Abstract
We investigated the additive therapeutic effect of the combination treatment of stroke with sub-therapeutic doses of Simvastatin, a HMG-CoA reductase inhibitor, and bone marrow stromal cells (BMSCs). Rats were administered Simvastatin (0.5 mg/kg), BMSCs (1x10(6)) or combination of Simvastatin and BMSCs starting at 24 h after stroke. Combination treatment significantly improved neurological outcome, enhanced angiogenesis and arteriogenesis, and increased the number of engrafted-BMSCs in the ischemic brain. The number of engrafted-BMSCs and arteriogenesis was significantly correlated with functional outcome. Simvastatin significantly increased stromal cell-derived factor-1 (SDF1) expression in the ischemic brain and chemokine (CXC motif) receptor-4 (CXCR4) in BMSCs, and increased BMSC migration to RBMECs and astrocytes. Combination treatment of stroke upregulates the SDF1/CXCR4 axis and enhances BMSC migration into the ischemic brain, amplifies arteriogenesis and angiogenesis, and improves functional outcome after stroke.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Animals
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Blood Vessels / drug effects*
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Blood Vessels / metabolism
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Bone Marrow Cells / cytology
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Bone Marrow Cells / physiology*
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Bone Marrow Transplantation / methods
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Bromodeoxyuridine / metabolism
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Cell Movement / drug effects
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Chemokine CXCL12 / metabolism
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Disease Models, Animal
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
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Infarction, Middle Cerebral Artery / therapy*
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Male
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Neovascularization, Physiologic / drug effects*
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Neovascularization, Physiologic / physiology
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Neurologic Examination / methods
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Rats
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Rats, Wistar
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Receptors, CXCR4 / metabolism
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Recovery of Function / drug effects
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Recovery of Function / physiology
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Simvastatin / pharmacology*
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Stromal Cells / physiology
Substances
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Chemokine CXCL12
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Cxcr4 protein, rat
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Receptors, CXCR4
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Simvastatin
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Bromodeoxyuridine