Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke.
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.
Chen
Jieli
J
Department of Neurology, Henry Ford Health Sciences Center, Detroit, MI 48202, USA.
Zhang
Zheng Gang
ZG
Li
Yi
Y
Wang
Ying
Y
Wang
Lei
L
Jiang
Hao
H
Zhang
Chenling
C
Lu
Mei
M
Katakowski
Mark
M
Feldkamp
Carolyn S
CS
Chopp
Michael
M
D000818:Animals; D000906:Antibodies / Q000276:immunology; D000069059:Atorvastatin; D001921:Brain / Q000098:blood supply* / Q000187:drug effects* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D013569:Synapses / Q000187:drug effects*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000276:immunology
D000906:Antibodies; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; D000069059:Atorvastatin; D019001:Nitric Oxide Synthase; D040301:Vascular Endothelial Growth Factor Receptor-2; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D019331:NG-Nitroarginine Methyl Ester