Institut National de la Santé et de la Recherche Médicale, UMR837, Alzheimer & Tauopathies, Institut de Médecine Prédictive et de Recherche Thérapeutique, Lille, France.
Anesthesiology. 2012 Apr;116(4):779-87. doi: 10.1097/ALN.0b013e31824be8c7.
There is a growing interest in the involvement of anesthetic agents in the etiology of postoperative cognitive dysfunction. Recent animal studies suggest that acute anesthesia induces transient hyperphosphorylation of tau, an effect essentially ascribed to hypothermia. The main aim of the present study was to investigate effects, in normothermic conditions, of acute or repeated exposure to sevoflurane, a halogenated anesthetic agent, on hippocampal tau phosphorylation and spatial memory in adult mice.
5 to 6-month-old C57Bl6/J mice were submitted to acute (1 h) or repeated (five exposures of 1h every month) anesthesia using 1.5 or 2.5% sevoflurane, in normothermic conditions. In the acute protocol, animals were sacrificed 1 and 24 h after exposure. In the chronic protocol, spatial memory was evaluated using the Morris water maze following the fourth exposure, and tau phosphorylation evaluated 1 month following the last exposure using bi- and mono-dimensional electrophoresis.
Acute sevoflurane anesthesia in normothermic conditions led to a significant dose-dependent and reversible hippocampal tau phosphorylation, 1 h following the end of exposure (P < 0.001). Conversely, repeated anesthesia led to persistent tau hyperphosphorylation and significant memory impairments, as seen in the retention phase of the Morris water maze in sevoflurane-anesthesized animals. These pathologic features may be related to the activation of both Akt and Erk pathways.
The present study demonstrates, in mice, that sevoflurane exposure is associated with increased tau phosphorylation through specific kinases activation and spatial memory deficits. These data support a correlation between exposures to this anesthetic agent and cognitive decline.
麻醉剂在术后认知功能障碍的病因学中的作用引起了越来越多的关注。最近的动物研究表明，急性麻醉会导致 tau 的瞬时过度磷酸化，这一效应主要归因于体温过低。本研究的主要目的是在正常体温条件下，研究急性或反复暴露于卤代麻醉剂七氟醚对成年小鼠海马 tau 磷酸化和空间记忆的影响。
5 至 6 个月大的 C57Bl6/J 小鼠在正常体温条件下接受 1.5 或 2.5%七氟醚的急性（1 小时）或重复（每月 5 次，每次 1 小时）麻醉。在急性方案中，动物在暴露后 1 小时和 24 小时处死。在慢性方案中，使用 Morris 水迷宫在第四次暴露后评估空间记忆，在最后一次暴露后 1 个月使用双向和单向电泳评估 tau 磷酸化。
正常体温条件下急性七氟醚麻醉导致剂量依赖性和可逆的海马 tau 磷酸化，在暴露结束后 1 小时（P < 0.001）。相反，重复麻醉导致 tau 过度磷酸化和显著的记忆损伤，如在 sevoflurane-anesthetized 动物的 Morris 水迷宫保留阶段所见。这些病理特征可能与 Akt 和 Erk 通路的激活有关。
本研究在小鼠中表明，七氟醚暴露与通过特定激酶激活导致的 tau 磷酸化增加和空间记忆缺陷相关。这些数据支持了这种麻醉剂暴露与认知能力下降之间的相关性。
