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Molecular Mechanisms and Neural Correlates of General Anesthesia-2nd Edition

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (1 December 2021) | Viewed by 6162

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Prof. Bernd Antkowiak

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Guest Editor

Universität Tübingen, Tubingen, Germany
Interests: Mechanisms of Anesthetic Actions; Benzodiazepines; Central Muscle Relaxants; Neuroinflammation
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Gerhard Rammes

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Guest Editor

Department of Anaesthesiology and Intensive Care Medicine, Technical University Munich, Ismaninger str. 22, 81675 Munich, Germany
Interests: electrophysiology; long-term potentiation; voltage-sensitive-dye imaging; Alzheimer; anesthetics
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Dear Colleagues,

Anesthetic agents are essential in modern medicine, allowing performance of surgery in more than 200 million human subjects every year. Besides desired actions including unconsciousness, amnesia, anti-nociception and immobility, currently administered drugs have a lengthy list of adverse effects. Expanding our knowledge of how anesthetic drugs act on a molecular and systemic level in different parts of the central nervous system, is a major source of new ideas in order to improve perioperative anaesthesia. In this respect, a key challenge is to determine which drug-receptor interactions and neural correlates contribute to clinically desired and unwanted behavioural effects. Thanks to animal models, in which targeted mutations rendered proteins insensitive to anesthetic modulation, we made significant progress in recent years. However, many questions remain unanswered, frequently including the problem of transferring knowledge from animal models to human subjects. This Special Issue is focussing on basic and translational research in the field of anesthesiology. It will feature original research, reviews and commentaries trying to open new insights into the mechanisms of anesthetic action.

Prof. Bernd Antkowiak
Prof. Gerhard Rammes
Guest Editors

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Molecular Mechanisms and Neural Correlates of General Anesthesia in International Journal of Molecular Sciences (8 articles)

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16 pages, 17616 KiB

Open AccessArticle

Sevoflurane Effects on Neuronal Energy Metabolism Correlate with Activity States While Mitochondrial Function Remains Intact

by Mathilde Maechler, Jörg Rösner, Iwona Wallach, Joerg R. P. Geiger, Claudia Spies, Agustin Liotta and Nikolaus Berndt

Int. J. Mol. Sci. 2022, 23(6), 3037; https://doi.org/10.3390/ijms23063037 - 11 Mar 2022

Cited by 4 | Viewed by 2515

Abstract

During general anesthesia, alterations in neuronal metabolism may induce neurotoxicity and/or neuroprotection depending on the dose and type of the applied anesthetic. In this study, we investigate the effects of clinically relevant concentrations of sevoflurane (2% and 4%, i.e., 1 and 2 MAC) on different activity states in hippocampal slices of young Wistar rats. We combine electrophysiological recordings, partial tissue oxygen (p_tiO₂) measurements, and flavin adenine dinucleotide (FAD) imaging with computational modeling. Sevoflurane minimally decreased the cerebral metabolic rate of oxygen (CMRO₂) while decreasing synaptic transmission in naive slices. During pharmacologically induced gamma oscillations, sevoflurane impaired network activity, thereby decreasing CMRO₂. During stimulus-induced neuronal activation, sevoflurane decreased CMRO₂ and excitability while basal metabolism remained constant. In this line, stimulus-induced FAD transients decreased without changes in basal mitochondrial redox state. Integration of experimental data and computer modeling revealed no evidence for a direct effect of sevoflurane on key enzymes of the citric acid cycle or oxidative phosphorylation. Clinically relevant concentrations of sevoflurane generated a decent decrease in energy metabolism, which was proportional to the present neuronal activity. Mitochondrial function remained intact under sevoflurane, suggesting a better metabolic profile than isoflurane or propofol. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Neural Correlates of General Anesthesia-2nd Edition)

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8 pages, 833 KiB

Open AccessArticle

Isoflurane Potentiation of GABA_A Receptors Is Reduced but Not Eliminated by the β3(N265M) Mutation

by Chong Lor, Misha Perouansky and Robert A. Pearce

Int. J. Mol. Sci. 2020, 21(24), 9534; https://doi.org/10.3390/ijms21249534 - 15 Dec 2020

Cited by 5 | Viewed by 1991

Abstract

Background: Mice carrying the GABA_A receptor β3(N265M) point mutation, which renders receptors incorporating β3-subunits insensitive to many general anesthetics, have been used experimentally to link modulation of different receptor subtypes to distinct behavioral endpoints. Remarkably, however, the effect of the mutation on the susceptibility to modulation by isoflurane (a standard reference agent for inhalational vapors) has never been tested directly. Therefore, we compared the modulation by isoflurane of expressed α5β3(N265M)γ2L receptors with their wild type counterparts. Methods: Using whole-cell electrophysiological recording and rapid solution exchange techniques, we tested the effects of isoflurane at concentrations ranging from 80 μM to 320 μM on currents activated by 1 μM GABA. We measured drug modulation of wild-type α5β3γ2L GABA_A receptors and their counterparts harboring the β3(N265M) mutation. Results: Currents elicited by GABA were enhanced two- to four-fold by isoflurane, in a concentration-dependent manner. Under the same conditions, receptors incorporating the β3(N265M) mutation were enhanced by approximately 1.5- to two-fold; i.e., modulation by isoflurane was attenuated by approximately one-half. Direct activation by isoflurane was also present in mutant receptors but also attenuated. Conclusions: In contrast to the complete insensitivity of β3(N265M) mutant receptors to etomidate and propofol, the mutation has only a partial effect on receptor modulation by isoflurane. Therefore, the persistence of isoflurane effects in mutant mice does not exclude a possible contribution of β3-GABA_A receptors. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Neural Correlates of General Anesthesia)

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19 pages, 3253 KiB

Open AccessArticle

Sleep/Wake Behavior and EEG Signatures of the TgF344-AD Rat Model at the Prodromal Stage

by Matthias Kreuzer, Glenda L. Keating, Thomas Fenzl, Lorenz Härtner, Christopher G. Sinon, Ihab Hajjar, Vincent Ciavatta, David B. Rye and Paul S. García

Int. J. Mol. Sci. 2020, 21(23), 9290; https://doi.org/10.3390/ijms21239290 - 5 Dec 2020

Cited by 7 | Viewed by 3039

Abstract

Transgenic modification of the two most common genes (APPsw, PS1ΔE9) related to familial Alzheimer’s disease (AD) in rats has produced a rodent model that develops pathognomonic signs of AD without genetic tau-protein modification. We used 17-month-old AD rats (n = 8) and age-matched controls (AC, n = 7) to evaluate differences in sleep behavior and EEG features during wakefulness (WAKE), non-rapid eye movement sleep (NREM), and rapid eye movement sleep (REM) over 24-h EEG recording (12:12h dark–light cycle). We discovered that AD rats had more sleep–wake transitions and an increased probability of shorter REM and NREM bouts. AD rats also expressed a more uniform distribution of the relative spectral power. Through analysis of information content in the EEG using entropy of difference, AD animals demonstrated less EEG information during WAKE, but more information during NREM. This seems to indicate a limited range of changes in EEG activity that could be caused by an AD-induced change in inhibitory network function as reflected by increased GABAAR-β2 expression but no increase in GAD-67 in AD animals. In conclusion, this transgenic rat model of Alzheimer’s disease demonstrates less obvious EEG features of WAKE during wakefulness and less canonical features of sleep during sleep. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Neural Correlates of General Anesthesia)

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17 pages, 4021 KiB

Open AccessArticle

Allopregnanolone Enhances GABAergic Inhibition in Spinal Motor Networks

by Berthold Drexler, Julia Grenz, Christian Grasshoff and Bernd Antkowiak

Int. J. Mol. Sci. 2020, 21(19), 7399; https://doi.org/10.3390/ijms21197399 - 7 Oct 2020

Cited by 1 | Viewed by 2638

Abstract

The neurosteroid allopregnanolone (ALLO) causes unconsciousness by allosteric modulation of γ-aminobutyric acid type A (GABA_A) receptors, but its actions on the spinal motor networks are unknown. We are therefore testing the hypothesis that ALLO attenuates the action potential firing of spinal interneurons and motoneurons predominantly via enhancing tonic, but not synaptic GABAergic inhibition. We used video microscopy to assess motoneuron-evoked muscle activity in organotypic slice cultures prepared from the spinal cord and muscle tissue. Furthermore, we monitored GABA_A receptor-mediated currents by performing whole-cell voltage-clamp recordings. We found that ALLO (100 nM) reduced the action potential firing of spinal interneurons by 27% and that of α-motoneurons by 33%. The inhibitory effects of the combination of propofol (1 µM) and ALLO on motoneuron-induced muscle contractions were additive. Moreover, ALLO evoked a tonic, GABA_A receptor-mediated current (amplitude: 41 pA), without increasing phasic GABAergic transmission. Since we previously showed that at a clinically relevant concentration of 1 µM propofol enhanced phasic, but not tonic GABAergic inhibition, we conclude that ALLO and propofol target distinct subpopulations of GABA_A receptors. These findings provide first evidence that the combined application of ALLO and propofol may help to reduce intraoperative movements and undesired side effects that are frequently observed under total intravenous anesthesia. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Neural Correlates of General Anesthesia)

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22 pages, 9776 KiB

Open AccessArticle

Interactions among Genetic Background, Anesthetic Agent, and Oxygen Concentration Shape Blunt Traumatic Brain Injury Outcomes in Drosophila melanogaster

by Amanda R. Scharenbrock, Hannah J. Schiffman, Zachariah P. G. Olufs, David A. Wassarman and Misha Perouansky

Int. J. Mol. Sci. 2020, 21(18), 6926; https://doi.org/10.3390/ijms21186926 - 21 Sep 2020

Cited by 3 | Viewed by 2446

Abstract

Following traumatic brain injury (TBI), the time window during which secondary injuries develop provides a window for therapeutic interventions. During this time, many TBI victims undergo exposure to hyperoxia and anesthetics. We investigated the effects of genetic background on the interaction of oxygen and volatile general anesthetics with brain pathophysiology after closed-head TBI in the fruit fly Drosophila melanogaster. To test whether sevoflurane shares genetic risk factors for mortality with isoflurane and whether locomotion is affected similarly to mortality, we used a device that generates acceleration–deceleration forces to induce TBI in ten inbred fly lines. After TBI, we exposed flies to hyperoxia alone or in combination with isoflurane or sevoflurane and quantified mortality and locomotion 24 and 48 h after TBI. Modulation of TBI–induced mortality and locomotor impairment by hyperoxia with or without anesthetics varied among fly strains and among combinations of agents. Resistance to increased mortality from hyperoxic isoflurane predicted resistance to increased mortality from hyperoxic sevoflurane but did not predict the degree of locomotion impairment under any condition. These findings are important because they demonstrate that, in the context of TBI, genetic background determines the latent toxic potentials of oxygen and anesthetics. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Neural Correlates of General Anesthesia)

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15 pages, 4460 KiB

Open AccessArticle

Propofol Affects Cortico-Hippocampal Interactions via β3 Subunit-Containing GABA_A Receptors

by Matthias Kreuzer, Sergejus Butovas, Paul S García, Gerhard Schneider, Cornelius Schwarz, Uwe Rudolph, Bernd Antkowiak and Berthold Drexler

Int. J. Mol. Sci. 2020, 21(16), 5844; https://doi.org/10.3390/ijms21165844 - 14 Aug 2020

Cited by 5 | Viewed by 2974

Abstract

Background: General anesthetics depress neuronal activity. The depression and uncoupling of cortico-hippocampal activity may contribute to anesthetic-induced amnesia. However, the molecular targets involved in this process are not fully characterized. GABA_A receptors, especially the type with β3 subunits, represent a main molecular target of propofol. We therefore hypothesized that GABA_A receptors with β3 subunits mediate the propofol-induced disturbance of cortico-hippocampal interactions. Methods: We used local field potential (LFP) recordings from chronically implanted cortical and hippocampal electrodes in wild-type and β3(N265M) knock-in mice. In the β3(N265M) mice, the action of propofol via β3subunit containing GABA_A receptors is strongly attenuated. The analytical approach contained spectral power, phase locking, and mutual information analyses in the 2–16 Hz range to investigate propofol-induced effects on cortico-hippocampal interactions. Results: Propofol caused a significant increase in spectral power between 14 and 16 Hz in the cortex and hippocampus of wild-type mice. This increase was absent in the β3(N265M) mutant. Propofol strongly decreased phase locking of 6–12 Hz oscillations in wild-type mice. This decrease was attenuated in the β3(N265M) mutant. Finally, propofol reduced the mutual information between 6–16 Hz in wild-type mice, but only between 6 and 8 Hz in the β3(N265M) mutant. Conclusions: GABA_A receptors containing β3 subunits contribute to frequency-specific perturbation of cortico-hippocampal interactions. This likely explains some of the amnestic actions of propofol. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Neural Correlates of General Anesthesia)

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13 pages, 2710 KiB

Open AccessArticle

A Metabolic Mechanism for Anaesthetic Suppression of Cortical Synaptic Function in Mouse Brain Slices—A Pilot Investigation

by Logan J. Voss and Jamie W. Sleigh

Int. J. Mol. Sci. 2020, 21(13), 4703; https://doi.org/10.3390/ijms21134703 - 1 Jul 2020

Cited by 5 | Viewed by 2563

Abstract

Regulation of synaptically located ionotropic receptors is thought to be the main mechanism by which anaesthetics cause unconsciousness. An alternative explanation, which has received much less attention, is that of primary anaesthetic disruption of brain metabolism via suppression of mitochondrial proteins. In this pilot study in mouse cortical slices, we investigated the effect of disrupting cellular metabolism on tissue oxygen handling and cortical population seizure-like event (SLE) activity, using the mitochondrial complex I inhibitor rotenone, and compared this to the effects of the general anaesthetics sevoflurane, propofol and ketamine. Rotenone caused an increase in tissue oxygen (98 mmHg to 157 mmHg (p < 0.01)) before any measurable change in SLE activity. Thereafter, tissue oxygen continued to increase and was accompanied by a significant and prolonged reduction in SLE root mean square (RMS) activity (baseline RMS of 1.7 to 0.7 µV, p < 0.001) and SLE frequency (baseline 4.2 to 0.4 events/min, p = 0.001). This temporal sequence of effects was replicated by all three anaesthetic drugs. In conclusion, anaesthetics with differing synaptic receptor mechanisms all effect changes in tissue oxygen handling and cortical network activity, consistent with a common inhibitory effect on mitochondrial function. The temporal sequence suggests that the observed synaptic depression—as seen in anaesthesia—may be secondary to a reduction in cellular metabolic capacity. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Neural Correlates of General Anesthesia)

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14 pages, 1504 KiB

Open AccessArticle

Conflicting Actions of Inhalational Anesthetics, Neurotoxicity and Neuroprotection, Mediated by the Unfolded Protein Response

by Hiroshi Kokubun, Hisayo Jin, Mari Komita and Tomohiko Aoe

Int. J. Mol. Sci. 2020, 21(2), 450; https://doi.org/10.3390/ijms21020450 - 10 Jan 2020

Cited by 8 | Viewed by 3515

Abstract

Preclinical studies have shown that exposure of the developing brain to inhalational anesthetics can cause neurotoxicity. However, other studies have claimed that anesthetics can exert neuroprotective effects. We investigated the mechanisms associated with the neurotoxic and neuroprotective effects exerted by inhalational anesthetics. Neuroblastoma cells were exposed to sevoflurane and then cultured in 1% oxygen. We evaluated the expression of proteins related to the unfolded protein response (UPR). Next, we exposed adult mice in which binding immunoglobulin protein (BiP) had been mutated, and wild-type mice, to sevoflurane, and evaluated their cognitive function. We compared our results to those from our previous study in which mice were exposed to sevoflurane at the fetal stage. Pre-exposure to sevoflurane reduced the expression of CHOP in neuroblastoma cells exposed to hypoxia. Anesthetic pre-exposure also significantly improved the cognitive function of adult wild-type mice, but not the mutant mice. In contrast, mice exposed to anesthetics during the fetal stage showed cognitive impairment. Our data indicate that exposure to inhalational anesthetics causes endoplasmic reticulum (ER) stress, and subsequently leads to an adaptive response, the UPR. This response may enhance the capacity of cells to adapt to injuries and improve neuronal function in adult mice, but not in developing mice. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Neural Correlates of General Anesthesia)

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19 pages, 610 KiB

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Do We Have Viable Protective Strategies against Anesthesia-Induced Developmental Neurotoxicity?

by Nemanja Useinovic, Stefan Maksimovic, Michelle Near, Nidia Quillinan and Vesna Jevtovic-Todorovic

Int. J. Mol. Sci. 2022, 23(3), 1128; https://doi.org/10.3390/ijms23031128 - 20 Jan 2022

Cited by 13 | Viewed by 3074

Abstract

Since its invention, general anesthesia has been an indispensable component of modern surgery. While traditionally considered safe and beneficial in many pathological settings, hundreds of preclinical studies in various animal species have raised concerns about the detrimental and long-lasting consequences that general anesthetics may cause to the developing brain. Clinical evidence of anesthetic neurotoxicity in humans continues to mount as we continue to contemplate how to move forward. Notwithstanding the alarming evidence, millions of children are being anesthetized each year, setting the stage for substantial healthcare burdens in the future. Hence, furthering our knowledge of the molecular underpinnings of anesthesia-induced developmental neurotoxicity is crucially important and should enable us to develop protective strategies so that currently available general anesthetics could be safely used during critical stages of brain development. In this mini-review, we provide a summary of select strategies with primary focus on the mechanisms of neuroprotection and potential for clinical applicability. First, we summarize a diverse group of chemicals with the emphasis on intracellular targets and signal-transduction pathways. We then discuss epigenetic and transgenerational effects of general anesthetics and potential remedies, and also anesthesia-sparing or anesthesia-delaying approaches. Finally, we present evidence of a novel class of anesthetics with a distinct mechanism of action and a promising safety profile. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Neural Correlates of General Anesthesia-2nd Edition)

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18 pages, 50272 KiB

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Molecular Diversity of Anesthetic Actions Is Evident in Electroencephalogram Effects in Humans and Animals

by Sarah Eagleman and M. Bruce MacIver

Int. J. Mol. Sci. 2021, 22(2), 495; https://doi.org/10.3390/ijms22020495 - 6 Jan 2021

Cited by 4 | Viewed by 4150

Abstract

Anesthetic agents cause unique electroencephalogram (EEG) activity resulting from actions on their diverse molecular targets. Typically to produce balanced anesthesia in the clinical setting, several anesthetic and adjuvant agents are combined. This creates challenges for the clinical use of intraoperative EEG monitoring, because computational approaches are mostly limited to spectral analyses and different agents and combinations produce different EEG responses. Thus, testing of many combinations of agents is needed to generate accurate, protocol independent analyses. Additionally, most studies to develop new computational approaches take place in young, healthy adults and electrophysiological responses to anesthetics vary widely at the extremes of age, due to physiological brain differences. Below, we discuss the challenges associated with EEG biomarker identification for anesthetic depth based on the diversity of molecular targets. We suggest that by focusing on the generalized effects of anesthetic agents on network activity, we can create paths for improved universal analyses. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Neural Correlates of General Anesthesia)

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