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Introduction: The fragile brain includes both the developing brain in childhood and the deteriorating brain in elderly. While the effects of general anesthesia on the myelin sheath of developing brain have been well-documented, limited research has explored its impact on degenerating brain in elderly individuals. Methods: In our study, aged marmosets in control group were only anesthetized with 6--8% sevoflurane and 100% oxygen (2 L/min) for 1--2 min for anesthesia induction. In addition to anesthesia induction, the anesthesia group was exposed to a clinical concentration of sevoflurane (1.5--2%) for 6 h to maintain anesthesia. After anesthesia, scanning electron microscopy (SEM) and artificial intelligence-assisted image analysis were utilized to observe the effects of general anesthesia on the myelin sheath in prefrontal cortex (PFC) of aged marmosets. Results: Compared with the control group, our findings revealed no evidence that 6 h of sevoflurane general anesthesia altered the thickness of myelin sheath, the diameter of myelinated axons, and the g-ratio in prefrontal cortex of aged marmosets. Conclusion: Clinical concentration of sevoflurane may have no short-term effect on the myelin sheath in prefrontal cortex of aged marmosets. [ABSTRACT FROM AUTHOR]

General anesthetic drugs cause cognitive deficits that persist after the drugs have been eliminated. Astrocytes may contribute to such cognition-impairing effects through the release of one or more paracrine factors that increase a tonic inhibitory conductance generated by extrasynaptic γ-aminobutyric acid type A (GABA A) receptors in hippocampal neurons. The mechanisms underlying this astrocyte-to-neuron crosstalk remain unknown. Interestingly, astrocytes express anesthetic-sensitive GABA A receptors. Here, we tested the hypothesis that anesthetic drugs activate astrocytic GABA A receptors to initiate crosstalk leading to a persistent increase in extrasynaptic GABA A receptor function in neurons. We also investigated the signaling pathways in neurons and aimed to identify the paracrine factors released from astrocytes. Astrocytes and neurons from mice were grown in primary cell cultures and studied using in vitro electrophysiological and biochemical assays. We discovered that the commonly used anesthetics etomidate (injectable) and sevoflurane (inhaled) stimulated astrocytic GABA A receptors, which in turn promoted the release paracrine factors, that increased the tonic current in neurons via a p38 MAPK-dependent signaling pathway. The increase in tonic current was mimicked by exogenous IL-1β and abolished by blocking IL-1 receptors; however, unexpectedly, IL-1β and other cytokines were not detected in astrocyte-conditioned media. In summary, we have identified a novel form of crosstalk between GABA A receptors in astrocytes and neurons that engages a p38 MAPK-dependent pathway. Brief commentary Many older patients experience cognitive deficits after surgery. Anesthetic drugs may be a contributing factor as they cause a sustained increase in the function of "memory blocking" extrasynaptic GABA A receptors in neurons. Interestingly, astrocytes are required for this increase; however, the mechanisms underlying the astrocyte-to-neuron crosstalk remain unknown. We discovered that commonly used general anesthetic drugs stimulate GABA A receptors in astrocytes, which in turn release paracrine factors that trigger a persistent increase in extrasynaptic GABA A receptor function in neurons via p38 MAPK. This novel form of crosstalk may contribute to persistent cognitive deficits after general anesthesia and surgery. [ABSTRACT FROM AUTHOR]

Perioperative neurocognitive disorders (PNDs) are some of the most common postoperative complications among the elderly and susceptible individuals, which significantly worsens the clinical outcome of patients. However, the prevention and treatment strategies of PNDs are difficult to determine and implement since the pathogenesis of PNDs is not well understood. The development of living organisms is associated with active and organized cell death, which is essential for maintaining the homeostasis of life. Ferroptosis is a programmed cell death (different from apoptosis and necrosis) mainly caused by an imbalance in the generation and degradation of intracellular lipid peroxides due to iron overload. Pyroptosis is an inflammatory cell death characterized by the creation of membrane holes mediated by the gasdermin (GSDM) family, followed by cell lysis and the release of pro-inflammatory cytokines. Ferroptosis and pyroptosis are involved in the pathogenesis of various central nervous system (CNS) diseases. Furthermore, ferroptosis and pyroptosis are closely associated with the occurrence and development of PNDs. This review summarizes the main regulatory mechanisms of ferroptosis and pyroptosis and the latest related to PNDs. Based on the available evidence, potential intervention strategies that can alleviate PNDs by inhibiting ferroptosis and pyroptosis have also been provided. [ABSTRACT FROM AUTHOR]

Mechanical thrombectomy (MT) has become a standard treatment for acute ischemic stroke (AIS) caused by large vessel occlusion (LVO). Recent evidence suggests that general anesthesia (GA) and mechanical ventilation do not lead to inferior neurologic outcomes if compared to non-GA. However, the guidelines lack specific recommendations for ventilation targets during MT under GA. This systematic review aims to identify ventilation strategies correlating with better neurological outcomes in AIS patients undergoing MT, particularly focusing on oxygenation and carbon dioxide (CO2) targets. A systematic search of multiple databases was conducted to identify human studies reporting the correlation between ventilation strategies and neurological outcomes in MT for AIS. Eligible studies included clinical trials, observational studies, and case–control studies. Out of 157 studies assessed, 11 met the inclusion criteria. Five studies investigated oxygenation targets, while six studies explored CO2 targets. The published studies highlighted the controversial role of supplemental normobaric oxygen therapy and its potential association with worse outcomes. Regarding CO2 targets, the studies identified a potential association between end tidal CO2 levels and functional outcomes, with hypocapnia being unfavorable. This systematic review demonstrates that the current available evidence still lacks strength to suggest specific ventilation targets, but it highlights the potential risks of hyperoxia and hypocapnia in this specific cohort of patients. [ABSTRACT FROM AUTHOR]

Effect-site concentration is widely used to determine drug dosage in anesthesia practice. To obtain effect-site concentration, a pharmacokinetic model with a corresponding equilibration rate constant between plasma and effect-site, ke0, is necessary. Remimazolam, a novel short-acting benzodiazepine, has been approved as anesthetic/sedative. Recently, a remimazolam pharmacokinetic model has been published using a large dataset including wide range of subject characteristics (416 males and 246 females, age 18–93 years, total body weight 34–149 kg, height 133–204 cm, body mass index 14–61 kg m−2, ASA physical status: I–IV, and Asian, White, American African, and 2 other races). This Masui model can be applicable to various patients, but a pharmacodynamic model including ke0 was not developed simultaneously. A previous article has indicated that the time to peak effect of drug after its bolus should be used to determine ke0 for a pharmacokinetic model without simultaneous development of corresponding pharmacodynamic model. The ke0 value can be calculated using numerical analysis but not algebraic solution. We provide the detail method of the numerical analysis and a tool to have ke0 value easily for the Masui remimazolam PK model. Additionally, we provide a multiple regression model to have ke0 value for the PK model. [ABSTRACT FROM AUTHOR]

Propofol (PFL) owing to its excellent inhibitory property of neurotransmitters in CNS by positive modulation of ligand gated ion channels to an integrated chloride channeled GABAA thereby acts as a general anesthetic. It differs from other general anesthetics chemically and pharmacologically as it has lesser side effects compared to other general anesthetics and is most commonly used. The present review focuses on two aspects (a) various analytical methods used in quantification of Propofol in pharmaceutical formulations and (b) various analytical methods used to determine Propofol in biological matrices and some biological markers like hair and end tidal nasal air for forensic purpose to estimate drug concentration in suspected cases. Here the various analytical methods are developed using different parameters and validation of employed methods are discussed. Estimated parameters like the linearity, LOQ (Limit of quantification), % recovery, slope, intercept, validation are discussed for the individual method. The critical quality attributes like the wavelength of detection, columns, flow rate, gas flow, and the sample preparation methods for the determination of PFL by bioanalytical methods are also discussed. Type of electrode, mechanism involved and the potential voltage applied for a particular electrochemical method are also discussed. [ABSTRACT FROM AUTHOR]

Sevoflurane is an inhalation anesthetic widely used for general anesthesia, but its genotoxic potential is controversial in clinical studies. It is unknown whether the effects are due to surgery or the anesthetic. Thus, for the first time, the present study investigated genotoxicity in peripheral blood cells and in target organs (liver, lung, and kidney) and micronucleus (MN) in the bone marrow of a single exposure to sevoflurane at three different concentrations in monitored mice. Ninety Swiss mice were distributed into the following groups: exposure to sevoflurane at 3.3% (low), 4.5% (intermediate), and 6.0% (high) in 40% oxygen (O 2 ) for 2 h; negative control (no exposure); negative control with O 2 ; and positive control. The exposed animals were heated, monitored for vital signs (temperature, O 2 saturation, heart rate/pulse, and respiratory rate), and anesthetized via a modern low-flow digital system. Mice were euthanized 2 and 24 h after exposure for evaluation by the comet assay and MN test, respectively. No DNA damage occurred in the 3.3% group for any of the organs evaluated, and no genotoxic or mutagenic effects were observed at any sevoflurane concentration in the peripheral blood or liver cells. However, a significant increase in DNA damage was observed at higher concentrations in kidney (4.5%) and lung cells (6.0%) and in the MN frequency (groups 4.5% and 6.0%). No cytotoxicity or histological alterations were observed. In conclusion, high concentrations of sevoflurane induce DNA damage, but concentrations equivalent to those used in clinical practice do not demonstrate genotoxic or mutagenic effects., (© 2024 Environmental Mutagenesis and Genomics Society.)

Etomidate is a synthetic imidazole anesthetic that exerts hypnotic effects by potentiating the action of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) or directly activating the anionic GABA (GABA A ) receptor. It stands out among many anesthetics because of its multiple advantages, such as good hemodynamic stability and minimal inhibition of spontaneous respiration. However, its low water solubility and side effects, such as adrenal cortex inhibition and myoclonus, have limited the clinical application of this drug. To address these issues, extensive research has been conducted on the drug delivery of etomidate in recent decades, which has led to the emergence of different etomidate preparations. Despite so many etomidate preparations, so far some of the toxic side effects have not yet been effectively addressed. Herein we discuss the pharmaceutical design of etomidate that may resolve the above problem. We also propose targeted strategies for future research on etomidate preparations and discuss the feasibility of different administration routes and dosage forms to expand the application of this drug. Through this review, we hope to draw more attention to the potential of etomidate and its application challenges and provide valuable insights into the development of new etomidate preparations.

Background Context: Length of hospital stay (LOS) is an important concern in all types of surgery, and the enhanced recovery after surgery (ERAS) protocol has been developed to improve perioperative management and outcomes, which require multidisciplinary management. In terms of pain control, intraoperative regional anesthesia and postoperative opioid-sparing analgesia are recommended. For open spine surgery, we aimed to combine thoracic epidural analgesia to reduce pain and opioid-related side effects, thereby hastening recovery.Purpose: This study aimed to compare the length of hospital stay after open complete laminectomy with fusion between general anesthesia and combined general anesthesia involving a single thoracic epidural injection.Design: A randomized single-blinded controlled study.Patient Sample: Thirty-eight patients scheduled for elective open laminectomy with fusion between I and III levels were selected.Outcome Measures: LOS, postoperative pain, patient-controlled morphine consumption at 24 hours, patient satisfaction score, and other opioid-related side effects were recorded.Methods: Patients were randomly selected to receive standard general anesthesia (GA) or GA combined with a single-shot thoracic epidural at T11-T12 or T12-L1, a block with 10 mL of 0.25% bupivacaine, and 4 mg of morphine.Results: There were no significant differences in the demographic variables between groups. LOS was significantly lower in the combined epidural and/or GA than in the control group (3.78±0.81 [mean±standard deviation] and 4.79±1.51 days, respectively; p=.017). Numeric rating score (at rest) at the post-anesthesia care unit, 24 hours postoperative morphine consumption (mg), operating time, and blood loss were significantly lower in the epidural group. Patients who received combined epidural and/or GA were more likely to report higher patient satisfaction (p=.008). However, the incidence of intraoperative hypotension was significantly higher in the epidural group (72.2% vs. 21.1%, p=.003). The incidences of adverse events and surgical field rating scores did not differ between the 2 patient groups.Conclusions: Combined lower thoracic epidural and/or GA in patients undergoing elective lumbar spine surgery was associated with decreased LOS. [ABSTRACT FROM AUTHOR]

Background: Remimazolam besylate is a novel short-acting benzodiazepine. An appropriate pharmacokinetic model of remimazolam is desirable in anesthesia practice. The aim of the study was to develop a pharmacokinetic model using plasma samples from patients anesthetized with remimazolam. Influence of patient characteristics, context-sensitive decrement-times, and dose regimens were also examined. Methods: Data were obtained from four trials on patients, and seven trials on healthy volunteers. The characteristics of 416 male and 246 female subjects were as follows: age, 18–93 years; body weight, 34–149 kg; and American Society of Anesthesiologists physical status (ASA-PS), I-IV. 2231 arterial and 3200 venous samples were used for the final model. The equilibration rate constant between arterial plasma and effect-site was estimated using the concept of time to peak effect. The final model was used to generate context-sensitive decrement times and dose regimens for general anesthesia. Results: A three-compartment model plus virtual venous compartment with allometric scaling of adjusted body weight (ABW), age, sex, and ASA-PS as covariates were selected as the final model. Elimination clearance was lower in males, and in subjects with higher ABW and ASA-PS scores. Approximately 10% or 20% higher dose rate was necessary in females than in males or ASA-PS I/II than III/IV patient. The context-sensitive half-time for effect-site concentration in a 55-year-old, 70-kg, 170-cm male or female ASA-PS I/II patient after > 6-h infusion was 16.7 or 15.9 min. Conclusion: Remimazolam pharmacokinetic model for general anesthesia was successfully developed. ABW, ASA-PS, and sex has a considerable impact on the remimazolam concentration. [ABSTRACT FROM AUTHOR]

Background: Surgery under general anesthesia leads to neural injury, especially in older patients. Sevoflurane anesthesia without surgery for 2 h does not induce neural injury, however, whether prolonger sevoflurane anesthesia without surgery has the same consequence is still unknown. Methods: In the present study, aged marmosets were exposed to a clinical concentration of sevoflurane (1.5–2%) for 6 h to access the effects of prolonged sevoflurane anesthesia on the levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), Caspase3 activity and myelin formation in the brain. Results: Sevoflurane anesthesia did not alter the expression of IL-6 (120.1 ± 2.21 vs. 120.8 ± 2.25, p = 0.74), TNF-α (189.3 ± 31.35 vs. 218.7 ± 21.47, p = 0.25) and Caspase3 (57.35 ± 1.54 vs. 58.67 ± 1.19, p = 0.53) in the prefrontal cortex (PFC) of aged marmosets. The amount of MBP expression (60.99 ± 6.21 vs. 58.91 ± 2.71, p = 0.77) did not change following sevoflurane exposure. Conclusion: Sevoflurane anesthesia did not increase the levels of IL-6 and TNF-α, activated the the expression of Caspase3, and induced myelination deficits in the PFC of aged marmosets. [ABSTRACT FROM AUTHOR]

Background: Status epilepticus (SE) persisting despite two anti‐seizures medications (ASM) and anesthetics is labeled super refractory (SRSE), correlating with important morbidity and mortality. Its treatment relies on expert opinions. Due to its pharmacological properties, ketamine (KET) has received increasing attention, but data are essentially retrospective. Aims: To describe an unselected cohort of adults receiving KET for SRSE. Methods: Analysis of a prospective registry of consecutive SE episodes, identifying SRSE patients receiving ketamine (KET). Comparison with recent adult series including more than 10 patients. Results: Eleven patients received KET after a median of 4 days (range: 2–20); median dose was 5 mg/kg/h (range: 2.5–15). KET provided permanent SE control in three (27%). Previous series, using KET administration delays and doses similar to our cohort, report KET efficacy in 28–96% of cases. Conclusions: We found a lower SE control rate than existing literature, whose data are, however, often retrospective, potentially selecting patients with less severe SE forms or responding to KET. This might explain outcome differences, as KET administration modalities were comparable with our cohort. Since randomized controlled studies are lacking on this subject, the analysis of this prospective, unselected cohort, if confirmed, suggests a current overestimation of KET efficacy in SRSE. [ABSTRACT FROM AUTHOR]

BackgroundSurgery under general anesthesia leads to neural injury, especially in older patients. Sevoflurane anesthesia without surgery for 2 h does not induce neural injury, however, whether prolonger sevoflurane anesthesia without surgery has the same consequence is still unknown.MethodsIn the present study, aged marmosets were exposed to a clinical concentration of sevoflurane (1.5–2%) for 6 h to access the effects of prolonged sevoflurane anesthesia on the levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), Caspase3 activity and myelin formation in the brain.ResultsSevoflurane anesthesia did not alter the expression of IL-6 (120.1 ± 2.21 vs. 120.8 ± 2.25, p = 0.74), TNF-α (189.3 ± 31.35 vs. 218.7 ± 21.47, p = 0.25) and Caspase3 (57.35 ± 1.54 vs. 58.67 ± 1.19, p = 0.53) in the prefrontal cortex (PFC) of aged marmosets. The amount of MBP expression (60.99 ± 6.21 vs. 58.91 ± 2.71, p = 0.77) did not change following sevoflurane exposure.ConclusionSevoflurane anesthesia did not increase the levels of IL-6 and TNF-α, activated the the expression of Caspase3, and induced myelination deficits in the PFC of aged marmosets.

OBJECTIVE: Testicular torsion is a condition that manifests with acute pain and can lead to infertility despite urgent surgical intervention. The aim of this study is to investigate the protective and preventive effects of etomidate, an imidazole derivative, a non-barbiturate general anesthetic agent, without analgesic effect, on testicular ischemia-reperfusion injury. MATERIALS AND METHODS: Twenty-four adult male Wistar rats weighing 200-250 g were used in the study. Torsion was created in all rats by rotating left testes 720° clockwise on the day of the experiment. 30 minutes before detorsion, 4 mg/kg etomidate and 10 mg/kg propofol were administered intraperitoneally to the etomidate and propofol groups, respectively. After an hour of ischemia, the left testis was reinstated, and the tissues were repaired according to their physiology. Following 24 hours of reperfusion, the animals were euthanized after ipsilateral and contralateral testes were removed. RESULTS: Etomidate applied before testicular detorsion significantly suppressed germ cell damage and Leydig cell loss in ipsilateral tissue. It did not cause any significant changes in the percentage of necrosis, histological score, and tubule rupture in ipsilateral tissue. Propofol administered before testicular detorsion significantly suppressed the percentage of necrosis only in the ipsilateral tissue. In addition, no signs of damage were observed in the contralateral testis. CONCLUSIONS: These findings show that etomidate administered before detortion creates a protective effect by preventing testicular ischemia- reperfusion injury. [ABSTRACT FROM AUTHOR]

GABA A receptors are pentameric ligand-gated ion channels that mediate most fast neuronal inhibition in the brain. In addition to their important physiological roles, they are noteworthy in their rich pharmacology; prominent drugs used for anxiety, insomnia, and general anesthesia act through positive modulation of GABA A receptors. Direct structural information for how these drugs work was absent until recently. Efforts in structural biology over the past few years have revealed how important drug classes and natural products interact with the GABA A receptor, providing a foundation for studies in dynamics and structure-guided drug design. Here, we review recent developments in GABA A receptor structural pharmacology, focusing on subunit assemblies of the receptor found at synapses. GABA A receptors are ion channels important in brain function and are the target of chemically diverse and clinically important drugs for insomnia, epilepsy, and anesthesia. Recent structures of GABA A receptors have revealed detailed interactions of the neurotransmitter GABA, benzodiazepines, general anesthetics, and antagonists. Intravenous anesthetics bind in both common and distinctive membrane sites. Electrophysiological and molecular dynamics studies build off the static structures, to probe mechanisms of potentiation and inhibition by chemically diverse compounds. [ABSTRACT FROM AUTHOR]

General anesthetic drugs cause cognitive deficits that persist after the drugs have been eliminated. Astrocytes may contribute to such cognition-impairing effects through the release of one or more paracrine factors that increase a tonic inhibitory conductance generated by extrasynaptic γ-aminobutyric acid type A (GABA A ) receptors in hippocampal neurons. The mechanisms underlying this astrocyte-to-neuron crosstalk remain unknown. Interestingly, astrocytes express anesthetic-sensitive GABA A receptors. Here, we tested the hypothesis that anesthetic drugs activate astrocytic GABA A receptors to initiate crosstalk leading to a persistent increase in extrasynaptic GABA A receptor function in neurons. We also investigated the signaling pathways in neurons and aimed to identify the paracrine factors released from astrocytes. Astrocytes and neurons from mice were grown in primary cell cultures and studied using in vitro electrophysiological and biochemical assays. We discovered that the commonly used anesthetics etomidate (injectable) and sevoflurane (inhaled) stimulated astrocytic GABA A receptors, which in turn promoted the release paracrine factors, that increased the tonic current in neurons via a p38 MAPK-dependent signaling pathway. The increase in tonic current was mimicked by exogenous IL-1β and abolished by blocking IL-1 receptors; however, unexpectedly, IL-1β and other cytokines were not detected in astrocyte-conditioned media. In summary, we have identified a novel form of crosstalk between GABA A receptors in astrocytes and neurons that engages a p38 MAPK-dependent pathway. Brief commentary BACKGROUND: Many older patients experience cognitive deficits after surgery. Anesthetic drugs may be a contributing factor as they cause a sustained increase in the function of "memory blocking" extrasynaptic GABA A receptors in neurons. Interestingly, astrocytes are required for this increase; however, the mechanisms underlying the astrocyte-to-neuron crosstalk remain unknown. TRANSLATIONAL SIGNIFICANCE: We discovered that commonly used general anesthetic drugs stimulate GABA A receptors in astrocytes, which in turn release paracrine factors that trigger a persistent increase in extrasynaptic GABA A receptor function in neurons via p38 MAPK. This novel form of crosstalk may contribute to persistent cognitive deficits after general anesthesia and surgery., Competing Interests: Declaration of Competing Interest All authors have read the journal's policy on disclosure of potential conflicts of interest. Dr. Beverley A. Orser serves as Chair of the Board of Trustees of the International Anesthesia Research Society (San Francisco, CA, USA) and is co-director of the Perioperative Brain Health Centre (Toronto, ON, Canada; http://www.perioperativebrainhealth.com). She is a named inventor on a Canadian patent (2,852,978) and two U.S. patents (9,517,265 and 10,981,954). The patents, which are held by the University of Toronto, are for new methods to prevent and treat delirium and persistent neurocognitive deficits after anesthesia and surgery, as well as to treat mood disorders. Dr. Beverley A. Orser also collaborates on clinical studies that are supported by in-kind software. All of the other authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Keywords: Remimazolam; General anesthetic; Benzodiazepine EN Remimazolam General anesthetic Benzodiazepine 479 482 4 07/25/20 20200801 NES 200801 Introduction: consideration of advantages In January 2020, remimazolam besilate, a novel benzodiazepine, was approved as a general anesthetic in Japan firstly in the world. Pediatric anesthesia For total intravenous anesthesia in pediatric patients [[25]], remimazolam might be preferable because of less injection pain and no risk of propofol infusion syndrome. 2007; 107: 60-66. 10.1097/01.anes.0000267503.85085.c0 30 Upton R, Martinez A, Grant C. A dose escalation study in sheep of the effects of the benzodiazepine CNS 7056 on sedation, the EEG and the respiratory and cardiovascular systems. [Extracted from the article]

In order to examine effects of general anesthetics on hippocampal synaptic transmission in the absence and presence of amygdala circuitry activation, we have developed a unique amygdala-hippocampal slice preparation in which projections between amygdala and hippocampal CA1 are conserved. Stimulating electrodes were placed in radiatum stratum (Rad) to stimulate CA1, and in amygdala-hippocampal area (AH) to simulate amygdala inputs to hippocampus. Two sets of extracellular recording microelectrodes were positioned in cell bodies and dendrites of CA1 to record population spikes (PSs) and excitatory post-synaptic potentials (EPSPs), respectively. Intravenous anesthetics did not elicit consistent effects on PS and EPSP following a test stimulus on Rad. A pre-pulse of AH in addition to a test-pulse on Rad produced significant reduction of PS amplitude without a change in EPSP. Pre-treatment with tetanus-pulse on AH reversed the anesthetic-induced reduction of PS. The results suggest that inhibitory actions of general anesthetics in CA1 can be modified by activation of amygdala, suggesting that preoperative anxiety and fear could modify anesthetic actions. The modification was more prominent in the presence of intravenous anesthetics than with volatile agents. • A unique amygdala-hippocampal slice in which the projections between amygdala and hippocampal CA1 are conserved was employed in the present study. • The first evidence that activation of amygdala circuitry can modulate hippocampal synaptic transmission in the presence of general anesthetics in vitro was determined. • The modification was more prominent in the presence of intravenous anesthetics than volatile agents. [ABSTRACT FROM AUTHOR]

Theories of general anesthesia have shifted in focus from bulk lipid effects to specific interactions with membrane proteins. Target receptors include several subtypes of pentameric ligandgated ion channels; however, structures of physiologically relevant proteins in this family have yet to define anesthetic binding at high resolution. Recent cocrystal structures of the bacterial protein GLIC provide snapshots of state-dependent binding sites for the common surgical agent propofol (PFL), offering a detailed model system for anesthetic modulation. Here, we combine molecular dynamics and oocyte electrophysiology to reveal differential motion and modulation upon modification of a transmembrane binding site within each GLIC subunit. WT channels exhibited net inhibition by PFL, and a contraction of the cavity away from the pore-lining M2 helix in the absence of drug. Conversely, in GLIC variants exhibiting net PFL potentiation, the cavity was persistently expanded and proximal to M2. Mutations designed to favor this deepened site enabled sensitivity even to subclinical concentrations of PFL, and a uniquely prolonged mode of potentiation evident up to ∼30 min after washout. Dependence of these prolonged effects on exposure time implicated the membrane as a reservoir for a lipid-accessible binding site. However, at the highest measured concentrations, potentiation appeared to be masked by an acute inhibitory effect, consistent with the presence of a discrete, water-accessible site of inhibition. These results support a multisite model of transmembrane allosteric modulation, including a possible link between lipid- and receptor-based theories that could inform the development of new anesthet [ABSTRACT FROM AUTHOR]

Early synchronized spontaneous network activity is a hallmark of the brain growth spurt period, during which general anesthetics cause widespread neuronal apoptosis and subsequent cognitive dysfunction. However, the relationship of such activity to anesthetic-induced neuronal apoptosis remains to be determined. In this study, we utilized patch-clamp electrophysiological recording, immunohistochemistry, and TUNEL assays to investigate the potential roles of spontaneous network activity in ketamine-induced neuronal apoptosis during early development. All experiments were performed using acutely dissected whole-mount Sprague–Dawley rat retinas (0–14 postnatal days [P0–P14]). Ketamine reversibly blocked spontaneous network activity in the rat retina from P0 to P9 and irreversibly blocked such activity from P10 to P12. The peak of physiological and ketamine-induced neuronal apoptosis mainly occurred from P7 to P9. Blockade of nicotinic acetylcholine receptors (nAChRs) also induced reversible inhibition of spontaneous network activity from P0 to P7 and extensive neuronal apoptosis in the P7 rat retina, while activation of nAChRs or increases in endogenous ACh levels attenuated ketamine-induced apoptotic responses. Furthermore, blockade of α7-nAChR and ß2-nAChR subtypes induced neuronal apoptosis in the developing retina, while activation of the α7-nAChR subtype attenuated ketamine-induced apoptotic responses. These results demonstrate that ketamine may inhibit early synchronized spontaneous network activity by blocking nAChRs, and that such inhibition may contribute to ketamine-induced neuronal apoptosis in the developing rat retina. [ABSTRACT FROM AUTHOR]

Propofol is widely used as a general anesthetic and is generally considered to exert its action by regulating neuronal firing via facilitation of GABA A receptors. However, accumulating evidence suggests that propofol also acts on astrocytes, including inhibitory effects on gap junctional coupling, but the underlying molecular mechanisms remain largely unknown. Here, using acute cortical brain slices prepared from mice, we characterize propofol-induced molecular changes in astrocytic gap junction protein connexin 43 (Cx43). Propofol does not change the protein expression level of Cx43 or its incorporation into gap junctional plaques, according to biochemical and immunohistochemical analyses. However, propofol alters migration pattern of Cx43 on western blot, suggesting changes in its posttranslational modifications. Indeed, this change is accompanied by an increase in the phosphorylation of Cx43 at serine 368, which is known to reduce permeability of Cx43 gap junctions. Finally, we show that this change occurs in the absence of neuronal firing or glutamatergic transmissions. Overall, these results show that propofol induces posttranslational modification of Cx43 directly on astrocytes at the site of gap junctional plaques, exerting direct pharmacological action on astrocytes in parallel with its action on neurons. [ABSTRACT FROM AUTHOR]

Postoperative cognitive dysfunction (POCD) is a common surgical complication that causes additional pain in patients and affects their quality of life. To address this problem, emerging studies have focused on the POCD. Recent studies have shown that aging and anesthetic exposure are the two major risk factors for developing POCD. However, few reports described the exact molecular mechanisms underlying POCD in elderly patients. In the previous studies, the endoplasmic reticulum (ER) stress and neuroapoptosis in the hippocampus were associated with inducing POCD; however, no further information on the related signaling pathways could be disclosed. The PERK-eIF2α-ATF4-CHOP pathway is identified as the main regulatory pathway involved in ER stress and cell apoptosis. Therefore, we assume that the occurrence of POCD induced by sevoflurane inhalation may potentially result from ER stress and neuroapoptosis in the hippocampus of aged mice mediated by the PERK-eIF2α-ATF4-CHOP pathway. In our study, we found a relationship between sevoflurane inhalation concentration and memory decline in aged mice, with a 'ceiling effect'. We have confirmed that POCD induced by sevoflurane results from ER stress and neuroapoptosis in the hippocampus of aged mice, which is regulated by the over-expression of PERK-eIF2α-ATF4-CHOP pathway. Furthermore, we also showed that the dephosphorylation inhibitor of eIF2α (salubrinal) could down-regulate PERK-eIF2α-ATF4-CHOP pathway expression to inhibit ER stress and enhance the cognitive function of aged mice. In general, our study has elucidated one of the molecular mechanisms of sevoflurane-related cognitive dysfunction in aged groups and provided new strategies for treating sevoflurane-induced POCD. • Sevoflurane induces POCD in aged mice with a 'ceiling effect.' • PERK-eIF2α-ATF4-CHOP signaling pathway regulates sevoflurane-related POCD in aged mice. • ER stress and neuronal apoptosis are important to sevoflurane-related POCD in aged mice. • Salubrinal improves the cognitive dysfunction induced by sevoflurane in aged mice. [ABSTRACT FROM AUTHOR]

Maria Hussain,1 Miles Berger,2 Roderic G Eckenhoff,3 Dallas P Seitz1 1Division of Geriatric Psychiatry, Department of Psychiatry, Queen’s University; 2Anesthesiology Department, Duke University Medical Center, Durham, NC, USA; 3Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA Abstract: In this review, we aim to provide clinical insights into the relationship between surgery, general anesthesia (GA), and dementia, particularly Alzheimer’s disease (AD). The pathogenesis of AD is complex, involving specific disease-linked proteins (amyloid-beta [Aß] and tau), inflammation, and neurotransmitter dysregulation. Many points in this complex pathogenesis can potentially be influenced by both surgery and anesthetics. It has been demonstrated in some in vitro, animal, and human studies that some anesthetics are associated with increased aggregation and oligomerization of Aß peptide and enhanced accumulation and hyperphosphorylation of tau protein. Two neurocognitive syndromes that have been studied in relation to surgery and anesthesia are postoperative delirium and postoperative cognitive dysfunction, both of which occur more commonly in older adults after surgery and anesthesia. Neither the route of anesthesia nor the type of anesthetic appears to be significantly associated with the development of postoperative delirium or postoperative cognitive dysfunction. A meta-analysis of case-control studies found no association between prior exposure to surgery utilizing GA and incident AD (pooled odds ratio =1.05, P=0.43). The few cohort studies on this topic have shown varying associations between surgery, GA, and AD, with one showing an increased risk, and another demonstrating a decreased risk. A recent randomized trial has shown that patients who received sevoflurane during spinal surgery were more likely to have progression of preexisting mild cognitive impairment compared to controls and to patients who received propofol or epidural anesthesia. Given the inconsistent evidence on the association between surgery, anesthetic type, and AD, well-designed and adequately powered studies with longer follow-up periods are required to establish a clear causal association between surgery, GA, and AD. Keywords: surgery, anesthesia, Alzheimer’s disease

The majority of currently used anesthetic agents are derived from or associated with natural products, especially plants, as evidenced by cocaine that was isolated from coca (Erythroxylum coca, Erythroxylaceae) and became a prototype of modern local anesthetics and by thymol and eugenol contained in thyme (Thymus vulgaris, Lamiaceae) and clove (Syzygium aromaticum, Myrtaceae), respectively, both of which are structurally and mechanistically similar to intravenous phenolic anesthetics. This paper reviews different classes of phytochemicals with the anesthetic activity and their characteristic molecular structures that could be lead compounds for anesthetics and anesthesia-related drugs. Phytochemicals in research papers published between 1996 and 2016 were retrieved from the point of view of well-known modes of anesthetic action, that is, the mechanistic interactions with Na+ channels, -aminobutyric acid type A receptors, N-methyl-D-aspartate receptors and lipid membranes. The searched phytochemicals include terpenoids, alkaloids and flavonoids because they have been frequently reported to possess local anesthetic, general anesthetic, antinociceptive, analgesic or sedative property. Clinical applicability of phytochemicals to local and general anesthesia is discussed by referring to animal in vivo experiments and human pre-clinical trials. This review will give structural suggestions for novel anesthetic agents of plant origin. [ABSTRACT FROM AUTHOR]

General anesthetics suppress CNS activity by modulating the function of membrane ion channels, in particular, by enhancing activity of GABAA receptors. In contrast, several volatile (isoflurane, desflurane) and i.v. (propofol) general anesthetics excite peripheral sensory nerves to cause pain and irritation upon administration. These noxious anesthetics activate transient receptor potential ankyrin repeat 1 (TRPA1), a major nociceptive ion channel, but the underlying mechanisms and site of action are unknown. Here we exploit the observation that pungent anesthetics activate mammalian but not Drosophila TRPA1. Analysis of chimeric Drosophila and mouse TRPA1 channels reveal a critical role for the fifth transmembrane domain (S5) in sensing anesthetics. Interestingly, we show that anesthetics share with the antagonist A-967079 a potential binding pocket lined by residues in the S5, S6, and the first pore helix; isoflurane competitively disrupts A-967079 antagonism, and introducing these mammalian TRPA1 residues into dTRPA1 recapitulates anesthetic agonism. Furthermore, molecular modeling predicts that isoflurane and propofol bind to this pocket by forming H-bond and halogen-bond interactions with Ser-876,Met-915, and Met-956. Mutagenizing Met-915 or Met-956 selectively abolishes activation by isoflurane and propofol without affecting actions of A-967079 or the agonist, menthol. Thus, our combined experimental and computational results reveal the potential binding mode of noxious general anesthetics at TRPA1. These data may provide a structural basis for designing drugs to counter the noxious and vasorelaxant properties of general anesthetics and may prove useful in understanding effects of anesthetics on related ion channels. [ABSTRACT FROM AUTHOR]

Anesthetics can affect the structure and biological function of tissues and systems differentially. The aim of the present study was to compare three injectable anesthetics generally used in experiments with animals in terms of the degree of hemolysis and glycogenolysis occurring after profound anesthesia. Twenty-four male Wistar rats (330-440 g) were divided into three groups (N = 8): chloral hydrate (CH), ketamine + xylazine (KX), Zoletil 50® (zolazepam and tiletamine) + xylazine (ZTX). After deep anesthesia, total blood was collected. The liver and white (WG) and red gastrocnemius (RG) muscles were also immediately removed. The degree of serum hemolysis was quantified on the basis of hemoglobin concentration (g/L). Hepatic and muscular glycogen concentrations (mmol/kg wet tissue) were quantified by the phenol-sulfuric method. The CH and KX groups exhibited serum hemolysis (4.0 ± 2.2 and 1.9 ± 0.9 g/L, respectively; P < 0.05) compared to the ZTX group, which presented none. Only KX induced elevated glycogenolysis (mmol/kg wet tissue) in the liver (86.9 ± 63.2) and in WG (18.7 ± 9.0) and RG (15.2 ± 7.2; P < 0.05). The CH and ZTX groups exhibited no glycogenolysis in the liver (164.4 ± 41.1 and 176.8 ± 54.4, respectively), WG (28.8 ± 4.4, 32.0 ± 6.5, respectively) or RG (29.0 ± 4.9; 25.3 ± 8.6, respectively). Our data indicate that ZTX seems to be an appropriate general anesthetic for studies that seek to simultaneously quantify the concentration of glycogen and serum biochemical markers without interferences. ZTX is reasonably priced, found easily at veterinary markets, quickly induces deep anesthesia, and presents a low mortality rate.

A simple, sensitive and precise HPTLC (high performance thin layer chromatography) method has been developed for quantitative estimation of ketamine in bulk and pharmaceutical formulations. The separation of ketamine was achieved over HPTLC glass plate of silica GF-254 by using cyclohexane:toluene:diethylamine (5:3:2 v/v) solvent system. Densitometric evaluation was carried out in the UV region at wavelength of 254. The method was found to be accurate (98.92-100.26%) and precise (CV = 0.43-0.67 for intra-day and CV = 0.58-1.45 for inter-day) within the corresponding linear range. The limit of detection (LOD) and limit of quantification (LOQ) of sample have been found to be 100 ng/spot and 303 ng/spot, respectively. [ABSTRACT FROM AUTHOR]

Excitotoxicity due to hyperactivation of glutamate receptors is thought to underlie acute spinal injury with subsequent strong deficit in spinal network function. Devising an efficacious protocol of neuroprotection to arrest excitotoxicity might, therefore, spare a substantial number of neurons and allow later recovery. In vitro preparations of the spinal cord enable detailed measurement of spinal damage evoked by the potent glutamate analogue kainate. Any clinically-relevant neuroprotective treatment should start after the initial lesion and spare networks for at least 24 h when cell damage plateaus. Using this strategy, we have observed that the gas anesthetic methoxyflurane provided strong, delayed neuroprotection. It is unclear if this beneficial effect was due to the mechanism of action by methoxyflurane, or it was the consequence of anesthetic depression. To test this hypothesis, we investigated the effect by propofol (commonly injected i.v. for general anesthesia) after kainate excitotoxicity induced on organotypic spinal slices. At 5 μM concentration, propofol significantly attenuated cell death, including neuronal losses and, especially, damage to the highly vulnerable motoneurons. The action by propofol was fully prevented when co-applied with the GABA A antagonist bicuculline, indicating that neuroprotection required intact GABA A receptor function. Although bicuculline per se was not neurotoxic, it largely enhanced the lesional effects of kainate, suggesting that GABA A receptor activity could limit excitotoxicity. Our data might offer an explanation for the beneficial clinical outcome of neurosurgery performed as soon as possible after spinal lesion: we posit that general anesthesia contributes to this outcome, regardless of the type of anesthetic used. [ABSTRACT FROM AUTHOR]