Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA.
Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an 710061, China.
Int J Mol Sci. 2024 Jun 19;25(12):6743. doi: 10.3390/ijms25126743.
Exposure to general anesthetics can adversely affect brain development, but there is little study of sedative agents used in intensive care that act via similar pharmacologic mechanisms. Using quantitative immunohistochemistry and neurobehavioral testing and an established protocol for murine sedation, we tested the hypothesis that lengthy, repetitive exposure to midazolam, a commonly used sedative in pediatric intensive care, interferes with neuronal development and subsequent cognitive function via actions on the mechanistic target of rapamycin (mTOR) pathway. We found that mice in the midazolam sedation group exhibited a chronic, significant increase in the expression of mTOR activity pathway markers in comparison to controls. Furthermore, both neurobehavioral outcomes, deficits in Y-maze and fear-conditioning performance, and neuropathologic effects of midazolam sedation exposure, including disrupted dendritic arborization and synaptogenesis, were ameliorated via treatment with rapamycin, a pharmacologic mTOR pathway inhibitor. We conclude that prolonged, repetitive exposure to midazolam sedation interferes with the development of neural circuitry via a pathologic increase in mTOR pathway signaling during brain development that has lasting consequences for both brain structure and function.
全身麻醉会对大脑发育产生不利影响，但对重症监护中使用的通过类似药理机制起作用的镇静剂研究甚少。我们使用定量免疫组织化学和神经行为测试以及已建立的用于鼠类镇静的方案，检验了一个假设，即长时间、重复接触咪达唑仑（儿科重症监护中常用的镇静剂）会通过作用于雷帕霉素（mTOR）途径的机制靶点来干扰神经元发育和随后的认知功能。我们发现，与对照组相比，咪达唑仑镇静组的小鼠表现出 mTOR 活性途径标志物的慢性、显著增加。此外，通过使用雷帕霉素（一种药理 mTOR 途径抑制剂）治疗，咪达唑仑镇静暴露的神经行为学结果（包括在 Y 迷宫和恐惧条件反射表现中的缺陷）和神经病理学效应，包括树突分支和突触发生的破坏，均得到改善。我们的结论是，长时间、重复接触咪达唑仑镇静会通过在大脑发育过程中病理性增加 mTOR 途径信号来干扰神经回路的发育，从而对大脑结构和功能产生持久影响。
