Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice.
Molecular mechanisms underlying the role of statins in the induction of brain plasticity and subsequent improvement of neurologic outcome after treatment of stroke have not been adequately investigated. Here, we use both in vivo and in vitro studies to investigate the potential roles of two prominent factors, vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF), in mediating brain plasticity after treatment of stroke with atorvastatin. Treatment of stroke in adult mice with atorvastatin daily for 14 days, starting at 24 hours after MCAO, shows significant improvement in functional recovery compared with control animals. Atorvastatin increases VEGF, VEGFR2 and BDNF expression in the ischemic border. Numbers of migrating neurons, developmental neurons and synaptophysin-positive cells as well as indices of angiogenesis were significantly increased in the atorvastatin treatment group, compared with controls. In addition, atorvastatin significantly increased brain subventricular zone (SVZ) explant cell migration in vitro. Anti-BDNF antibody significantly inhibited atorvastatin-induced SVZ explant cell migration, indicating a prominent role for BDNF in progenitor cell migration. Mouse brain endothelial cell culture expression of BDNF and VEGFR2 was significantly increased in atorvastatin-treated cells compared with control cells. Inhibition of VEGFR2 significantly decreased expression of BDNF in brain endothelial cells. These data indicate that atorvastatin promotes angiogenesis, brain plasticity and enhances functional recovery after stroke. In addition, VEGF, VEGFR2 and BDNF likely contribute to these restorative processes.
Chen
Jieli
J
Department of Neurology, Henry Ford Health Sciences Center, Detroit, Michigan 48202, USA.
Zhang
Chunling
C
Jiang
Hao
H
Li
Yi
Y
Zhang
Lijie
L
Robin
Adam
A
Katakowski
Mark
M
Lu
Mei
M
Chopp
Michael
M
D000818:Animals; D000069059:Atorvastatin; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006538:Heptanoic Acids / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D011758:Pyrroles / Q000627:therapeutic use*; D051381:Rats; D020127:Recovery of Function / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy*; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects*
D019208:Brain-Derived Neurotrophic Factor; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D000069059:Atorvastatin