Cdh1 介导的从磷酸戊糖途径到糖酵解的代谢转换有助于七氟醚诱导的大脑发育过程中的神经元凋亡。,ACS Chemical Neuroscience

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Cdh1 介导的从磷酸戊糖途径到糖酵解的代谢转换有助于七氟醚诱导的大脑发育过程中的神经元凋亡。
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2019-02-21 , DOI: 10.1021/acschemneuro.8b00644
Bin Liu ₁ , Wenjie Bai ₁ , Guoyao Ou ₁ , Jun Zhang ₁

Affiliation

Cdh1 是后期促进复合物/环体 (APC/C) 的调节亚基，已知参与调节神经元存活。Cdh1 在发育中的大脑中挥发性麻醉剂诱导的神经元凋亡中的作用尚不清楚。在这项研究中，我们使用出生后第 7 天 (P7) 和第 21 天 (P21) 小鼠暴露于 2.3% 七氟醚 6 小时，以研究暴露七氟醚的年龄和持续时间影响 Cdh1 和糖酵解酶 6-phosphofructo-2 的表达。 -激酶/果糖-2,6-二磷酸酶 3 (PFKFB3) 和磷酸戊糖途径 (PPP) 酶、葡萄糖-6-磷酸脱氢酶 (G6PD)。此外，我们测试了细胞周期蛋白依赖性激酶 (cdks) 抑制剂 roscovatine 是否可以抵消因暴露于七氟醚而引起的影响。最后，我们应用糖酵解抑制剂 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3-PO)、G6PD 抑制剂脱氢表雄酮 (DHEA) 和外源性还原型谷胱甘肽来检测七氟醚诱导的神经细胞凋亡的糖酵解途径和PPP。我们发现，与 P21 小鼠相比，延长七氟醚麻醉可显着降低 P7 小鼠的 Cdh1 水平。此外，Cdh1 水平的降低导致葡萄糖代谢从 PPP 转换为神经元糖酵解。这导致发育中的大脑中活性氧的产生和谷胱甘肽水平降低之间的不平衡，大脑更容易受到氧化应激的影响。因此，七氟醚通过 Cdh1 介导的葡萄糖代谢重编程诱导神经细胞凋亡。我们的研究通过将 PPP 转移到发育中的大脑中的糖酵解途径，证明了 Cdh1 在七氟醚诱导的神经细胞凋亡中的关键作用。这些发现表明，Cdh1 可能是预防挥发性麻醉剂引起的神经毒性和记忆障碍的新靶点。

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Cdh1-Mediated Metabolic Switch from Pentose Phosphate Pathway to Glycolysis Contributes to Sevoflurane-Induced Neuronal Apoptosis in Developing Brain.

Cdh1 is a regulatory subunit of the anaphase promoting complex/cyclosome (APC/C), known to be involved in regulating neuronal survival. The role of Cdh1 in volatile anesthetics-induced neuronal apoptosis in the developing brain is unknown. In this study, we used postnatal day 7 (P7) and day 21 (P21) mice exposed to 2.3% sevoflurane for 6 h to investigate at which age and duration of exposure sevoflurane affects the expression of Cdh1 and glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and that of the pentose phosphate pathway (PPP) enzyme, glucose-6-phosphate dehydrogenase (G6PD). Furthermore, we tested whether the cyclin-dependent kinases (cdks) inhibitor roscovatine could counteract the effects caused by exposure to sevoflurane. Finally, we applied the glycolysis inhibitor 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3-PO), G6PD inhibitor dehydroepiandrosterone (DHEA), and exogenous reduced glutathione to examine the contribution of the glycolysis pathway and PPP to sevoflurane-induced neuroapoptosis. We found that prolonged sevoflurane anesthesia significantly reduces the Cdh1 level in P7 mice compared to in the P21 ones; moreover, the decrease in Cdh1 level results in a switch in glucose metabolism from the PPP to neuronal glycolysis. This leads to an imbalance between reactive oxygen species production and reduced glutathione level in the developing brain, which is more susceptible to oxidative stress. As a result, sevoflurane induces neuroapoptosis through Cdh1-mediated glucose metabolism reprogramming. Our study demonstrates a critical role of Cdh1 in sevoflurane-induced neuroapoptosis by shifting PPP to the glycolytic pathway in the developing brain. These findings suggest that Cdh1 may be a novel target for preventing volatile anesthetics-induced neurotoxicity and memory impairment.

更新日期：2019-02-11

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