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Studies on the mechanism of general anesthesia.

ABSTRACT: Inhaled anesthetics are a chemically diverse collection of hydrophobic molecules that robustly activate TWIK-related K+ channels (TREK-1) and reversibly induce loss of consciousness. For 100 y, anesthetics were speculated to target cellular membranes, yet no plausible mechanism emerged to explain a membrane effect on ion channels. Here we show that inhaled anesthetics (chloroform and isoflurane) activate TREK-1 through disruption of phospholipase D2 (PLD2) localization to lipid rafts and subsequent production of signaling lipid phosphatidic acid (PA). Catalytically dead PLD2 robustly blocks anesthetic TREK-1 currents in whole-cell patch-clamp recordings. Localization of PLD2 renders the TRAAK channel sensitive, a channel that is otherwise anesthetic insensitive. General anesthetics, such as chloroform, isoflurane, diethyl ether, xenon, and propofol, disrupt lipid rafts and activate PLD2. In the whole brain of flies, anesthesia disrupts rafts and PLDnull flies resist anesthesia. Our results establish a membrane-mediated target of inhaled anesthesia and suggest PA helps set thresholds of anesthetic sensitivity in vivo.

SUBMITTER: Pavel MA

PROVIDER: S-EPMC7306821 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Studies on the mechanism of general anesthesia.

Pavel Mahmud Arif MA Petersen E Nicholas EN Wang Hao H Lerner Richard A RA Hansen Scott B SB

Proceedings of the National Academy of Sciences of the United States of America 20200528 24

Inhaled anesthetics are a chemically diverse collection of hydrophobic molecules that robustly activate TWIK-related K<sup>+</sup> channels (TREK-1) and reversibly induce loss of consciousness. For 100 y, anesthetics were speculated to target cellular membranes, yet no plausible mechanism emerged to explain a membrane effect on ion channels. Here we show that inhaled anesthetics (chloroform and isoflurane) activate TREK-1 through disruption of phospholipase D2 (PLD2) localization to lipid rafts ...[more]

PMID: 32467161

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Project description:ObjectiveAnimals underwent combined general-epidural anesthesia (EGA) is reported to have better long-time outcome than general anesthesia (GA). This study aimed to make overall evaluation of the association between these two anesthetic techniques and prognosis of cancer patients undergoing surgery.MethodsRelated databases such as PubMed and EMbase were searched for eligible studies that evaluated the influence of EGA and GA on the prognosis of cancer patients undergoing surgery. Selected studies were evaluated according to the inclusion criteria by two reviewers respectively, followed by data extraction and quality assessment. The odds ratio (OR) with their 95% confidence intervals (CIs) were calculated to assess the influence strength of EGA and GA on prognosis of cancer patients.ResultsA total of ten studies involving 3254 patients were included. The overall results demonstrated that there was no significant difference between EGA and GA group (OR?=?0.88, 95% CI 0.73 to 1.06, P?=?0.187) concerning postoperative recurrence and metastasis rate. In regard to the following two factors: cancer category and time of follow-up, subgroup analysis identified significant differences between EGA and GA in the group of patients with prostate cancer and the group with follow-up less than or equal to two years (OR?=?0.66, 95% CI 0.46 to 0.95, P?=?0.027; OR?=?0.70, 95% CI 0.51 to 0.98, P?=?0.035; respectively) concerning postoperative recurrence and metastasis rate. However, no significant difference was found in the group of patients with colorectal cancer (OR?=?1.06, 95% CI 0.84-1.33, P?=?0.62).ConclusionsThis meta-analysis showed that EGA might be associated with improvement in prognosis of patients with operable prostate cancer and the cancer patients with follow-up less than or equal to two years. However, no obvious relationship between the improvement in prognosis of colorectal cancer and EGA were detected, comparing to GA. Furthermore, all the results should be interpreted cautiously, as heterogeneous data were used for analyzing.

Project description: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 V ) 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 V . 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 V was induced primarily by a low concentration of propofol (0.3-10 μM), while a left shift in inactivation of Na V was induced by an increasing concentration (0.3-30 μM). Mathematical simulation indicated that a left shift of Na V activation produced a Hopf bifurcation, leading to cell oscillations. Left shift of Na V 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 V 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 V plays in the mechanism of general anesthesia. Since the activation and inactivation of Na V are structurally independent, it should be possible to avoid side effects by state-dependent binding to the Na V to achieve precision medicine in the future.

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Studies on the mechanism of general anesthesia.

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Studies on the mechanism of general anesthesia.

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