Sevoflurane Acts on Ubiquitination-Proteasome Pathway to Reduce Postsynaptic Density 95 Protein Levels in Young Mice.
Sevoflurane Acts on Ubiquitination-Proteasome Pathway to Reduce Postsynaptic Density 95 Protein Levels in Young Mice.
复制标题
七氟烷作用于泛素化 — 蛋白酶体途径，降低幼鼠突触后密度 95 蛋白水平
DOI：
10.1097/aln.0000000000001889
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发表时间：
2017-12
期刊：
影响因子：
8.8
通讯作者：
Xie Z
中科院分区：
文献类型：
--
作者：
Lu H;Liufu N;Dong Y;Xu G;Zhang Y;Shu L;Soriano SG;Zheng H;Yu B;Xie Z
背景：多次暴露于麻醉和手术的儿童可能会增加发生认知障碍的风险。据报道，七氟烷是儿童常用的麻醉剂，可降低突触后密度95蛋白的水平。然而，七氟烷诱导的突触后密度95蛋白水平降低的上游机制和下游后果在很大程度上仍然未知。因此，我们着手评估七氟烷是否作用于泛素化-蛋白酶体途径以促进突触后密度95蛋白降解。方法：6日龄野生型小鼠从出生后第6天开始接受3%七氟烷麻醉，每天2 h，持续3天。我们确定了七氟醚麻醉对幼年小鼠神经元、突触体和海马中突触后密度95蛋白的mRNA、蛋白和泛素化水平的影响。在出生后第31天通过使用Morris水迷宫测定小鼠的认知功能。蛋白酶体抑制剂MG 132和E3连接酶小鼠双突变体2同源物抑制剂Nutlin-3用于相互作用研究。结果如下：七氟烷麻醉降低了幼龄小鼠神经元、突触体和海马中突触后密度95的蛋白质水平，但未降低mRNA水平，并降低了泛素化突触后密度95蛋白质水平。MG 132和Nutlin-3均阻断了这些七氟烷诱导的效应。七氟烷促进神经元中小鼠双突变体2同源物和突触后密度95蛋白的相互作用。最后，MG 132和Nutlin-3改善了七氟烷诱导的小鼠认知障碍。结论：这些数据表明，七氟烷作用于泛素化-蛋白酶体途径，促进突触后密度95蛋白降解，然后降低突触后密度95蛋白水平，导致幼龄小鼠的认知障碍。这些研究将进一步促进麻醉神经毒性在发育脑中的机制研究。
Background: Children with multiple exposures to anesthesia and surgery may have an increased risk of developing cognitive impairment. Sevoflurane, a commonly used anesthetic in children, has been reported to decrease levels of postsynaptic density 95 protein. However, the upstream mechanisms and downstream consequences of the sevoflurane-induced reduction in postsynaptic density 95 protein levels remains largely unknown. We therefore set out to assess whether sevoflurane acts on ubiquitination–proteasome pathway to facilitate postsynaptic density 95 protein degradation. Methods: Six-day-old wild-type mice received anesthesia with 3% sevoflurane 2 h daily for 3 days starting on postnatal day 6. We determined the effects of the sevoflurane anesthesia on mRNA, protein and ubiquitinated levels of postsynaptic density 95 protein in neurons, and synaptosomes and hippocampus of young mice. Cognitive function in the mice was determined at postnatal day 31 by using a Morris water maze. Proteasome inhibitor MG132 and E3 ligase mouse double mutant 2 homolog inhibitor Nutlin-3 were used for the interaction studies. Results: The sevoflurane anesthesia decreased protein, but not mRNA, levels of postsynaptic density 95, and reduced ubiquitinated postsynaptic density 95 protein levels in neurons, synaptosomes, and hippocampus of young mice. Both MG132 and Nutlin-3 blocked these sevoflurane-induced effects. Sevoflurane promoted the interaction of mouse double mutant 2 homolog and postsynaptic density 95 protein in neurons. Finally, MG132 and Nutlin-3 ameliorated the sevoflurane-induced cognitive impairment in the mice. Conclusions: These data suggest that sevoflurane acts on the ubiquitination–proteasome pathway to facilitate postsynaptic density 95 protein degradation, which then decreases postsynaptic density 95 protein levels, leading to cognitive impairment in young mice. These studies would further promote the mechanistic investigation of anesthesia neurotoxicity in the developing brain.