Abstract
We demonstrate that the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors atorvastatin and simvastatin enhance functional outcome and induce brain plasticity when administered after stroke to rats. With atorvastatin treatment initiated 1 day after stroke, animals exhibited significant increases in vascular endothelial growth factor, cyclic guanosine monophosphate, angiogenesis, endogenous cell proliferation and neurogenesis, and an increase in the synaptic protein, synaptophysin. Atorvastatin-induced angiogenesis in a tube formation assay was reduced by an antibody against the vascular endothelial growth factor receptor 2 (FIK-1) and by the nitric oxide synthase inhibitor, N-mono-methyl-L-arginine (L-NAME). Atorvastatin also induced phosphorylation of Akt and Erk in cultured primary cortical neurons. These data indicate that atorvastatin induced brain plasticity and has neurorestorative activity after experimental stroke.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibodies / immunology
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Atorvastatin
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Brain / blood supply*
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Brain / drug effects*
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Brain / pathology
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Enzyme Inhibitors / pharmacology
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Heptanoic Acids / pharmacology
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Heptanoic Acids / therapeutic use*
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
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Immunohistochemistry
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Male
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Mitogen-Activated Protein Kinases / drug effects
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NG-Nitroarginine Methyl Ester / pharmacology
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Neovascularization, Physiologic / drug effects
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Neuronal Plasticity / drug effects
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Neurons / drug effects*
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Nitric Oxide Synthase / antagonists & inhibitors
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins c-akt
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Pyrroles / pharmacology
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Pyrroles / therapeutic use*
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Rats
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Rats, Wistar
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Signal Transduction / drug effects
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Stroke / drug therapy*
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Stroke / immunology
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Stroke / pathology
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Synapses / drug effects*
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Vascular Endothelial Growth Factor Receptor-2 / immunology
Substances
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Antibodies
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Enzyme Inhibitors
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Heptanoic Acids
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Proto-Oncogene Proteins
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Pyrroles
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Atorvastatin
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Nitric Oxide Synthase
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Vascular Endothelial Growth Factor Receptor-2
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Akt1 protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases
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NG-Nitroarginine Methyl Ester