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. (Circulation. 2005;112:3486-3494.)

Effects of Pretreatment With Statins on Infarct Size in Patients With Acute Myocardial Infarction Who Receive Fibrinolytic Therapy

“…5 Following plaque disruption, statins promote vascular fibrinolysis by exerting various inhibitory actions on platelet deposition and aggregation, coagulation factors, and rheology. 14,15 However, our study found no significant difference in the coronary artery reperfusion rate as assessed by initial TIMI flow grade after fibrinolytic therapy between patients with and without statin pretreatment.…”

“…2,3 Statins also reduce hemostasis by inhibiting platelet activation and the procoagulation cascade, and by augmenting the anticoagulation cascade. 4 Thus, statins appear to effectively enhance the fibrinolytic activity of t-PA. An experimental study in animals has shown that combination treatment with a statin and t-PA after stroke increases cerebral blood flow and reduces infarct volume as compared with fibrinolytic treatment alone; 5 however, data in humans are lacking. Prompt reperfusion of the occluded artery is crucial to limiting the size of an infarct.…”

Neurorestorative treatment of stroke: Cell and pharmacological approaches

“…44,45 Combination atorvastatin and recombinant human tissue plasminogen activator (rhtPA) treatment 4 hours after stroke induces downregulation of tissue factor, protease-activated receptor 1, intercellular adhesion molecule 1, and matrix metalloproteinase 9 (MMP 9); concomitantly, it reduces cerebral microvascular thrombosis and enhances microvascular integrity. 46 Patients who had taken statins prior to the onset of stroke have significantly decreased mortality and improved outcome after acute ischemic stroke. 47,48 The results of the recently reported in stroke prevention by aggressive reduction in cholesterol levels (SPARCL) trial indicate that atorvastatin is likely efficacious in reducing the incidence of recurring stroke.…”

Stroke Induces Gene Profile Changes Associated with Neurogenesis and Angiogenesis in Adult Subventricular Zone Progenitor Cells

“…Semiquantitative measurements of immunoreactive cells were performed, according to our previously published methods (Zhang et al, 1999(Zhang et al, , 2005a. Briefly, immunoreactive cells in the nonstroke and stroke SVZ were digitized under a 40 Â objective (BX40; Olympus Optical) using a 3-CCD color video camera (DXC-970MD; Sony, Tokyo, Japan) interfaced with an MCID image analysis system.…”