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.