Background

Sevoflurane anaesthesia induces phosphorylation of the microtubule-associated protein tau and cognitive impairment in neonatal, but not adult, mice. The underlying mechanisms remain largely to be determined. Sex hormones can be neuroprotective, but little is known about the influence of testosterone on age-dependent anaesthesia effects.

Methods

Six- and 60-day-old male mice received anaesthesia with sevoflurane 3% for 2 h daily for 3 days. Morris water maze, immunoassay, immunoblotting, co-immunoprecipitation, nanobeam technology, and electrophysiology were used to assess cognition; testosterone concentrations; tau phosphorylation; glycogen synthase kinase-3β (GSK3β) activation; binding or interaction between tau and GSK3β; and neuronal activation in mice, cells, and neurones.

Results

Compared with 60-day-old male mice, 6-day-old male mice had lower testosterone concentrations (3.03 [0.29] vs 0.44 [0.12] ng ml⁻¹; P<0.01), higher sevoflurane-induced tau phosphorylation in brain (133 [20]% vs 100 [6]% in 6-day-old mice, P<0.01; 103 [8]% vs 100 [13]% in 60-day-old mice, P=0.77), and sevoflurane-induced cognitive impairment. Testosterone treatment increased brain testosterone concentrations (1.76 [0.10] vs 0.39 [0.05] ng ml⁻¹; P<0.01) and attenuated the sevoflurane-induced tau phosphorylation and cognitive impairment in neonatal male mice. Testosterone inhibited the interaction between tau and GSK3β, and attenuated sevoflurane-induced inhibition of excitatory postsynaptic currents in hippocampal neurones.

Conclusions

Lower brain testosterone concentrations in neonatal compared with adult male mice contributed to age-dependent tau phosphorylation and cognitive impairment after sevoflurane anaesthesia. Testosterone might attenuate the sevoflurane-induced tau phosphorylation and cognitive impairment by inhibiting the interaction between tau and GSK3β.

中文翻译：

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睾酮减轻新生雄性小鼠七氟烷诱导的 tau 蛋白磷酸化和认知障碍

背景

七氟烷麻醉会诱导新生小鼠而非成年小鼠微管相关蛋白 tau 的磷酸化和认知障碍。基本机制在很大程度上仍有待确定。性激素可以起到神经保护作用，但关于睾酮对年龄依赖性麻醉效果的影响知之甚少。

方法

6 日龄和 60 日龄雄性小鼠接受 3% 七氟醚麻醉，每天 2 小时，持续 3 天。莫里斯水迷宫、免疫测定、免疫印迹、免疫共沉淀、纳米束技术和电生理学用于评估认知；睾酮浓度；tau磷酸化；糖原合酶激酶 3β (GSK3β) 激活；tau 和 GSK3β 之间的结合或相互作用；小鼠、细胞和神经元中的神经元激活。

结果

与 60 日龄雄性小鼠相比，6 日龄雄性小鼠的睾酮浓度较低（3.03 [0.29] vs 0.44 [0.12] ng ml ^-1；P <0.01），脑内七氟烷诱导的 tau 磷酸化水平较高（6 日龄小鼠133 [20]% vs 100 [6]%， P <0.01；60 日龄小鼠103 [8]% vs 100 [13]%， P =0.77）和七氟烷-诱发的认知障碍。睾酮治疗增加脑睾酮浓度（1.76 [0.10]对比0.39 [0.05] ng ml ^-1；P<0.01) 并减轻新生雄性小鼠七氟烷诱导的 tau 磷酸化和认知障碍。睾酮抑制 tau 和 GSK3β 之间的相互作用，并减弱七氟烷诱导的海马神经元兴奋性突触后电流抑制。

结论

与成年雄性小鼠相比，新生儿大脑睾酮浓度较低导致七氟烷麻醉后年龄依赖性 tau 磷酸化和认知障碍。睾酮可能通过抑制 tau 和 GSK3β 之间的相互作用来减弱七氟醚诱导的 tau 磷酸化和认知障碍。