ATPase Inhibitory Factor 1 Is Critical for Regulating Sevoflurane-Induced Microglial Inflammatory Responses and Caspase-3 Activation

Postoperative delirium (POD) is one of the most important complications after surgery with general anesthesia, for which the neurotoxicity of general anesthetics is a high-risk factor. However, the mechanism remains largely unknown, which also hinders the effective treatment of POD. Here, we confirmed that a clinical concentration of the general anesthetic sevoflurane increased the expression of inflammatory factors and activated the caspase-3 by upregulating ATPase inhibitory factor 1 (ATPIF1) expression in microglia. Upregulation of ATPIF1 decreased the synthesis of ATP which is an important signaling molecule secreted by microglia. Extracellular supplementation with ATP attenuated the microglial inflammatory response and caspase-3 activation caused by sevoflurane or overexpression of ATPIF1. Additionally, the microglial inflammatory response further upregulated ATPIF1 expression, resulting in a positive feedback loop. Animal experiments further indicated that intraperitoneal injection of ATP significantly alleviated sevoflurane anesthesia-induced POD-related anxiety behavior and memory damage in mice. This study reveals that ATPIF1, an important protein regulating ATP synthesis, mediates sevoflurane-induced neurotoxicity in microglia. ATP supplementation may be a potential clinical treatment to alleviate sevoflurane-induced POD.

Modeling Synaptic Effects of Anesthesia and its Cortical Cholinergic Reversal

General anesthetics work through a variety of molecular mechanisms while resulting in the common end point of sedation and loss of consciousness. Generally, the administration of common inhalation anesthetics induces decreases in synaptic excitation while promoting synaptic inhibition. Animal studies have shown that, during anesthesia, exogenously induced increases in acetylcholine-mediated effects in the brain can elicit wakeful-like behavior despite the continued presence of the anesthetic. Less investigated, however, is the question of whether the brain's electrophysiological activity is also restored to pre-anesthetic levels and quality by such interventions. Here we apply a computational model of a network composed of excitatory and inhibitory neurons to simulate the network effects of changes in synaptic inhibition and excitation due to anesthesia and its reversal by muscarinic receptor-mediated cholinergic effects. We use a differential evolution algorithm to fit model parameters to match measures of spiking activity, neuronal connectivity, and network dynamics recorded in the visual cortex of rodents during anesthesia with desflurane in vivo. We find that facilitating muscarinic receptor effects of acetylcholine on top of anesthetic-induced synaptic changes predicts reversal of the neurons’ spiking activity, functional connectivity, as well as pairwise and population interactions. Thus, our model results predict a possible neuronal mechanism for the induced reversal of the effects of anesthesia on post synaptic potentials, consistent with experimental behavioral observations.

Inference of Brain States under Anesthesia with Meta Learning Based Deep Learning Models

Monitoring the depth of unconsciousness during anesthesia is useful in both clinical settings and neuroscience investigations to understand brain mechanisms. Electroencephalogram (EEG) has been used as an objective means of characterizing brain altered arousal and/or cognition states induced by anesthetics in real-time. Different general anesthetics affect cerebral electrical activities in different ways. However, the performance of conventional machine learning models on EEG data is unsatisfactory due to the low Signal to Noise Ratio (SNR) in the EEG signals, especially in the office-based anesthesia EEG setting. Deep learning models have been used widely in the field of Brain Computer Interface (BCI) to perform classification and pattern recognition tasks due to their capability of good generalization and handling noises. Compared to other BCI applications, where deep learning has demonstrated encouraging results, the deep learning approach for classifying different brain consciousness states under anesthesia has been much less investigated. In this paper, we propose a new framework based on meta-learning using deep neural networks, named Anes-MetaNet, to classify brain states under anesthetics. The Anes-MetaNet is composed of Convolutional Neural Networks (CNN) to extract power spectrum features, and a time consequence model based on Long Short-Term Memory (LSTM) Networks to capture the temporal dependencies, and a meta-learning framework to handle large cross-subject variability. We used a multi-stage training paradigm to improve the performance, which is justified by visualizing the high-level feature mapping. Experiments on the office-based anesthesia EEG dataset demonstrate the effectiveness of our proposed Anes-MetaNet by comparison of existing methods.

Epileptic status: reality 2021

Epileptic status is one of the urgent conditions in neurology that requires clear and urgent measures at any stage of medical care. It ranks second among all urgent neurological conditions. The therapeutic principle time-brain is applicable not only for urgent measures in acute cerebrovascular accident, but also for the relief of epileptic status, since the worst prognosis is associated with an increase in the duration of seizure activity. According to the standards proposed in the world for the treatment of epileptic status, benzodiazepines, intravenous forms of antiepileptic drugs, and general anesthetics are used. In the Russian Federation, the use of many drugs is limited due to the lack of registration, their lack in standards, and unavailability in hospitals. Due to the lack of studies on the treatment of epileptic status that go beyond the early stage of status, most of the recommendations presented worldwide remain based on case series or expert judgment. The efficacy benefits of anti-status drugs used in the second and third stages of epileptic status therapy remain unclear. Therefore, if there is a choice of anti-status drugs, the decision of which drug, in what dose and in what sequence will be used, should be made by the senior and most trained doctor in this matter, taking into account the characteristics of each patient. Based on modern international and personal experience, the paper presents a step-by-step protocol for the treatment of generalized convulsive epileptic status, discusses the successes and problems of providing care to patients with this pathology in Russia. The quality of medical care in epileptic status can be significantly improved provided that medical personnel at all stages of the treatment protocol are required to evacuate patients with epileptic status to specialized centers of multidisciplinary hospitals with the possibility of examination and therapy, including the availability of EEG monitors, neuroimaging and laboratory capabilities, and also access to modern antiepileptic drugs (1 table, bibliography: 30 refs)

Propofol and Sevoflurane Anesthesia in Early Childhood Do Not Influence Seizure Threshold in Adult Rats

Experimental studies have demonstrated that general anesthetics administered during the period of synaptogenesis may induce widespread neurodegeneration, which results in permanent cognitive and behavioral deficits. What remains to be elucidated is the extent of the potential influence of the commonly used hypnotics on comorbidities including epilepsy, which may have resulted from increased neurodegeneration during synaptogenesis. This study aimed to test the hypothesis that neuropathological changes induced by anesthetics during synaptogenesis may lead to changes in the seizure threshold during adulthood. Wistar rat pups were treated with propofol, sevoflurane, or saline on the sixth postnatal day. The long-term effects of prolonged propofol and sevoflurane anesthesia on epileptogenesis were assessed using corneal kindling, pilocarpine-, and pentylenetetrazole-induced seizure models in adult animals. Body weight gain was measured throughout the experiment. No changes in the seizure threshold were observed in the three models. A significant weight gain after exposure to anesthetics during synaptogenesis was observed in the propofol group but not in the sevoflurane group. The results suggest that single prolonged exposure to sevoflurane or propofol during synaptogenesis may have no undesirable effects on epileptogenesis in adulthood.

Paradoxical excitation of lateral habenula neurons by propofol involves enhanced presynaptic release of glutamate

Sleep is a fundamental physiological process conserved across most species. As such, deficits in sleep can result in a myriad of psychological and physical health issues. However, the mechanisms underlying the induction of sleep are relatively unknown. Interestingly, general anesthetics cause unconsciousness by positively modulating GABA-A receptors (GABAARs). Based on this observation, it is hypothesized that GABAARs play a critical role in modulating circuits involved in sleep to promote unconsciousness. Recently, the lateral habenula (LHb) has been demonstrated to play a role in sleep physiology and sedation. Specifically, propofol has been shown to excite LHb neurons to promote sedation. However, the mechanism by which this occurs is unknown. Here, we utilize whole-cell voltage and current clamp recordings from LHb neurons obtained from 8-10 week old male mice to determine the physiological mechanisms for this phenomenon. We show that bath application of 1.5μM propofol is sufficient to increase LHb neuronal excitability involving synaptic transmission, but not through modulation of intrinsic properties. Additionally, although there is increased LHb neuronal excitability, GABAARs localized postsynaptically on LHb neurons are still responsive to propofol, as indicated by an increase in the decay time. Lastly, we find that propofol increases the synaptic drive onto LHb neurons involving enhanced presynaptic release of both glutamate and GABA. However, the greatest contributor to the potentiated synaptic drive is the increased release of glutamate which shifts the balance of synaptic transmission towards greater excitation. Taken together, this study is the first to identify the physiological basis for why LHb neurons are excited by propofol, rather than inhibited, and as a result promote sedation.

Neonatal Isoflurane Does Not Affect Sleep Architecture and Minimally Alters Neuronal Beta Oscillations in Adolescent Rats

General anesthetics are neurotoxic to the developing rodent and primate brains leading to neurocognitive and socio-affective impairment later in life. In addition, sleep patterns are important predictors of cognitive outcomes. Yet, little is known about how anesthetics affect sleep-wake behaviors and their corresponding oscillations. Here we examine how neonatal general anesthesia affects sleep and wake behavior and associated neuronal oscillations. We exposed male and female rat pups to either 6 h of continuous isoflurane or sham anesthesia (compressed air) at the peak of their brain development (postnatal day 7). One cohort of animals was used to examine neurotoxic insult 2 h post-anesthesia exposure. At weaning age, a second cohort of rats was implanted with cortical electroencephalogram electrodes and allowed to recover. During adolescence, we measured sleep architecture (divided into wake, non-rapid eye movement, and rapid eye movement sleep) and electroencephalogram power spectra over a 24 h period. We found that exposure to neonatal isoflurane caused extensive neurotoxicity but did not disrupt sleep architecture in adolescent rats. However, these animals had a small but significant reduction in beta oscillations, specifically in the 12–20 Hz beta 1 range, associated with wake behavior. Furthermore, beta oscillations play a critical role in cortical development, cognitive processing, and homeostatic sleep drive. We speculate that dysregulation of beta oscillations may be implicated in cognitive and socio-affective outcomes associated with neonatal anesthesia.

Anesthetic Preconditioning of Traumatic Brain Injury is Ineffective in a Drosophila Model of Obesity

We tested the hypothesis that obesity influences the pharmacodynamics of volatile general anesthetics (VGAs) by comparing effects of anesthetic exposure on mortality from traumatic brain injury (TBI) in lean and obese Drosophila melanogaster. We induced TBI with a High-Impact Trauma device. Starvation-selection over multiple generations resulted in an obese phenotype (SS flies). Fed flies served as lean controls (FC flies). Adult (1-7 day old) SS and FC flies were exposed to equianesthetic doses of isoflurane or sevoflurane either before or after TBI. The principal outcome was percent mortality 24 hours after injury, expressed as the Mortality Index at 24 hours (MI24). TBI resulted in lower MI24 in FC than in SS flies (21 (2.35) and 57.8 (2.14), respectively n= 12, p=0.0001). Preexposure to isoflurane or sevoflurane preconditioned FC flies to TBI reducing the risk of death to 0.53 [0.25 to 1.13] and 0.82 [0.43 to 1.58], respectively, but had no preconditioning effect in SS flies. Postexposure to isoflurane or sevoflurane increased the risk of death in SS flies. Only postexposure to isoflurane increased the risk in FC flies (1.39 [0.81 to 2.38]). Thus, obesity affects the pharmacodynamics of VGAs, thwarting the preconditioning effect of isoflurane and sevoflurane in TBI.

Inhalational Anesthetics Do Not Deteriorate Amyloid-β-Derived Pathophysiology in Alzheimer’s Disease: Investigations on the Molecular, Neuronal, and Behavioral Level

Background: Studies suggest that general anesthetics like isoflurane and sevoflurane may aggravate Alzheimer’s disease (AD) neuropathogenesis, e.g., increased amyloid-β (Aβ) protein aggregation resulting in synaptotoxicity and cognitive dysfunction. Other studies showed neuroprotective effects, e.g., with xenon. Objective: In the present study, we want to detail the interactions of inhalational anesthetics with Aβ-derived pathology. We hypothesize xenon-mediated beneficial mechanisms regarding Aβ oligomerization and Aβ-mediated neurotoxicity on processes related to cognition. Methods: Oligomerization of Aβ 1–42 in the presence of anesthetics has been analyzed by means of TR-FRET and silver staining. For monitoring changes in neuronal plasticity due to anesthetics and Aβ 1–42, Aβ 1–40, pyroglutamate-modified amyloid-(AβpE3), and nitrated Aβ (3NTyrAβ), we quantified long-term potentiation (LTP) and spine density. We analyzed network activity in the hippocampus via voltage-sensitive dye imaging (VSDI) and cognitive performance and Aβ plaque burden in transgenic AD mice (ArcAβ) after anesthesia. Results: Whereas isoflurane and sevoflurane did not affect Aβ 1–42 aggregation, xenon alleviated the propensity for aggregation and partially reversed AβpE3 induced synaptotoxic effects on LTP. Xenon and sevoflurane reversed Aβ 1–42-induced spine density attenuation. In the presence of Aβ 1–40 and AβpE3, anesthetic-induced depression of VSDI-monitored signaling recovered after xenon, but not isoflurane and sevoflurane removal. In slices pretreated with Aβ 1–42 or 3NTyrAβ, activity did not recover after washout. Cognitive performance and plaque burden were unaffected after anesthetizing WT and ArcAβ mice. Conclusion: None of the anesthetics aggravated Aβ-derived AD pathology in vivo. However, Aβ and anesthetics affected neuronal activity in vitro, whereby xenon showed beneficial effects on Aβ 1–42 aggregation, LTP, and spine density.

Volatile anesthetics maintain tidal volume and minute ventilation to a greater degree than propofol under spontaneous respiration

Background Although general anesthetics depress spontaneous respiration, the comprehensive effect of general anesthetics on respiratory function remains unclear. We aimed to investigate the effects of general anesthetics on spontaneous respiration in non-intubated mice with different types and doses of general anesthetic. Methods Adult C57BL/6 J mice were administered intravenous anesthetics, including propofol and etomidate, and inhalational anesthetics, including sevoflurane and isoflurane in vivo at doses of 0.5-, 1.0-, and 2.0-times the minimum alveolar concentration (MAC)/median effective dose (ED50) to induce loss of the righting reflex (LORR). Whole-body plethysmography (WBP) was applied to measure parameters of respiration under unrestricted conditions without endotracheal intubation. The alteration in respiratory sensitivity to carbon dioxide (CO2) under general anesthesia was also determined. The following respiratory parameters were continuously recorded during anesthesia or CO2 exposure: respiratory frequency (FR), tidal volume (TV), minute ventilation (MV), expiratory time (TE), inspiratory time (TI), and inspiratory–expiratory time ratio (I/E), and peak inspiratory flow. Results Sub-anesthetic concentrations (0.5 MAC) of sevoflurane or isoflurane increased FR, TV, and MV. With isoflurane and sevoflurane exposure, the CO2-evoked increases in FR, TV, and MV were decreased. Compared with inhalational anesthetics, propofol and etomidate induced respiratory suppression, affecting FR, TV, and MV. In 100% oxygen (O2), FR in the group that received propofol 1.0-times the ED50 was 69.63 ± 33.44 breaths/min compared with 155.68 ± 64.42 breaths/min in the etomidate-treated group. In the same groups, FR was 88.72 ± 34.51 breaths/min and 225.10 ± 59.82 breaths/min, respectively, in 3% CO2 and 144.17 ± 63.25 breaths/min and 197.70 ± 41.93 breaths/min, respectively, in 5% CO2. A higher CO2 sensitivity was found in etomidate-treated mice compared with propofol-treated mice. In addition, propofol induced a greater decrease in FR, MV, and I/E ratio compared with etomidate, sevoflurane, and isoflurane at equivalent doses (all P < 0.05). Conclusions General anesthetics differentially modulate spontaneous breathing in vivo. Volatile anesthetics increase FR, TV, and MV at sub-anesthetic concentrations, while they decrease FR at higher concentrations. Propofol consistently depressed respiratory parameters to a greater degree than etomidate.