Treatment of embolic stroke in rats with bortezomib and recombinant human tissue plasminogen activator
| Autor: | Michael Chopp, Li Zhang, Nancy E. Stagliano, Xianshuang Liu, Mei Lu, Zheng Gang Zhang, William Riordan, Ann Hozeska |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Pathology medicine.medical_specialty Time Factors Nitric Oxide Synthase Type III Platelet Aggregation Endothelium Anti-Inflammatory Agents Pharmacology Neuroprotection Tissue plasminogen activator Bortezomib Fibrinolytic Agents medicine Animals Humans Vascular Patency Protease Inhibitors cardiovascular diseases Rats Wistar Stroke T-plasminogen activator business.industry Vascular disease NF-kappa B Brain Infarction Middle Cerebral Artery Hematology medicine.disease Boronic Acids Recombinant Proteins Rats Disease Models Animal medicine.anatomical_structure Intracranial Embolism Pyrazines Tissue Plasminogen Activator Drug Therapy Combination Endothelium Vascular business medicine.drug |
| Zdroj: | Thrombosis and Haemostasis. 95:166-173 |
| ISSN: | 2567-689X 0340-6245 |
| DOI: | 10.1160/th05-07-0477 |
| Popis: | SummaryStroke 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. |
| Databáze: | OpenAIRE |
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