Division of Animal and Human Physiology, Department of Biology, National and Kapodistrian University of Athens, Panepistimiopolis, 15784 Athens, Greece.
Laboratory of Animal Physiology, Department of Biochemistry and Biotechnology, University of Thessaly, 41500 Larissa, Greece.
Int J Mol Sci. 2022 Jan 26;23(3):1386. doi: 10.3390/ijms23031386.
The two crucial cellular insults that take place during cerebral ischemia are the loss of oxygen and loss of glucose, which can both activate a cascade of events leading to neuronal death. In addition, the toxic overactivation of neuronal excitatory receptors, leading to Ca overload, may contribute to ischemic neuronal injury. Brain ischemia can be simulated in vitro by oxygen/glucose deprivation, which can be reversible by the re-establishment of physiological conditions. Accordingly, we examined the effects of glucose deprivation on the PI3K/Akt survival signaling pathway and its crosstalk with HIF-1α and Ca homeostasis in SH-SY5Y human neuroblastoma cells. It was found that glucose withdrawal decreased HIF-1α protein levels even in the presence of the ischemia-mimicking CoCl On the contrary, and despite neuronal death, we identified a strong activation of the master pro-survival kinase Akt, a finding that was also confirmed by the increased phosphorylation of GSK3, a direct target of p-Akt. Remarkably, the elevated Ca influx recorded was found to promptly trigger the activation of Akt, while a re-addition of glucose resulted in rapid restoration of both Ca entry and p-Akt levels, highlighting the plasticity of neurons to respond to ischemic challenges and the important role of glucose homeostasis for multiple neurological disorders.
在脑缺血期间发生的两个关键的细胞损伤是缺氧和葡萄糖缺失，这两者都能激活一系列导致神经元死亡的事件。此外，神经元兴奋性受体的毒性过度激活，导致 Ca 超载，可能导致缺血性神经元损伤。脑缺血可以通过氧/葡萄糖剥夺在体外进行模拟，通过恢复生理条件可以使其逆转。因此，我们研究了葡萄糖剥夺对 SH-SY5Y 人神经母细胞瘤细胞中 PI3K/Akt 存活信号通路及其与 HIF-1α 和 Ca 动态平衡的相互作用的影响。结果发现，即使在模拟缺血的 CoCl2 存在下，葡萄糖剥夺也会降低 HIF-1α 蛋白水平。相反，尽管发生了神经元死亡，但我们发现主生存激酶 Akt 被强烈激活，这一发现也被 Akt 的直接靶标 GSK3 的磷酸化增加所证实。值得注意的是，记录到的升高的 Ca 内流被发现能迅速触发 Akt 的激活，而葡萄糖的重新添加则迅速恢复 Ca 内流和 p-Akt 水平，这突出了神经元对缺血性挑战的反应的可塑性，以及葡萄糖动态平衡对多种神经疾病的重要作用。
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