College of Life Science, Shandong Agricultural University, Taian, Shandong, China; Institute of Neurobiology, Jining Medical University, Jining, Shandong, China.
Institute of Neurobiology, Jining Medical University, Jining, Shandong, China; Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Exp Neurol. 2018 Apr;302:136-144. doi: 10.1016/j.expneurol.2018.01.006. Epub 2018 Jan 11.
Cerebral ischemia/reperfusion (I/R) injury-induced neuronal apoptosis contributes to the death and disability in patients with ischemic stroke. However, underlying mechanisms remain elusive and it lacks effective treatment. Here we reported that the expression of casein kinase 2 (CK2) was significantly reduced in brains of middle cerebral artery occlusion/reperfusion (MACO/R) model rats and oxygen-glucose deprivation/reperfusion (OGD/R) model neurons, which was associated with the activation of eIF2-ATF4-CHOP signaling pathway, leading to neuronal apoptosis. Moreover, we found that apelin-13 significantly upregulated CK2 expression and inhibited eIF2-ATF4-CHOP activation, attenuating cerebral I/R injury-induced infarct and neuronal apoptosis in MACO/R model rats and OGD/R model neurons. Furthermore, we demonstrated that the rescue effect of apelin-13 on I/R injury-induced neuronal apoptosis was mediated by Gα/Gα-CK2-dependent inhibition of eIF2-ATF4-CHOP activation. These data indicated cerebral I/R injury reduced CK2 expression and activated eIF2-ATF4-CHOP signaling contributing to neuronal apoptosis, and apelin-13 can activate Gα/Gα-CK2 signaling attenuating eIF2-ATF4-CHOP-mediated neuronal apoptosis. It provides a novel insight that not only apelin-13 but also CK2 agonists may have therapeutic potential for protecting neurons from I/R injury-induced apoptosis, facilitating post-stroke recovery.
脑缺血/再灌注（I/R）损伤诱导的神经元凋亡导致缺血性脑卒中患者的死亡和残疾。然而，其潜在机制尚不清楚，且缺乏有效的治疗方法。在这里，我们报道在大脑中动脉闭塞/再灌注（MACO/R）模型大鼠和氧葡萄糖剥夺/再灌注（OGD/R）模型神经元中，酪蛋白激酶 2（CK2）的表达显著降低，这与 eIF2-ATF4-CHOP 信号通路的激活有关，从而导致神经元凋亡。此外，我们发现阿片肽-13 可显著上调 CK2 的表达，并抑制 eIF2-ATF4-CHOP 的激活，减轻 MACO/R 模型大鼠和 OGD/R 模型神经元中的脑 I/R 损伤诱导的梗死和神经元凋亡。此外，我们证明了阿片肽-13 对 I/R 损伤诱导的神经元凋亡的保护作用是通过 Gα/Gα-CK2 依赖性抑制 eIF2-ATF4-CHOP 的激活来介导的。这些数据表明脑 I/R 损伤降低了 CK2 的表达并激活了 eIF2-ATF4-CHOP 信号通路，导致神经元凋亡，而阿片肽-13 可以激活 Gα/Gα-CK2 信号通路，减轻 eIF2-ATF4-CHOP 介导的神经元凋亡。这为我们提供了一个新的见解，即不仅阿片肽-13，而且 CK2 激动剂可能具有治疗潜力，可保护神经元免受 I/R 损伤诱导的凋亡，促进卒中后恢复。
