Effect of fluoxetine on HIF-1α- Netrin/VEGF cascade, angiogenesis and neuroprotection in a rat model of transient middle cerebral artery occlusion
Effect of fluoxetine on HIF-1α- Netrin/VEGF cascade, angiogenesis and neuroprotection in a rat model of transient middle cerebral artery occlusion
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DOI：
10.1016/j.expneurol.2020.113312
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发表时间：
2020-07-01
影响因子：
5.3
通讯作者：
Wang, Qiaoshu
中科院分区：
文献类型：
--
作者：
Hu, Qimin;Liu, Lan;Wang, Qiaoshu
氟西汀是改善缺血性脑卒中患者临床结局最有前途的药物之一。该体内研究使用大鼠短暂性大脑中动脉闭塞（tMCAO）模型研究了氟西汀可能影响HIF-1 α-Netrin/VEGF级联反应、血管生成和神经保护的假设。tMCAO后给予氟西汀或生理盐水4周。然后在tMCAO后1、2、4周检测HIF-1 α-Netrin/VEGF级联反应的蛋白表达。tMCAO 4周后，采用同步辐射线在体脑微血管造影观察缺血脑组织的形态学变化。于tMCAO后1 ~ 4周进行脑梗死面积和神经行为学检查。结果显示氟西汀治疗组HIF-1 α表达上调。同样，氟西汀增加了Netrin及其受体DCC、VEGF及其受体VEGFR的蛋白表达。同步辐射血管造影显示氟西汀治疗组大鼠有更多的分支。tMCAO后1周，氟西汀治疗组和生理盐水治疗组大鼠的梗死体积无差异，tMCAO后4周，氟西汀治疗组缺血诱导的脑萎缩体积减轻。氟西汀治疗的大鼠在tMCAO后3周和4周的神经功能缺损得到改善。我们的研究结果表明，氟西汀可以上调HIF-1 α-Netrin/VEGF级联的蛋白表达，促进血管生成，并改善缺血性卒中后的长期功能恢复。
Fluoxetine is one of the most promising drugs for improving clinical outcome in patients with ischemic stroke. This in vivo study investigated the hypothesis that fluoxetine may affect HIF-1 alpha-Netrin/VEGF cascade, angiogenesis and neuroprotection using a rat model of transient middle cerebral artery occlusion (tMCAO). The rats were given fluoxetine or saline after tMCAO for 4 weeks. Then, protein expression of HIF-1 alpha-Netrin/VEGF cascade was examined at 1, 2, 4 weeks after tMCAO. In vivo synchrotron radiation were performed to observe microangiography of ischemic brain after 4 weeks of tMCAO. The infarct size and neurobehavioral test were carried out 1 to 4 weeks after tMCAO. Results revealed that HIF-1 alpha expression was upregulated in fluoxetine-treated group. Similarly, fluoxetine increased protein expression of Netrin and its receptor DCC, VEGF and its receptor VEGFR. Synchrotron radiation angiography revealed more branches in fluoxetine-treated rats. We found no difference of infarct volume between fluoxetine and saline treated rats after 1 week of tMCAO, and ischemia-induced brain atrophy volume in fluoxetine-treated group was attenuated after 4 weeks of tMCAO. Neurological deficits were improved in fluoxetine-treated rats at 3 and 4 weeks after tMCAO. Our results indicated that fluoxetine could upregulate protein expression of HIF-1 alpha-Netrin/VEGF cascade, promote angiogenesis, and improve long-term functional recovery after ischemic stroke.