Vascular endothelial growth factor mediates atorvastatin-induced mammalian achaete-scute homologue-1 gene expression and neuronal differentiation after stroke in retired breeder rats

Abstract

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.

Atorvastatin Promotes Presenilin-1 Expression and Notch1 Activity and Increases Neural Progenitor Cell Proliferation After Stroke

“…Permanent middle cerebral artery occlusion (MCAo) was induced by advancing a 3-0 surgical nylon suture to block the origin of the MCA by using a method of intraluminal vascular occlusion modified in our laboratory. 15 Sham-operated rats underwent the same surgical procedure without suture insertion. Because 3 mg/kg atorvastatin was found to promote functional outcome after stroke in rats, 14 this dose was used in the present study.…”

“…Immunohistochemical staining was used for BrdU (mouse monoclonal antibody, 1:100; Boehringer Mannheim, Indianapolis, Ind), PS1 (1:300 dilution, mouse monoclonal antibody), and NICD (1:3000 dilution, rabbit polyclonal antibody), as previously described. 15 Control experiments consisted of staining the brain coronal tissue sections as outlined earlier but without the primary antibodies, as previously described. 16 …”

Neurorestorative treatment of stroke: Cell and pharmacological approaches

“…Low-dose statin administered 24 hours after stroke promotes angiogenesis, neurogenesis, and synaptic plasticity and improves neurological functional outcome after stroke in young and in older retired breeder rats (middle age). 49,50 Treatment of patients within 4 weeks after acute ischemic stroke with statins significantly increased favorable outcome at 12 weeks. 51 In addition, the efficacy, safety, and tolerability of statins have been confirmed in randomized, controlled, multicenter trials involving large numbers of patients aged Ն65 years.…”

“…62 Atorvastatin increased Mash1 gene and protein expression in the ischemic brain, and promoted neuronal differentiation in retired breeder rats. 49 Thus, the molecular mechanisms by which statins alter vascular and neurogenic status in young and older brains are becoming more clear.…”

The role of vascular endothelial growth factor in the regulation of development and functioning of the brain: new target molecules for pharmacotherapy

“…При применении аторвастатина для терапии экспериментального ишемического инсульта у пожилых крыс наблюдалась опосредованная VEGF экспрессия генов дифференцировки нервных клеток Mash1 и TUJ1 в субвентрикулярной зоне. Этот эффект атровастатина был нивелирован при ингибировании VEGF [80]. Гиперлипидемия дифференцированно (в зависимости от концентрации атерогенных липидов в крови) подавляет VEGF-индуциованный рост капилляров и покрытие перицитами эндотелиального слоя сосудов головного мозга [81].…”