Iron overload contributes to general anaesthesia-induced neurotoxicity and cognitive deficits
Iron overload contributes to general anaesthesia-induced neurotoxicity and cognitive deficits
复制标题
铁过载会导致全身麻醉引起的神经毒性和认知缺陷
DOI：
10.1186/s12974-020-01777-6
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发表时间：
2020-04-11
影响因子：
9.3
通讯作者：
Li, Kuanyu
中科院分区：
文献类型：
--
作者：
Wu, Jing;Yang, Jian-Jun;Li, Kuanyu
越来越多的证据表明，多次或长时间暴露于全身麻醉（GA）可能对年轻受试者的认知发育有害，也可能导致老年人神经退行性变加速。铁对正常的神经元功能至关重要，脑中过量的铁与几种神经退行性疾病有关。然而，铁在GA诱导的神经毒性和认知缺陷中的作用仍然难以捉摸。方法采用原代海马神经元和啮齿类动物（包括年轻大鼠和老年小鼠），研究GA是否影响铁代谢以及这种影响是否有助于神经元的结局。此外，进行铁代谢的药理学抑制以探索GA介导的脑中铁过载的分子机制。结果氯胺酮或七氟醚诱导的GA均能破坏体外培养海马神经元和在体海马的铁稳态，引起铁超载。有趣的是，氯胺酮或七氟烷诱导的认知缺陷很可能是由一种新型铁依赖性调节细胞死亡（铁凋亡）引起的。值得注意的是，铁螯合剂去铁酮减弱了GA诱导的线粒体功能障碍、铁凋亡和进一步的认知缺陷。此外，我们发现GA诱导的铁过载被NMDAR-RASD 1信号通过DMT 1在大脑中的作用激活。结论铁代谢紊乱可能参与GA神经毒性和认知功能障碍的发生。我们的研究为GA相关神经系统疾病的考虑提供了新的视野。
Background Increasing evidence suggests that multiple or long-time exposure to general anaesthesia (GA) could be detrimental to cognitive development in young subjects and might also contribute to accelerated neurodegeneration in the elderly. Iron is essential for normal neuronal function, and excess iron in the brain is implicated in several neurodegenerative diseases. However, the role of iron in GA-induced neurotoxicity and cognitive deficits remains elusive. Methods We used the primary hippocampal neurons and rodents including young rats and aged mice to examine whether GA impacted iron metabolism and whether the impact contributed to neuronal outcomes. In addition, a pharmacological suppression of iron metabolism was performed to explore the molecular mechanism underlying GA-mediated iron overload in the brain. Results Our results demonstrated that GA, induced by intravenous ketamine or inhalational sevoflurane, disturbed iron homeostasis and caused iron overload in both in vitro hippocampal neuron culture and in vivo hippocampus. Interestingly, ketamine- or sevoflurane-induced cognitive deficits, very likely, resulted from a novel iron-dependent regulated cell death, ferroptosis. Notably, iron chelator deferiprone attenuated the GA-induced mitochondrial dysfunction, ferroptosis, and further cognitive deficits. Moreover, we found that GA-induced iron overload was activated by NMDAR-RASD1 signalling via DMT1 action in the brain. Conclusion We conclude that disturbed iron metabolism may be involved in the pathogenesis of GA-induced neurotoxicity and cognitive deficits. Our study provides new vision for consideration in GA-associated neurological disorders.