Treatment of embolic stroke in rats with bortezomib and recombinant human tissue plasminogen activator

Li Zhang; Zheng Gang Zhang; Xianshuang Liu; Ann Hozeska; Nancy Stagliano; William Riordan; Mei Lu; Michael Chopp

doi:10.1160/TH05-07-0477

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 95(01): 166-173
DOI: 10.1160/TH05-07-0477

Animal Models

Schattauer GmbH

Treatment of embolic stroke in rats with bortezomib and recombinant human tissue plasminogen activator

Li Zhang

¹Department of Neurology

,

Zheng Gang Zhang

¹Department of Neurology

,

Xianshuang Liu

¹Department of Neurology

,

Ann Hozeska

¹Department of Neurology

,

Nancy Stagliano

²Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA

,

William Riordan

²Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA

,

Mei Lu

³Department of Biostatistics and Research Epidemiology Henry Ford Health Sciences Center, Detroit, Michigan, USA

,

Michael Chopp

¹Department of Neurology

⁴Department of Physics, Oakland University, Rochester, Michigan, USA

› Author Affiliations

Abstract

Summary

Stroke elicits a progressive vascular dysfunction, which contributes to the evolution of brain injury. Thrombolysis with tissue plasminogen activator (tPA) promotes adverse vascular events that limit the therapeutic window of stroke to three hours. Proteasome inhibitors reduce vascular thrombotic and inflammatory events, and consequently protect vascular function. The present study evaluated the neuroprotective effect of bortezomib,a potent and selective inhibitor of the proteasome, alone and in combination with delayed thrombolytic therapy on a rat model of embolic focal cerebral ischemia. Treatment with bortezomib reduces adverse cerebrovascular events including secondary thrombosis,inflammatory responses,and blood brain barrier (BBB) disruption, and hence reduces infarct volume and neurological functional deficit when administrated within 4 h after stroke onset. Combination of bortezomib and tPA extends the thrombolytic window for stroke to6 h, which is associated with the improvement of vascular patency and integrity. Real time RT-PCR of endothelial cells isolated by laser-capture microdissection from brain tissue and Western blot analysis showed that bortezomib upregulates endothelial nitric oxide synthase (eNOS) expression and blocks NF-κB activation. These results demonstrate that bortezomib promotes eNOS dependent vascular protection, and reduces NF-κB dependent vascular disruption, all of which may contribute to neuroprotection after stroke.

Keywords

Animal models - adhesion molecules - plasminogen activators

Full Text

References

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