Neurogenesis declines with advancing age. The mammalian achaete-scute homologue-1 encodes a
basic helix-loop-helix transcription factor, which controls neuronal differentiation. In this study, we first tested whether
atorvastatin treatment enhances neurological functional outcome and neuronal differentiation after
stroke in retired breeder 12 month rats. Rats were subjected to
middle cerebral artery occlusion and treated with or without
atorvastatin (3 mg/kg) for 7 days.
Atorvastatin significantly increased expression of mammalian achaete-scute homologue-1,
beta-tubulin III, and
vascular endothelial growth factor in the ischemic brain, and concomitantly improved functional outcome compared with
middle cerebral artery occlusion control rats. Increased neurogenesis significantly correlated with functional recovery after
stroke. To further investigate the mechanisms of
atorvastatin-induced neuronal differentiation, experiments were performed on neurospheres derived from retired breeder rat subventricular zone cells.
Atorvastatin increased neuronal differentiation and upregulated
vascular endothelial growth factor and mammalian achaete-scute homologue-1 gene expression in cultured neurospheres.
Vascular endothelial growth factor-treated neurospheres significantly increased mammalian achaete-scute homologue-1 and
beta-tubulin III expression. Inhibition of
vascular endothelial growth factor decreased
atorvastatin-induced mammalian achaete-scute homologue-1 and
beta-tubulin III expression. These data indicate that
atorvastatin increases neuronal differentiation in retired breeder rats. In addition,
atorvastatin upregulation of
vascular endothelial growth factor expression, influences mammalian achaete-scute homologue-1
transcription factor, which in turn, facilitates an increase in subventricular zone neuronal differentiation. These
atorvastatin-mediated molecular events may contribute to the improved functional outcome in retired breeder rats subjected to
stroke.