Inhibition of protein tyrosine phosphatase 1B protects against sevoflurane-induced neurotoxicity mediated by ER stress in developing brain
Inhibition of protein tyrosine phosphatase 1B protects against sevoflurane-induced neurotoxicity mediated by ER stress in developing brain
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DOI：
10.1016/j.brainresbull.2018.12.006
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发表时间：
2019-03-01
影响因子：
3.8
通讯作者：
Zhang, Jun
中科院分区：
文献类型：
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作者：
Liu, Bin;Ou, Guoyao;Zhang, Jun
背景：内质网应激与七氟醚诱导的神经毒性有关。已知存在于 ER 膜中的蛋白酪氨酸磷酸酶 1B (PTP1B) 可以调节 ER 应激。然而，PTP1B在七氟醚引起的神经毒性中的作用尚不清楚。方法：用2.3%七氟醚处理7日龄小鼠6 h作为动物模型。暴露于七氟醚后收获海马组织，用蛋白质印迹评估内质网应激标记物，用透射电子显微镜评估内质网形态，用高尔基体染色评估树突棘密度。在另一组小鼠中，麻醉后 4 周使用莫里斯水迷宫测试评估神经认知功能。我们还检测了 PTP1B 或 PERK 抑制剂对七氟醚诱导的海马神经变性的影响。结果：结果显示，PTP1B 的抑制显着改善七氟醚诱导的 (1) 超微结构 ER 改变和 ER 应激激活，如 PERK 和 eIF2 α 磷酸化上调所示； (2) 裂解的 caspase-3 表达增加； (3)促炎性NF-κB和TNFα表达升高；(4)突触素、Arc和BDNF-TrkB蛋白表达减少以及海马树突棘损失； (5)青春期神经行为表现受损。同样，ER 应激抑制剂也被发现可以下调 eIF2 α 磷酸化和神经炎症，并增加突触蛋白和 BDNF-TrkB 信号蛋白的表达。 结论：我们的研究表明，PTP1B 抑制可减轻七氟烷诱导的神经变性，可能是由发育中的大脑中 ER 应激介导的，并最终改善认知功能。这表明 PTP1B 抑制可能是预防七氟烷诱导的神经毒性的一种有前途的策略。
Background: ER stress is involved in sevoflurane-induced neurotoxicity. Protein tyrosine phosphatase 1B (PTP1B) resided in the ER membrane is known to regulate ER stress. However, the role of PTP1B in sevoflurane-induced neurotoxicity is unknown.Method: Seven-day-old mice treated with 2.3% sevoflurane for 6 h as animal model. The hippocampal tissues were harvested following sevoflurane exposure for evaluation of ER stress markers with Western blot, ER morphology with transmission electron microscopy and density of dendrite spine with Golgi staining. In another subset of mice, neurocognitive function was assessed 4 weeks after anesthesia using Morris water maze test. We also examined the effects of PTP1B or PERK inhibitor on sevoflurane-induced neurodegeneration in the hippocampus.Result: The results showed inhibition of PTP1B significantly ameliorated sevoflurane-induced (1) ultrastructural ER alternations and ER stress activation as indicated by upregulation of PERK and eIF2 alpha phosphorylation; (2) increase in cleaved caspase-3 expression; (3) elevated expressions of proinflammatory NF-kappa B and TNF alpha;(4) decreases in expression of synaptophysin, Arc and BDNF-TrkB proteins as well as loss of dendrite spine in the hippocampus; and (5) impairment in neurobehavioural performance at adolescence. Similarly, ER stress inhibitor is also found to downregulate eIF2 alpha phosphorylation and neuroinflammation, and increase expressions of synaptic proteins and BDNF-TrkB signaling proteins.Conclusions: Our study shows PTP1B inhibition mitigates sevoflurane-induced neurodegeneration maybe mediated by ER stress in developing brain, and eventually improves cognitive function. This suggests PTP1B inhibition could represent a promising strategy to prevent sevoflurane-induced neurotoxicity.