Extension of the Therapeutic Window for Recombinant Tissue Plasminogen Activator With Argatroban in a Rat Model of Embolic Stroke

Morris, Daniel C.; Zhang, Li; Zhang, Zheng Gang; Lü, Mei; Berens, Kurt L.; Brown, Philip M.; Chopp, Michael

doi:10.1161/hs1101.097390

Cited by 62 publications

(58 citation statements)

References 39 publications

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“…29,30 Accordingly, the thrombin inhibitor argatroban reduces brain injury after ischemia/reperfusion in experimental animals [28][29][30] and extends the therapeutic window of recombinant tissue-type plasminogen activator.…”

Section: Discussionmentioning

confidence: 99%

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Mannose-Binding Lectin Promotes Local Microvascular Thrombosis After Transient Brain Ischemia in Mice

Rosa

Cervera

Kristoffersen

et al. 2014

Stroke

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Background and Purpose-Several lines of evidence support the involvement of mannose-binding lectin (MBL) in stroke brain damage. The lectin pathway of the complement system facilitates thrombin activation and clot formation under certain experimental conditions. In the present study, we examine whether MBL promotes thrombosis after ischemia/ reperfusion and influences the course and prognosis of ischemic stroke. Methods-Middle cerebral artery occlusion/reperfusion was performed in MBL-deficient (n=85) and wild-type (WT; n=83) mice, and the brain lesion was assessed by MRI at days 1 and 7. Relative cerebral blood flow was monitored up to 6 hours after middle cerebral artery occlusion with laser speckle contrast imaging. Fibrin(ogen) was analyzed in the brain vasculature and plasma, and the effects of thrombin inhibitor argatroban were evaluated to assess the role of MBL in thrombin activation. Results-Infarct volumes and neurological deficits were smaller in MBL knockout mice than in WT mice. Relative cerebral blood flow values during middle cerebral artery occlusion and at reperfusion were similar in both groups, but decreased during the next 6 hours in the WT group only. Also, the WT mice showed more fibrin(ogen) in brain vessels and a better outcome after argatroban treatment. In contrast, argatroban did not improve the outcome in MBL knockout mice. Conclusions-MBL promotes brain damage and functional impairment after brain ischemia/reperfusion in mice. These effects are secondary to intravascular thrombosis and impaired relative cerebral blood flow during reperfusion. Argatroban protects WT mice, but not MBL knockout mice, emphasizing a role of MBL in local thrombus formation in acute ischemia/reperfusion. (Stroke. 2014;45:1453-1459.)Key Words: brain ◼ complement pathway, mannose-binding lectin ◼ complement system proteins ◼ infarction, middle cerebral artery ◼ reperfusion Mannose-Binding Lectin Promotes Local Microvascular Thrombosis After Transient Brain Ischemia in MiceXavier de la Rosa, MS; Alvaro Cervera, MD, PhD; Anna K. Kristoffersen, PhD; Claudia P. Valdés, MS; Hari M. Varma, MS; Carles Justicia, PhD; Turgut Durduran, PhD;Ángel Chamorro, MD, PhD; Anna M. Planas, PhD Received November 11, 2013; final revision received February 26, 2014; accepted February 28, 2014. MethodsAn extended version of methods can be found in the online-only Data Supplement. Animal WorkAnimal work was undertaken with approval of the Ethical Committee of the University of Barcelona and in compliance with the Spanish law. Adult (3-4-month-old), male wild-type (WT) and MBL KO mice 31 in the C57BL/6J background were used. 17 Brain Ischemia/ReperfusionIschemia was produced by intraluminal 90-minute occlusion of the right middle cerebral artery (MCAO) in WT (n=83) and MBL KO (n=85) mice. Cerebral perfusion was assessed with laser Doppler flowmetry (Perimed AB, Järfälla, Sweden). A neurological score ranging from 0 (no deficit) to 20 (maximal deficit) was performed at days 1 and 7 after MCAO. MRI StudiesMRI was performed in a 7.0-T ...

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Section: Discussionmentioning

confidence: 99%

“…21,22 Proteins of the lectin pathway can induce thrombus formation through thrombin activation, [23][24][25][26][27] thus exacerbating brain damage after ischemia/ reperfusion. [28][29][30] In this study, we evaluated the role of MBL in thrombus formation and whether this interaction is involved in brain damage after ischemia/reperfusion in mice.…”

mentioning

confidence: 99%

Mannose-Binding Lectin Promotes Local Microvascular Thrombosis After Transient Brain Ischemia in Mice

Rosa

Cervera

Kristoffersen

et al. 2014

Stroke

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“…Indeed, Lo's group shows that, in cerebral ischemia, tPA can increase MMP-9 (Wang et al, 2003). Accordingly, by down-regulating MMP-9 activity, Ang-1 in combination with tPA might reduce tPA-induced BBB deleterious effects and increase the therapeutic window for tPA in stroke (Morris et al, 2001;Zhang et al, 2002a).…”

Section: Discussionmentioning

confidence: 99%

VEGF-Induced BBB Permeability is Associated with an MMP-9 Activity Increase in Cerebral ischemia: Both Effects Decreased by ANG-1

Valable

Montaner

Bellail

et al. 2005

J Cereb Blood Flow Metab

177

125

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After cerebral ischemia, angiogenesis, by supplying for the deficient perfusion, may be a beneficial process for limiting neuronal death and promoting tissue repair. In this study, we showed that the combination of Ang-1 and vascular endothelial growth factor (VEGF) provides a more adapted therapeutic strategy than the use of VEGF alone. Indeed, we showed on a focal ischemia model that an early administration of VEGF exacerbates ischemic damage, because of its effects on bloodbrain barrier (BBB) permeability. In contrast, a coapplication of Ang-1 and VEGF leads to a significant reduction of the ischemic and edema volumes by 50% and 42%, respectively, in comparison with VEGF-treated mice. We proposed that Ang-1 blocks the BBB permeability effect of VEGF in association with a modulation of matrix metalloproteinase (MMP) activity. Indeed, we showed on both ischemic in vivo and BBB in vitro models that VEGF enhances BBB damage and MMP-9 activity and that Ang-1 counteracts both effects. However, we also showed a synergic angiogenic effect of Ang-1 and VEGF in the brain. Taken together, these results allow to propose that, in cerebral ischemia, the combination of Ang-1 and VEGF could be used early to promote the formation of mature neovessels without inducing side effects on BBB permeability.

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“…In the current rat model of embolic focal cerebral ischemia, earlier studies have documented that treatment with tPA is effective only when given within 2 to 3 h of onset of stroke (Morris et al, 2001). Here, we asked whether combination therapy with tPA plus rA2 can also extend the time window for thrombolysis.…”

Section: Low-dose Tpa In Combination With Ra2 Extends the Thrombolymentioning

confidence: 95%

Annexin A2 Combined with Low-Dose tPA Improves Thrombolytic Therapy in a Rat Model of Focal Embolic Stroke

Zhu

Fan

et al. 2010

J Cereb Blood Flow Metab

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Recent studies showed that soluble annexin A2 dramatically increases tissue plasminogen activator (tPA)-mediated plasmin generation in vitro, and reduces thrombus formation in vivo. Here, we hypothesize that combining annexin A2 with tPA can significantly enhance thrombolysis efficacy, so that lower doses of tPA can be applied in ischemic stroke to avoid neurotoxic and hemorrhagic complications. In vitro activity assays confirmed tPA-specific amplification of plasmin generation by recombinant annexin A2. In a rat focal embolic stroke model, combination therapy with tPA and recombinant annexin A2 protein at 2 h post-ischemia decreased the effective dose required for tPA by four-fold and reduced brain infarction. Combining annexin A2 with tPA also lengthened the time window for thrombolysis. Compared with tPA (10 mg/kg) alone, the combination of annexin A2 (5 mg/kg) plus low-dose tPA (2.5 mg/kg) significantly enhanced fibrinolysis, attenuated mortality, brain infarction, and hemorrhagic transformation, even when administered at 4 h post-ischemia. Combination with recombinant annexin A2, the effective thrombolytic dose of tPA can be decreased. As a result, brain hemorrhage and infarction are reduced, and the time window for stroke reperfusion prolonged. Our present findings provide a promising new approach for enhancing tPA-based thrombolytic stroke therapy.

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Extension of the Therapeutic Window for Recombinant Tissue Plasminogen Activator With Argatroban in a Rat Model of Embolic Stroke

Cited by 62 publications

References 39 publications

Mannose-Binding Lectin Promotes Local Microvascular Thrombosis After Transient Brain Ischemia in Mice

Mannose-Binding Lectin Promotes Local Microvascular Thrombosis After Transient Brain Ischemia in Mice

VEGF-Induced BBB Permeability is Associated with an MMP-9 Activity Increase in Cerebral ischemia: Both Effects Decreased by ANG-1

Annexin A2 Combined with Low-Dose tPA Improves Thrombolytic Therapy in a Rat Model of Focal Embolic Stroke

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