rats. Male Sprague-Dawley rats underwent middle cerebral artery occlusion with reperfusion at 4.5 hours and tPA treatment at 4.5 hours, or PROG treatment intraperitoneally at 2 hours followed by subcutaneous injection at 6 hours post occlusion. Rats were killed at 24 hours and brains evaluated for cerebral hemorrhage, swelling, blood-brain barrier (BBB) permeability, and levels of matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor level (VEGF), and tight junction (TJ) proteins. We also evaluated PROG's efficacy in preventing tPA-induced impairment of transendothelial electrical resistance (TEER) and TJ proteins under hypoxia/reoxygenation in the endothelial cells. Delayed tPA treatment induced significant hemorrhagic conversion and brain swelling. Treatment with PROG plus tPA ameliorated hemorrhage, hemispheric swelling, BBB permeability, MMP-9 induction, and VEGF levels compared with controls. Progesterone treatment significantly prevented tPA-induced decrease in TEER and expression of occludin and claudin-5, and attenuated VEGF levels in culture media subjected to hypoxia. The study concluded that PROG may extend the time window for tPA administration in ischemic stroke and reduce hemorrhagic conversion.

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“…1,2 Tissue-type plasminogen activator (tPA) may enhance expression and activity of MMPs, particularly matrix metalloproteinase-9 (MMP9). 3 MMP antagonists administered to animals treated with tPA lower the risk of hemorrhagic transformation 4 and reduce infarct volume. 5 MMPs have been poorly explored in the human stroke setting.…”

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confidence: 99%

MMP9 Variation After Thrombolysis Is Associated With Hemorrhagic Transformation of Lesion and Death

Inzitari

Giusti

Nencini

et al. 2013

Stroke

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Eligible were patients admitted for thrombolysis in 14 Italian centers and were registered in the Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR), according to SITS-Monitoring Study criteria. 6 Study protocol was approved from each ethical committee, and all patients gave informed consent.Background and Purpose-Experimentally, matrix metalloproteinases (MMPs) play a detrimental role related to hemorrhagic transformation and severity of an ischemic brain lesion. Tissue-type plasminogen activator (tPA) enhances such effects. This study aimed to expand clinical evidence in this connection. Methods-We measured MMPs 1, 2, 3,7,8, 9, and Blood samples were taken before and 24 hours after tPA. Outcomes were defined as follows: (1) symptomatic intracerebral hemorrhage (SICH), using the National Institute of Neurological Disorders and Stroke criteria; 7 (2) 3-month death; (3) modified Rankin disability score, dichotomized into good (modified Rankin scale, 0-2) or poor (modified Rankin scale, 3-6) outcome. As a main explanatory variable, we used single patient's relative pre-and post-thrombolysis variation (Δ median value) of both MMPs and TIMPs levels, calculated according to the formula: (24-hour post-tPA MMP or TIMP-pre-tPA MMP or TIMP)/pre-tPA MMP or TIMP. Differences in these Δ values were analyzed in relation to demographic and clinical features and across subgroups of patients with different outcomes. Methods details are in the online-only Data Supplement. ResultsBetween October 2008 and June 2011, 534 patients were registered in the SITS-ISTR, of whom 327 (mean age, 68.9±12.1 years; 58% males) were investigated. The remaining 207 were not studied because of not fulfilling SITS-MOST criteria, not giving consent, blood samples not taken or not stored appropriately, outcomes not assessed, and other protocol violations. Except for onset-to-treatment time, the prevalence of major outcomes determinants did not differ significantly between the 2 groups (demographics and clinical characteristics of both groups are in Table I in the online-only Data Supplement).Absolute TIMPs or MMPs measures taken before thrombolysis and 24 hours after are reported in the Table II in the online-only Data Supplement.The Figure shows pre-and post-thrombolysis changes of each MMP and TIMP level measured in patients with and without SICH, in patients who died and in those who survived, and in patients scoring 3 to 6 or 0 to 2 on the 3-month modified Rankin scale. MMP9, TIMP4, and MMP2 level changes showed a tendency toward the association with SICH. Variations of MMP8, MMP9, and TIMP1 levels were significantly associated with death, whereas variations of MMP8, MMP9, and TIMP4 levels were associated with scoring 3 to 6 on the 3-month modified Rankin scale. Grading of hemorrhage severity (according to the European Cooperative Acute Stroke Study II criteria) in the 27 patients with SICH is shown in Table III in the online-only Data Supplement. The association of MMP9 level variation with he...

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A broad-spectrum matrix metalloproteinase inhibitor prevents hemorrhagic complications induced by tissue plasminogen activator in mice

Cited by 57 publications

References 38 publications

Plasma kallikrein mediates brain hemorrhage and edema caused by tissue plasminogen activator therapy in mice after stroke

Plasma kallikrein mediates brain hemorrhage and edema caused by tissue plasminogen activator therapy in mice after stroke

Progesterone Attenuates Hemorrhagic Transformation after Delayed tPA Treatment in an Experimental Model of Stroke in Rats: Involvement of the VEGF–MMP Pathway

MMP9 Variation After Thrombolysis Is Associated With Hemorrhagic Transformation of Lesion and Death

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