Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice
Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice
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DOI：
10.1038/sj.jcbfm.9600034
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发表时间：
2005-02-01
影响因子：
6.3
通讯作者：
Chopp, M
中科院分区：
文献类型：
--
作者：
Chen, JL;Zhang, CL;Chopp, M
他汀类药物在诱导大脑可塑性以及中风治疗后神经系统结果改善中的作用的分子机制尚未得到充分研究。在这里，我们利用体内和体外研究来研究血管内皮生长因子（VEGF）和脑源性神经营养因子（BDNF）这两个重要因素在阿托伐他汀治疗中风后调节大脑可塑性中的潜在作用。从 MCAO 后 24 小时开始，每天用阿托伐他汀治疗成年小鼠中风，持续 14 天，与对照动物相比，功能恢复显着改善。阿托伐他汀增加缺血边缘 VEGF、VEGFR2 和 BDNF 的表达。与对照组相比，阿托伐他汀治疗组的迁移神经元、发育神经元和突触素阳性细胞的数量以及血管生成指数显着增加。此外，阿托伐他汀显着增加体外脑室下区（SVZ）外植体细胞的迁移。抗 BDNF 抗体显着抑制阿托伐他汀诱导的 SVZ 外植体细胞迁移，表明 BDNF 在祖细胞迁移中发挥着重要作用。与对照细胞相比，阿托伐他汀处理的小鼠脑内皮细胞培养物中 BDNF 和 VEGFR2 的表达显着增加。抑制 VEGFR2 显着降低脑内皮细胞中 BDNF 的表达。这些数据表明阿托伐他汀可促进血管生成、大脑可塑性并增强中风后的功能恢复。此外，VEGF、VEGFR2 和 BDNF 可能有助于这些恢复过程。
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.