Li Xiao-Min, Su Fan, Ji Mu-Huo, Zhang Guang-Fen, Qiu Li-Li, Jia Min, Gao Jun, Xie Zhongcong, Yang Jian-Jun
From the Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China (X.-M.L., M.-H.J., G.-F.Z., L.-L.Q., M.J., J.-J.Y.); Department of Anesthesiology, Affiliate Hospital, Shandong Medical University of Traditional Chinese Medicine, Jinan, China (F.S.); Departments of Neurobiology and Pharmacology, Key Laboratory for Neurodegenerative Disease of Jiangsu Province, Nanjing Medical University, Nanjing, China (J.G.); and Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts (Z.X.).
Anesthesiology. 2014 Jul;121(1):79-88. doi: 10.1097/ALN.0000000000000191.
A prolonged isoflurane exposure may lead to cognitive decline in rodents. Neuregulin 1 (NRG1)-ErbB4 signaling plays a key role in the modulation of hippocampal synaptic plasticity through regulating the neurotransmission. The authors hypothesized that hippocampal NRG1-ErbB4 signaling is involved in isoflurane-induced cognitive impairments in aged mice.
Fourteen-month-old C57BL/6 mice were randomized to receive 100% O2 exposure, vehicle injection after 100% O2 exposure, vehicle injection after exposure to isoflurane carried by 100% O2, NRG1-β1 injection after exposure to isoflurane carried by 100% O2, and NRG1-β1 and an ErbB4 inhibitor AG1478 injection after exposure to isoflurane carried by 100% O2. Fear conditioning test was used to assess the cognitive function of mice 48-h postexposure. The brain tissues were harvested 48-h postexposure to determine the levels of NRG1, ErbB4, p-ErbB4, parvalbumin, and glutamic acid decarboxylase 67 in the hippocampus using Western blotting, enzyme-linked immunosorbent assay, and immunofluorescence.
The percentage of freezing time to context was decreased from 50.28 ± 11.53% to 30.82 ± 10.00%, and the hippocampal levels of NRG1, p-ErbB4/ErbB4, parvalbumin, and glutamic acid decarboxylase 67 were decreased from 172.79 ± 20.85 ng/g, 69.15 ± 12.20%, 101.68 ± 11.21%, and 104.71 ± 6.85% to 112.92 ± 16.65 ng/g, 42.26 ± 9.71%, 75.89 ± 10.26%, and 73.87 ± 16.89%, respectively, after isoflurane exposure. NRG1-β1 attenuated the isoflurane-induced hippocampus-dependent cognitive impairment and the declines in the hippocampal NRG1, p-ErbB4/ErbB4, parvalbumin, and glutamic acid decarboxylase 67. AG1478 inhibited the rescuing effects of NRG1-β1.
Disruption of NRG1-ErbB4 signaling in the parvalbumin-positive interneurons might, at least partially, contribute to the isoflurane-induced hippocampus-dependent cognitive impairment after exposure to isoflurane carried by 100% O2 in aged mice.
长时间暴露于异氟烷可能导致啮齿动物认知能力下降。神经调节蛋白1（NRG1）-表皮生长因子受体4（ErbB4）信号通路通过调节神经传递在海马突触可塑性的调节中起关键作用。作者推测海马NRG1-ErbB4信号通路参与了异氟烷诱导的老年小鼠认知障碍。
将14个月大的C57BL/6小鼠随机分为接受100%氧气暴露组、100%氧气暴露后注射溶剂组、100%氧气携带异氟烷暴露后注射溶剂组、100%氧气携带异氟烷暴露后注射NRG1-β1组以及100%氧气携带异氟烷暴露后注射NRG1-β1和ErbB4抑制剂AG1478组。采用恐惧条件反射试验在暴露后48小时评估小鼠的认知功能。暴露后48小时收集脑组织，使用蛋白质免疫印迹法、酶联免疫吸附测定法和免疫荧光法测定海马中NRG1、ErbB4、磷酸化ErbB4（p-ErbB4）、小白蛋白和谷氨酸脱羧酶67的水平。
异氟烷暴露后，对环境的冻结时间百分比从50.28±11.53%降至30.82±10.00%，海马中NRG1、p-ErbB4/ErbB4、小白蛋白和谷氨酸脱羧酶67的水平分别从172.79±20.85 ng/g、69.15±12.20%、101.68±11.21%和104.71±6.85%降至112.92±16.65 ng/g、42.26±9.71%、75.89±10.26%和73.87±16.89%。NRG1-β1减轻了异氟烷诱导的海马依赖性认知障碍以及海马中NRG1、p-ErbB4/ErbB4、小白蛋白和谷氨酸脱羧酶67的下降。AG1478抑制了NRG1-β1的挽救作用。
在老年小鼠中，100%氧气携带异氟烷暴露后，小白蛋白阳性中间神经元中NRG1-ErbB4信号通路的破坏可能至少部分导致了异氟烷诱导的海马依赖性认知障碍。
