Sevoflurane-Induced Neurotoxicity in the Developing Hippocampus via HIPK2/AKT/mTOR Signaling
Sevoflurane-Induced Neurotoxicity in the Developing Hippocampus via HIPK2/AKT/mTOR Signaling
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DOI：
10.1007/s12640-021-00445-8
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发表时间：
2022-04
影响因子：
3.7
通讯作者：
Lirong Liang;Ze Fan;Danyi He;Youyi Zhao;T. Zeng;Bing Liu;Tianyuan Ma;Junjun Kang;Hui Zhang
中科院分区：
文献类型：
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作者：
Lirong Liang;Ze Fan;Danyi He;Youyi Zhao;T. Zeng;Bing Liu;Tianyuan Ma;Junjun Kang;Hui Zhang
七氟烷（Sevoflurane，Sev）是一种广泛应用于小儿全身麻醉的吸入麻醉药。以往的研究已经证实，多次吸入麻醉剂可以诱导新生小鼠的长期神经毒性。然而，根本的机制仍然难以捉摸。在这项研究中，我们研究了同源结构域相互作用蛋白激酶2（HIPK 2），一种参与神经存活和突触可塑性的应激激活激酶的作用，及其在七氟烷诱导的神经毒性中的潜在机制。实验研究表明，七氟醚暴露后神经细胞凋亡增加。同时，在麻醉暴露后，在小鼠原代海马神经元和海马中观察到HIPK 2和AKT/mTOR信号的上调。HIPK 2拮抗剂A64可显著降低七氟醚诱导的AKT/mTOR活化和细胞凋亡。AKT拮抗剂MK 2206可部分减轻神经元凋亡，但不影响HIPK 2的表达。实验结果表明，HIPK 2/AKT/mTOR信号转导在七氟烷的神经毒性中起着至关重要的作用。因此，HIPK 2/AKT/mTOR信号通路可以作为未来保护吸入麻醉诱导的细胞毒性的潜在靶点。
Sevoflurane (Sev) is a widely used inhalational anesthetic for general anesthesia in children. Previous studies have confirmed that multiple exposures to inhaled anesthetic can induce long-term neurotoxicity in newborn mice. However, the underlying mechanisms remain elusive. In this study, we investigated the role of homeodomain interacting protein kinase 2 (HIPK2), a stress activating kinase involved in neural survival and synaptic plasticity, and its underlying mechanism in sevoflurane-induced neurotoxicity. Empirical study showed that neuronal apoptosis was elevated after exposure to sevoflurane. Meanwhile, up-regulation of HIPK2 and AKT/mTOR signaling was observed in primary hippocampal neurons and hippocampus in mice upon anesthetic exposure. A64, antagonist of HIPK2, could significantly reduce increased apoptosis and activation of AKT/mTOR induced by sevoflurane. AKT antagonist MK2206 partially alleviated neuronal apoptosis without affecting the expression of HIPK2. Experimental results demonstrated a crucial role of HIPK2/AKT/mTOR signaling in neurotoxicity of sevoflurane. Thus, HIPK2/AKT/mTOR signaling can serve as a potential target for the protection of inhalation anesthesia-induced cytotoxicity in the future.