Alpha-Ketoglutarate Alleviates Neuronal Apoptosis Induced by Central Insulin Resistance through Inhibiting S6K1 Phosphorylation after Subarachnoid Hemorrhage.
Alpha-Ketoglutarate Alleviates Neuronal Apoptosis Induced by Central Insulin Resistance through Inhibiting S6K1 Phosphorylation after Subarachnoid Hemorrhage.
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DOI：
10.1155/2022/9148257
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发表时间：
2022
影响因子：
--
通讯作者：
Li, Wei
中科院分区：
文献类型：
--
作者：
Ding, Peng-Fei;Zhu, Qi;Sheng, Bin;Yang, Heng;Xu, Hua-Jie;Tao, Tao;Peng, Zheng;Chen, Xiang-Xin;Li, Xiao-Jian;Zhou, Yan;Zhang, Hua-Sheng;Gao, Yong-Yue;Zhuang, Zong;Hang, Chun-Hua;Li, Wei
蛛网膜下腔出血（SAH）后神经元凋亡被认为在SAH后早期脑损伤中起重要作用。神经元的能量代谢与其存活密切相关。SAH后胰岛素抵抗（IR）引起的一过性高血糖严重影响患者的预后。然而，SAH后IR的具体机制尚不清楚。研究表明，α-KG参与IR和细胞凋亡的调节。本研究旨在探讨α-KG是否能降低SAH后IR，改善神经元糖代谢紊乱，减轻神经元凋亡，最终在SAH诱导的EBI中发挥神经保护作用。我们首先测量了SAH患者脑脊液（CSF）中的α-KG水平。然后，我们通过血红蛋白（Hb）刺激HT 22细胞建立SAH模型，以进一步研究SAH的机制。此外，通过血管内穿孔建立小鼠体内SAH模型。我们的研究结果表明，脑脊液中α-KG水平在SAH患者中显著升高，并可作为潜在的预后生物标志物。在SAH体外模型中，我们发现α-KG不仅能抑制IR诱导的SAH后神经元葡萄糖摄取减少，而且能减轻SAH诱导的神经元凋亡。从机制上讲，我们发现α-KG通过抑制SAH后S6 K1的激活来抑制神经元IR。此外，当葡萄糖摄取减少时，神经元凋亡显著增加。此外，我们的研究结果表明，α-KG还可以减轻体内SAH模型中神经元的凋亡。本研究提示α-KG通过抑制SAH后S6 K1激活诱导的IR来抑制SAH后细胞凋亡。
Neuronal apoptosis after subarachnoid hemorrhage (SAH) is believed to play an important role in early brain injury after SAH. The energy metabolism of neuron is closely related to its survival. The transient hyperglycemia caused by insulin resistance (IR) after SAH seriously affects the prognosis of patients. However, the specific mechanisms of IR after SAH are still not clear. Studies have shown that α-KG takes part in the regulation of IR and cell apoptosis. In this study, we aim to investigate whether α-KG can reduce IR after SAH, improve the disorder of neuronal glucose metabolism, alleviate neuronal apoptosis, and ultimately play a neuroprotective role in SAH-induced EBI. We first measured α-KG levels in the cerebrospinal fluid (CSF) of patients with SAH. Then, we established a SAH model through hemoglobin (Hb) stimulation with HT22 cells for further mechanism research. Furthermore, an in vivo SAH model in mice was established by endovascular perforation. Our results showed that α-KG levels in CSF significantly increased in SAH patients and could be used as a potential prognostic biomarker. In in vitro model of SAH, we found that α-KG not only inhibited IR-induced reduction of glucose uptake in neurons after SAH but also alleviated SAH-induced neuronal apoptosis. Mechanistically, we found that α-KG inhibits neuronal IR by inhibiting S6K1 activation after SAH. Moreover, neuronal apoptosis significantly increased when glucose uptake was reduced. Furthermore, our results demonstrated that α-KG could also alleviate neuronal apoptosis in vivo SAH model. In conclusion, our study suggests that α-KG alleviates apoptosis by inhibiting IR induced by S6K1 activation after SAH.
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