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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
1   Department of Neurology
,
Zheng Gang Zhang
1   Department of Neurology
,
Xianshuang Liu
1   Department of Neurology
,
Ann Hozeska
1   Department of Neurology
,
Nancy Stagliano
2   Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA
,
William Riordan
2   Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA
,
Mei Lu
3   Department of Biostatistics and Research Epidemiology Henry Ford Health Sciences Center, Detroit, Michigan, USA
,
Michael Chopp
1   Department of Neurology
4   Department of Physics, Oakland University, Rochester, Michigan, USA
› Author AffiliationsThis work was supported by NINDS grants PO1 NS23393, RO1 NS38292, and RO1 HL64766.
Further Information

Publication History

Received 07 July 2005

Accepted after resubmission 07 November 2005

Publication Date:
28 November 2017 (online)

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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
 

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