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The effects of the general anesthetic sevoflurane on neurotransmission: an experimental and computational study.

ABSTRACT: The brain functions can be reversibly modulated by the action of general anesthetics. Despite a wide number of pharmacological studies, an extensive analysis of the cellular determinants of anesthesia at the microcircuits level is still missing. Here, by combining patch-clamp recordings and mathematical modeling, we examined the impact of sevoflurane, a general anesthetic widely employed in the clinical practice, on neuronal communication. The cerebellar microcircuit was used as a benchmark to analyze the action mechanisms of sevoflurane while a biologically realistic mathematical model was employed to explore at fine grain the molecular targets of anesthetic analyzing its impact on neuronal activity. The sevoflurane altered neurotransmission by strongly increasing GABAergic inhibition while decreasing glutamatergic NMDA activity. These changes caused a notable reduction of spike discharge in cerebellar granule cells (GrCs) following repetitive activation by excitatory mossy fibers (mfs). Unexpectedly, sevoflurane altered GrCs intrinsic excitability promoting action potential generation. Computational modelling revealed that this effect was triggered by an acceleration of persistent sodium current kinetics and by an increase in voltage dependent potassium current conductance. The overall effect was a reduced variability of GrCs responses elicited by mfs supporting the idea that sevoflurane shapes neuronal communication without silencing neural circuits.

SUBMITTER: Mapelli J

PROVIDER: S-EPMC7900247 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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The effects of the general anesthetic sevoflurane on neurotransmission: an experimental and computational study.

Mapelli Jonathan J Gandolfi Daniela D Giuliani Enrico E Casali Stefano S Congi Luigi L Barbieri Alberto A D'Angelo Egidio E Bigiani Albertino A

Scientific reports 20210222 1

The brain functions can be reversibly modulated by the action of general anesthetics. Despite a wide number of pharmacological studies, an extensive analysis of the cellular determinants of anesthesia at the microcircuits level is still missing. Here, by combining patch-clamp recordings and mathematical modeling, we examined the impact of sevoflurane, a general anesthetic widely employed in the clinical practice, on neuronal communication. The cerebellar microcircuit was used as a benchmark to a ...[more]

PMID: 33619298

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Project description:BackgroundAlthough immunomodulatory effects of anesthetics have been increasingly recognized, their underlying molecular mechanisms are not completely understood. Toll-like receptors (TLRs) are one of the major receptors to recognize invading pathogens and danger signals from damaged host tissues to initiate immune responses. Among the TLR family, TLR2 and TLR4 recognize a wide range of ligands and are considered to be important players in perioperative pathophysiology. Based on our recent finding that volatile anesthetics modulate TLR4 function, we tested our hypothesis that they would also modulate TLR2 function.MethodsThe effect of anesthetics isoflurane, sevoflurane, propofol, and dexmedetomidine on TLR2 activation was examined by reporter assays. An anesthetic that affected the activation was subjected to in silico rigid docking simulation on TLR2. To test our prediction that sevoflurane and a TLR1/TLR2 ligand Pam3CSK4 would compete for the same pocket of TLR2, we performed Pam3CSK4 competitive binding assay to TLR2 using HEK cells stably transfected with TLR2 (HEK-TLR2) with or without sevoflurane. We examined the effect of different anesthetics on the functions of human neutrophils stimulated with TLR2 ligands. Kruskal-Wallis test and Mann-Whitney U test were used for statistical analysis.ResultsWe observed that the attenuation of TLR1/TLR2 activation was seen on sevoflurane exposure but not on isoflurane, propofol, or dexmedetomidine exposure. The attenuation of TLR2/TLR6 activation was not seen in any of the anesthetics tested. The rigid docking simulation predicted that sevoflurane and Pam3CSK4 bound to the same pocket of TLR1/TLR2 complex. The binding of Pam3CSK4 to HEK-TLR2 cells was impaired in the presence of sevoflurane, indicating that sevoflurane and Pam3CSK4 competed for the pocket, as predicted in silico. The stimulation of neutrophils with Pam3CSK4 induced L-selection shedding but did not affect phagocytosis and reactive oxygen species production. L-selectin shedding from neutrophils was attenuated only by sevoflurane, consistent with the result of our reporter assays.ConclusionsWe found that TLR1/TLR2 activation was attenuated by sevoflurane, but we found no evidence for attenuation by isoflurane, propofol, or dexmedetomidine at clinically relevant concentrations. Our structural analysis and competition assay supported that sevoflurane directly bound to TLR2 at the interphase of the TLR1/TLR2 complex. Sevoflurane attenuated neutrophil L-selectin shedding, an important step for neutrophil migration.

Project description:Surgery patients in Japan undergo routine spirometry testing prior to general anesthesia. The use of a flow sensor during general anesthesia has recently become common. However, it is not certain whether the information derived from flow-volume curves is being adequately used for mechanical ventilation management during general anesthesia. So far, there have been no attempts to calculate airway resistance using flow-volume curves. Therefore, we performed a prospective, observational study to investigate the relationship between pre-anesthetic and intra-anesthetic airway resistance in patients scheduled for surgery under general anesthesia. We calculated pre-anesthetic and intra-anesthetic airway resistance in each patient, based on the slopes of flow-volume curves obtained prior to and during general anesthesia. We also calculated endotracheal tube resistance to correct the intra-anesthetic airway resistance values calculated. A total of 526 patients were included in the study, and 98 patients had a forced expiratory volume in the first second/forced vital capacity ratio of < 70%. Pre-anesthetic airway resistance was significantly higher in patients with airflow obstruction than in those without airflow obstruction (p < 0.001), whereas no significant difference in intra-anesthetic airway resistance was found between patients with and without airflow obstruction during mechanical ventilation (p = 0.48). Pre-anesthetic and intra-anesthetic airway resistance values were closer to each other in patients without airflow obstruction, with a mean difference < 1.0 cmH2O L-1s-1, than in those with airflow obstruction, although these respiratory parameters were significantly different (p < 0.001). Intra-anesthetic airway resistance was not related to the FEV1/FVC ratio, regardless of the degree to which the FEV1/FVC ratio reflected pre-anesthetic airway resistance. As compared with patients with airflow obstruction, the mean difference between pre-anesthetic and intra-anesthetic airway resistance was small in patients without airflow obstruction.

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The effects of the general anesthetic sevoflurane on neurotransmission: an experimental and computational study.

Publications

The effects of the general anesthetic sevoflurane on neurotransmission: an experimental and computational study.

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