Treatment of embolic stroke in rats with bortezomib and recombinant human tissue plasminogen activator.
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 to 6 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-kappaB activation. These results demonstrate that bortezomib promotes eNOS dependent vascular protection, and reduces NF-kappaB dependent vascular disruption, all of which may contribute to neuroprotection after stroke.
Department of Neurology, Henry Ford Health Sciences Center, Detroit, MI 48202, USA.
Li
L
Zhang
Zheng Gang
ZG
Zhang
Xianshuang
X
Liu
Ann
A
Hozeska
Nancy
N
Stagliano
William
W
Riordan
Mei
M
Lu
Michael
M
Chopp
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D001921:Brain / Q000098:blood supply; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D020766:Intracranial Embolism / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D020521:Stroke / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D014654:Vascular Patency / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D001897:Boronic Acids; D005343:Fibrinolytic Agents; D016328:NF-kappa B; D011480:Protease Inhibitors; D011719:Pyrazines; D011994:Recombinant Proteins; D000069286:Bortezomib; D052250:Nitric Oxide Synthase Type III; D010959:Tissue Plasminogen Activator