Xiao Jinglei, Chen Zhengguo, Yu Buwei
Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
College of Computer, National University of Defence Technology, Changsha, China.
Front Cell Neurosci. 2020 Dec 4;14:593050. doi: 10.3389/fncel.2020.593050. eCollection 2020.
General anesthesia has revolutionized healthcare over the past 200 years and continues to show advancements. However, many phenomena induced by general anesthetics including paradoxical excitation are still poorly understood. Voltage-gated sodium channels (Na ) were believed to be one of the proteins targeted during general anesthesia. Based on electrophysiological measurements before and after propofol treatments of different concentrations, we mathematically modified the Hodgkin-Huxley sodium channel formulations and constructed a thalamocortical model to investigate the potential roles of Na . The ion channels of individual neurons were modeled using the Hodgkin-Huxley type equations. The enhancement of propofol-induced GABAa current was simulated by increasing the maximal conductance and the time-constant of decay. Electroencephalogram (EEG) was evaluated as the post-synaptic potential from pyramidal (PY) cells. We found that a left shift in activation of Na was induced primarily by a low concentration of propofol (0.3-10 μM), while a left shift in inactivation of Na was induced by an increasing concentration (0.3-30 μM). Mathematical simulation indicated that a left shift of Na activation produced a Hopf bifurcation, leading to cell oscillations. Left shift of Na activation around a value of 5.5 mV in the thalamocortical models suppressed normal bursting of thalamocortical (TC) cells by triggering its chaotic oscillations. This led to irregular spiking of PY cells and an increased frequency in EEG readings. This observation suggests a mechanism leading to paradoxical excitation during general anesthesia. While a left shift in inactivation led to light hyperpolarization in individual cells, it inhibited the activity of the thalamocortical model after a certain depth of anesthesia. This finding implies that high doses of propofol inhibit the network partly by accelerating Na toward inactivation. Additionally, this result explains why the application of sodium channel blockers decreases the requirement for general anesthetics. Our study provides an insight into the roles that Na plays in the mechanism of general anesthesia. Since the activation and inactivation of Na are structurally independent, it should be possible to avoid side effects by state-dependent binding to the Na to achieve precision medicine in the future.
在过去的200年里，全身麻醉彻底改变了医疗保健行业，并且仍在不断发展。然而，包括反常兴奋在内的许多由全身麻醉药引起的现象仍未得到充分理解。电压门控钠通道（Na ）被认为是全身麻醉期间的靶点蛋白之一。基于不同浓度丙泊酚处理前后的电生理测量结果，我们对霍奇金-赫胥黎钠通道公式进行了数学修正，并构建了一个丘脑皮质模型来研究Na 的潜在作用。单个神经元的离子通道使用霍奇金-赫胥黎类型方程进行建模。通过增加最大电导和衰减时间常数来模拟丙泊酚诱导的GABAa电流增强。脑电图（EEG）被评估为锥体（PY）细胞的突触后电位。我们发现，低浓度丙泊酚（0.3 - 10 μM）主要诱导Na 激活的左移，而随着浓度增加（0.3 - 30 μM）则诱导Na 失活的左移。数学模拟表明，Na 激活的左移产生了霍普夫分岔，导致细胞振荡。在丘脑皮质模型中，Na 激活在约5.5 mV处的左移通过触发混沌振荡抑制了丘脑皮质（TC）细胞的正常爆发。这导致PY细胞的不规则放电和EEG读数频率增加。这一观察结果提示了全身麻醉期间导致反常兴奋的一种机制。虽然失活的左移导致单个细胞轻度超极化，但在一定麻醉深度后它抑制了丘脑皮质模型的活动。这一发现意味着高剂量丙泊酚部分通过加速Na 进入失活状态来抑制神经网络。此外，这一结果解释了为什么应用钠通道阻滞剂会降低全身麻醉药的需求量。我们的研究深入了解了Na 在全身麻醉机制中所起的作用。由于Na 的激活和失活在结构上是独立的，未来应该有可能通过与Na 进行状态依赖性结合来避免副作用，从而实现精准医疗。
