Tao Guorong, Zhang Jie, Zhang Lei, Dong Yuanlin, Yu Buwei, Crosby Gregory, Culley Deborah J, Zhang Yiying, Xie Zhongcong
From the Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, and Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China (G.T.); Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, and Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R China (J.Z.); Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, and Department of Anesthesiology, East Hospital, Tongji University School of Medicine, Shanghai, P. R. China (L.Z.); Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts (Y.D., Y.Z., Z.X.); Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China (B.Y.); and Department of Anesthesia, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (G.C., D.J.C.).
Anesthesiology. 2014 Sep;121(3):510-27. doi: 10.1097/ALN.0000000000000278.
Children with multiple exposures to anesthesia and surgery may have an increased risk of developing cognitive impairment. Sevoflurane is a commonly used anesthetic in children. Tau phosphorylation contributes to cognitive dysfunction. The authors therefore assessed the effects of sevoflurane on Tau phosphorylation and the underlying mechanisms in young mice.
Six-day-old wild-type and Tau knockout mice were exposed to sevoflurane. The authors determined the effects of sevoflurane anesthesia on Tau phosphorylation, levels of the kinases and phosphatase related to Tau phosphorylation, interleukin-6 and postsynaptic density protein-95 in hippocampus, and cognitive function in both young wild-type and Tau knockout mice.
Anesthesia with 3% sevoflurane 2 h daily for 3 days induced Tau phosphorylation (257 vs. 100%, P = 0.0025, n = 6) and enhanced activation of glycogen synthase kinase 3β, which is the kinase related to Tau phosphorylation in the hippocampus of postnatal day-8 wild-type mice. The sevoflurane anesthesia decreased hippocampus postsynaptic density protein-95 levels and induced cognitive impairment in the postnatal day-31 mice. Glycogen synthase kinase 3β inhibitor lithium inhibited the sevoflurane-induced glycogen synthase kinase 3β activation, Tau phosphorylation, increased levels of interleukin-6, and cognitive impairment in the wild-type young mice. Finally, the sevoflurane anesthesia did not induce an increase in interleukin-6 levels, reduction in postsynaptic density protein-95 levels in hippocampus, or cognitive impairment in Tau knockout young mice.
These data suggested that sevoflurane induced Tau phosphorylation, glycogen synthase kinase 3β activation, increase in interleukin-6 and reduction in postsynaptic density protein-95 levels in hippocampus of young mice, and cognitive impairment in the mice. Future studies will dissect the cascade relation of these effects.
多次接受麻醉和手术的儿童发生认知障碍的风险可能会增加。七氟醚是儿童常用的麻醉剂。tau蛋白磷酸化会导致认知功能障碍。因此，作者评估了七氟醚对幼鼠tau蛋白磷酸化的影响及其潜在机制。
对6日龄的野生型和tau蛋白基因敲除小鼠进行七氟醚暴露。作者测定了七氟醚麻醉对幼龄野生型和tau蛋白基因敲除小鼠tau蛋白磷酸化、与tau蛋白磷酸化相关的激酶和磷酸酶水平、海马中白细胞介素-6和突触后致密蛋白95的影响以及认知功能。
每天用3%七氟醚麻醉2小时，持续3天，可诱导tau蛋白磷酸化（257%对100%，P = 0.0025，n = 6），并增强糖原合酶激酶3β的激活，糖原合酶激酶3β是出生后第8天野生型小鼠海马中与tau蛋白磷酸化相关的激酶。七氟醚麻醉可降低出生后第31天小鼠海马突触后致密蛋白95水平，并诱导认知障碍。糖原合酶激酶3β抑制剂锂可抑制七氟醚诱导的野生型幼鼠糖原合酶激酶3β激活、tau蛋白磷酸化、白细胞介素-6水平升高和认知障碍。最后，七氟醚麻醉未诱导tau蛋白基因敲除幼鼠白细胞介素-6水平升高、海马突触后致密蛋白95水平降低或认知障碍。
这些数据表明，七氟醚可诱导幼鼠tau蛋白磷酸化、糖原合酶激酶3β激活、海马中白细胞介素-6增加和突触后致密蛋白95水平降低以及小鼠认知障碍。未来的研究将剖析这些效应的级联关系。
