Abstract
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 (NaV) 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 NaV. 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 NaV was induced primarily by a low concentration of propofol (0.3–10 μM), while a left shift in inactivation of NaV was induced by an increasing concentration (0.3–30 μM). Mathematical simulation indicated that a left shift of NaV activation produced a Hopf bifurcation, leading to cell oscillations. Left shift of NaV 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 NaV 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 NaV plays in the mechanism of general anesthesia. Since the activation and inactivation of NaV are structurally independent, it should be possible to avoid side effects by state-dependent binding to the NaV to achieve precision medicine in the future.
Highlights
Anesthesia is considered one of the 10 greatest discoveries in medical history (Lawrence, 1999)
As shown in the IV curve, when the propofol tremendously affects activation, peak current of NaV is increased compared with the control results, implying that a low concentration of propofol should have a positive influence on sodium channels (Supplementary Figure 2A and Table 3)
We found that the followings: (i) Enhancement of activation is mainly induced by low concentrations of propofol, and acceleration of inactivation takes place in a dose-dependent manner. (ii) By altering gating parameters related to the equations of NaV activation and inactivation based on the H-H model, we found that varying the shift of NaV activation parameters enhanced cell activity by inducing Hopf bifurcation in neuron models with the essential channels. (iii)
Summary
Anesthesia is considered one of the 10 greatest discoveries in medical history (Lawrence, 1999). Several unexpected phenomena have been reported in general anesthesia. Some general anesthetics, typically propofol, could lead to a paradoxical excitation in light anesthesia with an incidence ranging from 14 to 70% (Jeong et al, 2011). Potentiation of γ -GABAa receptor is a widely accepted molecular mechanism of general anesthetics, which results in an inhibition of the central nervous system (Yip et al, 2013; Jayakar et al, 2014). It cannot properly explain these unexpected phenomena. Further research may ensure better understanding of these phenomena to ensure the clinical safety of patients
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