Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 650 New Songjiang Road, Shanghai 201620, China.
Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China.
Exp Neurol. 2020 Jul;329:113312. doi: 10.1016/j.expneurol.2020.113312. Epub 2020 Apr 12.
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-1α-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-1α-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-1α 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-1α-Netrin/VEGF cascade, promote angiogenesis, and improve long-term functional recovery after ischemic stroke.
氟西汀是改善缺血性脑卒中患者临床预后最有希望的药物之一。本体内研究通过短暂性大脑中动脉闭塞（tMCAO）大鼠模型，假设氟西汀可能通过影响 HIF-1α-Netrin/VEGF 级联、血管生成和神经保护来发挥作用。tMCAO 后 4 周内，大鼠给予氟西汀或生理盐水。然后，在 tMCAO 后 1、2、4 周检测 HIF-1α-Netrin/VEGF 级联的蛋白表达。在 tMCAO 后 4 周进行同步辐射以观察缺血性脑的微血管造影。在 tMCAO 后 1 至 4 周进行梗死面积和神经行为学测试。结果显示，氟西汀治疗组 HIF-1α 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。我们发现 tMCAO 后 1 周氟西汀与生理盐水治疗组的梗死体积无差异，tMCAO 后 4 周氟西汀治疗组的缺血性脑萎缩体积减轻。tMCAO 后 3 周和 4 周，氟西汀治疗组的神经功能缺损得到改善。我们的结果表明，氟西汀可以上调 HIF-1α-Netrin/VEGF 级联的蛋白表达，促进血管生成，并改善缺血性脑卒中后的长期功能恢复。
