FGF21 promotes functional recovery after hypoxic-ischemic brain injury in neonatal rats by activating the PI3K/Akt signaling pathway via FGFR1/β-klotho
FGF21 promotes functional recovery after hypoxic-ischemic brain injury in neonatal rats by activating the PI3K/Akt signaling pathway via FGFR1/β-klotho
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FGF21 通过 FGFR1/β-klotho 激活 PI3K/Akt 信号通路促进新生大鼠缺氧缺血性脑损伤后的功能恢复
DOI：
10.1016/j.expneurol.2019.02.013
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发表时间：
2019-07-01
影响因子：
5.3
通讯作者：
Lin, Zhenlang
中科院分区：
文献类型：
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作者：
Ye, Lixia;Wang, Xue;Lin, Zhenlang
围产期窒息常导致新生儿脑缺氧缺血（HI），这与新生儿的高死亡率和严重的长期神经功能缺损有关。目前，没有有效的药物来减轻HI后的功能障碍。先前的研究表明，成纤维细胞生长因子21（FGF 21）对脑损伤具有潜在的神经保护作用。然而，FGF 21对新生儿HI脑损伤的影响尚不清楚。本研究采用体内外模型研究重组人FGF 21（rhFGF 21）对缺氧缺血性损伤（HI）后神经元的保护作用，并探讨其作用机制。结果表明，rhFGF 21治疗可明显缩小新生大鼠HI后的梗死体积，改善新生大鼠的体重和组织结构。此外，rhFGF 21处理延长了旋转棒测试中的跑步耐力时间，降低了Morris水迷宫测试中的平均逃避潜伏期，并增加了HI损伤后21 d的平台穿越次数。相反，FGFR 1抑制剂PD 173074和PI 3 K抑制剂LY 294002部分逆转了这些治疗作用。在分离的原代皮层神经元中，rhFGF 21处理通过抑制神经元凋亡和促进神经元存活来保护原代神经元免受氧-葡萄糖剥夺（OGD）损伤。我们的体内和体外结果均表明，rhFGF 21可以通过FGF 21/FGFR 1/beta-klotho复合物的形成激活PI 3 K/Akt信号通路来抑制神经元凋亡。因此，rhFGF 21可能是一个有前途的治疗剂，促进HI诱导的新生儿脑损伤后的功能恢复。
Perinatal asphyxia often results in neonatal cerebral hypoxia-ischemia (HI), which is associated with high mortality and severe long-term neurological deficits in newborns. Currently, there are no effective drugs to mitigate the functional impairments post-HI. Previous studies have shown that fibroblast growth factor 21 (FGF21) has a potential neuroprotective effect against brain injury. However, the effect of FGF21 on neonatal HI brain injury is unclear. In the present study, both in vivo and in vitro models were used to assess whether recombinant human FGF21 (rhFGF21) could exert a neuroprotective effect after HI and explore the associated mechanism. The results showed that the rhFGF21 treatment remarkably reduced the infarct volume, ameliorated the body weight and improved the tissue structure after HI in neonatal rats. In addition, the rhFGF21 treatment lengthened the running endurance times in the rotarod test and decreased the mean escape latencies and increased the number of platform crossings in the Morris water maze test at 21 d post-HI insult. In contrast, the FGFR1 inhibitor PD173074 and PI3K inhibitor LY294002 partially reversed these therapeutic effects. In isolated primary cortical neurons, the rhFGF21 treatment protected primary neurons from oxygen-glucose deprivation (OGD) insult by inhibiting neuronal apoptosis and promoting neuronal survival. Both our in vivo and in vitro results reveal that rhFGF21 could inhibit neuronal apoptosis by activating the PI3K/Akt signaling pathway via FGF21/FGFR1/beta-klotho complex formation. Therefore, rhFGF21 may be a promising therapeutic agent for promoting functional recovery after HI-induced neonatal brain injury.