Multitargeted effects of statin-enhanced thrombolytic therapy for stroke with recombinant human tissue-type plasminogen activator in the rat.

Abstract:

BACKGROUND:Microvascular dysfunction posttreatment of stroke with recombinant human tissue-type plasminogen activator (rht-PA) constrains the therapeutic window to 3 hours. Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) promote vascular thrombolysis and reduce the inflammation response. We therefore investigated the neuroprotective effects of a combination of atorvastatin and delayed rht-PA treatment in a rat model of embolic stroke. METHODS AND RESULTS:Rats subjected to embolic middle cerebral artery occlusion were treated with atorvastatin in combination with rht-PA 4 hours after stroke. Magnetic resonance imaging measurements revealed that combination treatment with atorvastatin and rht-PA blocked the expansion of the ischemic lesion, which improved neurological function compared with saline-treated rats. Real-time reverse transcription-polymerase chain reaction analysis of single endothelial cells isolated by laser-capture microdissection from brain tissue and immunostaining showed that combination treatment downregulated expression of tissue factor, von Willebrand factor, protease-activated receptor-1, intercellular adhesion molecule-1, and matrix metalloproteinase-9, which concomitantly reduced cerebral microvascular thrombosis and enhanced microvascular integrity. Combination treatment did not increase cerebrovascular endothelial nitric oxide synthase (eNOS) levels or eNOS activity, and inhibition of NOS activity with N-nitro-L-arginine methyl ester did not block the beneficial effects of combination treatment on stroke. Furthermore, combination treatment compared with thrombolytic monotherapy increased cerebral blood flow and reduced infarct volume in eNOS-null mice. CONCLUSIONS:These data demonstrate that combination treatment with atorvastatin and rht-PA exerts a neuroprotective effect when administered 4 hours after stroke and that the therapeutic benefits are likely attributed to its multitargeted effects on cerebrovascular patency and integrity.

journal_name

Circulation

journal_title

Circulation

authors

Zhang L,Zhang ZG,Ding GL,Jiang Q,Liu X,Meng H,Hozeska A,Zhang C,Li L,Morris D,Zhang RL,Lu M,Chopp M

doi

10.1161/CIRCULATIONAHA.104.516757

subject

Has Abstract

pub_date

2005-11-29 00:00:00

pages

3486-94

issue

22

eissn

0009-7322

issn

1524-4539

pii

112/22/3486

journal_volume

112

pub_type

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