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Background: Subarachnoid hemorrhage (SAH) is associated with neurocognitive impairment. Recent data suggest that sevoflurane attenuates edema formation after SAH in rats. However, so far, no information is available about the long-term repair phase, nor if sevoflurane impacts functionality by increasing vascularity. This study tested whether sevoflurane postconditioning would improve long-term neurologic deficit through increased formation of new vessels close to the hemorrhage area., Methods: Fifty-three animals were subjected to SAH or sham surgery with or without a 2-hour sevoflurane postconditioning (versus propofol anesthesia). Animal survival, including dropout animals due to death or reaching termination criteria, as well as neurologic deficit, defined by the Garcia score, were assessed 2 hours after recovery until postoperative day 14. On day 14, blood samples and brain tissue were harvested. Vessel density was determined by the number of cluster of differentiation 31 (CD31)-positive vessels, and activated glial cells by glial fibrillary acidic protein (GFAP)-positive astrocytes per field of view., Results: The survival rate for sham animals was 100%, 69% in the SAH-propofol and 92% in the SAH-sevoflurane groups. According to the log-rank Mantel-Cox test, survival curves were significantly different ( P = .024). The short-term neurologic deficit was higher in SAH-propofol versus SAH-sevoflurane animals 2 hours after recovery and on postoperative day 1 (propofol versus sevoflurane: 14. 6 ± 3.4 vs 15. 9 ± 2.7 points, P = .034, and 16. 2 ± 3.5 vs 17. 8 ± 0.9 points, P = .015). Overall complete recovery from neurologic deficit was observed on day 7 in both SAH groups (18. 0 ± 0.0 vs 18. 0 ± 0.0 points, P = 1.000). Cortical vascular density increased to 80. 6 ± 15.0 vessels per field of view in SAH-propofol animals (vs 71. 4 ± 10.1 in SAH-sevoflurane, P < .001). Activation of glial cells, an indicator of neuroinflammation, was assessed by GFAP-positive astrocytes GFAP per field of view. Hippocampal GFAP-positive cells were 201 ± 68 vs 179 ± 84 cells per field of view in SAH-propofol versus SAH-sevoflurane animals ( P < .001)., Conclusions: Sevoflurane postconditioning improves survival by 23% (SAH-sevoflurane versus SAH-propofol). The sevoflurane intervention could attenuate the early neurologic deficit, while the long-term outcome was similar across the groups. A higher vascular density close to the SAH area in the propofol group was not associated with improved outcomes., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2024 International Anesthesia Research Society.)

Objective: To investigate if fentanyl induces immobility through activation of the serotonergic 5HT 1A receptor, by using the 5HT 1A -antagonist robalzotan., Study Design: A prospective, blinded, randomized, two-group study., Animals: A group of 12 mixed-breed pigs aged 71-79 days., Methods: The motor response to clamping a claw was assessed in isoflurane-anaesthetized pigs at baseline, then fentanyl was infused intravenously (IV) for 40 minutes and clamping was repeated. The infusion started at 20 μg kg -1 hour -1 and was increased by 60% until fentanyl produced immobility, defined as no motor response for 60 seconds. Subsequently, either robalzotan (1 mg kg -1 ) or the same volume of saline was injected IV and clamping was repeated. The change in response was compared with Fisher's exact test. Mean arterial blood pressure (MAP) and heart rate (HR) were extracted for 2 minutes before and after 60 seconds of clamping, and the differences compared with a Wilcoxon signed-rank test. Dynamic respiratory compliance was calculated at baseline and after fentanyl; p < 0.05., Results: Baseline clamping produced a motor response within 5 seconds. This was abolished by fentanyl. Robalzotan or saline did not alter this (p = 0.45). As a response to clamping, MAP and HR changed with median (range) -0.5 (-4.4 to 22.2) mmHg and -1 (-7 to 1.5), respectively, where HR changed significantly (p = 0.039). The 95% confidence interval for the effect size of fentanyl upon dynamic compliance was -3.25 to -1.65 mL cmH 2 O -1 ., Conclusions and Clinical Relevance: No indication was found for the 5HT 1A receptor to be involved in fentanyl-induced reduction of the motor response to claw clamping. The decreased compliance after fentanyl could suggest onset of chest wall rigidity., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Analgesia is an important effect of volatile anaesthetics, for which the spinal cord is a critical neural target. However, how supraspinal mechanisms modulate analgesic potency of volatile anaesthetics is not clear. We investigated the contribution of the central amygdala (CeA) to the analgesic effects of isoflurane and sevoflurane., Methods: Analgesic potencies of volatile anaesthetics were tested during optogenetic and chemogenetic inhibition of CeA neurones. In vivo calcium imaging was used to measure neuronal activities of CeA neuronal subtypes under volatile anaesthesia. Contributions of the sodium leak channel (NALCN) in GABAergic CeA (CeA GABA ) neurones to analgesic effects of volatile anaesthetics were explored by specific NALCN knockdown. Electrophysiological recordings on acute brain slices were applied to measure volatile anaesthetic modulation of CeA neuronal activity by NALCN., Results: Optogenetic or chemogenetic silencing CeA neurones reduced the analgesic effects of isoflurane or sevoflurane in vivo. The calcium signals of CeA GABA neurones increased during exposure to isoflurane or sevoflurane at analgesic concentrations. Knockdown of NALCN in CeA GABA neurones attenuated antinociceptive effects of isoflurane, sevoflurane, or both. For example, mean concentrations of isoflurane, sevoflurane, or both that induced immobility to tail-flick stimuli were significantly increased (isoflurane: 1.17 [0.05] vol% vs 1.24 [0.04] vol%, P=0.01; sevoflurane: 2.65 [0.07] vol% vs 2.81 [0.07] vol%; P<0.001). In brain slices, isoflurane, sevoflurane, or both at clinical concentrations increased NALCN-mediated holding currents and conductance in CeA GABA neurones, which increased excitability of CeA GABA neurones in an NALCN-dependent manner., Conclusions: The analgesic potencies of volatile anaesthetics are partially mediated by modulation of NALCN in CeA GABA neurones., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Objective: To evaluate induced hypothermia and rewarming times in Hispaniolan Amazon parrots (HAP; Amazona ventralis) anesthetized using isoflurane, sevoflurane or desflurane, and to describe selected cardiovascular and respiratory effects., Study Design: Randomized, balanced, crossover experimental study., Animals: A group of 12 adult HAP., Methods: Parrots were premedicated with intramuscular butorphanol (0.5 mg kg -1 ) and anesthetized with the three inhalants with a 7 day washout period between events. Anesthesia was induced using isoflurane at 4 vol%, sevoflurane at 6 vol% or desflurane 12 vol% carried in oxygen, delivered via face mask. After orotracheal intubation, anesthesia maintenance was with end-tidal concentrations of 1.4-2% (Fe'Iso), 2.4-3% (Fe'Sevo) and 8.5-9.2% (Fe'Des). Hypothermia was defined as an esophageal temperature (BT) below 37.8 °C. External heat support was provided when BT dropped to 37.5 °C. Time for temperature decrease from 38.9 °C to 37.5 °C (T1), time to first increase in BT above 37.5 °C (T2) and time from external heat support to achieving 38.9 °C (T3) were recorded and compared via Friedman tests with post hoc Dunn's test. Heart rate, respiratory rate and end-tidal carbon dioxide, amongst other variables, were evaluated., Results: All inhalants caused hypothermia (T1): isoflurane, 12 (2-37) minutes [median (range)]; sevoflurane, 12 (4-18) minutes; desflurane, 11.5 (6-24) minutes, with no significant differences between treatments (p > 0.05). T2 was significantly (p = 0.042) longer for sevoflurane than for desflurane but not isoflurane. Transient apnea was observed with all inhalants, including 25% of birds anesthetized with sevoflurane. Second-degree atrioventricular block and ventricular escape beats occurred with all inhalants with hypothermia potentially exacerbating cardiac arrhythmias., Conclusions and Clinical Relevance: Hypothermia rapidly developed in butorphanol-sedated HAP anesthetized using isoflurane, sevoflurane or desflurane. Sevoflurane prolonged warming time. Hypothermia may be associated with an increased likelihood of bradyarrhythmia in parrots anesthetized with inhalants., (Copyright © 2024 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Isoflurane, a commonly used inhaled anesthetic, has been found to have a cardioprotective effect. However, the precise mechanisms have not been fully elucidated. Here, we found that isoflurane preconditioning enhanced OGD/R-induced upregulation of miR-210, a hypoxia-responsive miRNA, in AC16 human myocardial cells. To further test the roles of miR-210 in regulating the effects of isoflurane preconditioning on OGD/R-induced cardiomyocyte injury, AC16 cells were transfected with anti-miR-210 or control anti-miRNA. Results showed that isoflurane preconditioning attenuated OGD/R-induced cardiomyocyte cytotoxicity (as assessed by cell viability, LDH and CK-MB levels), which could be reversed by anti-miR-210. Isoflurane preconditioning also prevented OGD/R-induced increase in apoptotic rate, caspase-3 and caspase-9 activities, and Bax level and decrease in Bcl-2 expression level, while anti-miR-210 blocked these effects. We also found that anti-miR-210 prevented the inhibitory effects of isoflurane preconditioning on OGD/R-induced decrease in adenosine triphosphate content; mitochondrial volume; citrate synthase activity; complex I, II, and IV activities; and p-DRP1 and MFN2 expression. Besides, the expression of BNIP3, a reported direct target of miR-210, was significantly decreased under hypoxia condition and could be regulated by isoflurane preconditioning. In addition, BNIP3 knockdown attenuated the effects of miR-210 silencing on the cytoprotection of isoflurane preconditioning. These findings suggested that isoflurane preconditioning exerted protective effects against OGD/R-induced cardiac cytotoxicity by regulating the miR-210/BNIP3 axis., (© 2024 John Wiley & Sons, Ltd.)

Purpose: The purpose of this study was to determine the effect of sevoflurane anesthesia on spikes, high-frequency oscillations (HFOs), and phase-amplitude coupling using a modulation index in MRI-normal hippocampus, with the aim of evaluating the utility of intraoperative electrocorticography in identifying the epileptogenic hippocampus during sevoflurane administration., Methods: Eleven patients with intractable temporal lobe epilepsy with a normal hippocampus on MRI underwent extra-operative electrocorticography evaluation. Patients were assigned to the Ictal (+) or Ictal (-) group depending on whether the parahippocampal gyrus was included in the seizure onset zone. Intraoperative electrocorticography was performed under 0.5 and 1.5 minimum alveolar concentration of sevoflurane. The rates of spikes, ripples, fast ripples (FRs), ripples on spikes, FRs on spikes, and MI HFO(3-4 Hz) were evaluated., Results: During the intraoperative electrocorticography procedure, sevoflurane administration was found to significantly increase the rate of spikes, ripples on spikes, fast ripples on spikes, and MI HFO(3-4 Hz) in the Ictal (+) group ( P < 0.01). By contrast, the Ictal (-) group exhibited a paradoxical increase in the rate of ripples and fast ripple ( P < 0.05)., Conclusions: Our findings indicate that the administration of sevoflurane during intraoperative electrocorticography in patients with MRI-normal hippocampus can lead to a dose-dependent enhancement of epileptic biomarkers (spikes, ripples on spikes, fast ripples on spikes, and MI (HFO 3-4) ) in the epileptogenic hippocampus, while paradoxically increasing the rate of ripples and fast ripple in the nonepileptogenic hippocampus. These results have significant implications for the identification of the MRI-normal hippocampus that requires surgical intervention and preservation of the nonepileptogenic hippocampus., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 by the American Clinical Neurophysiology Society.)

Sevoflurane causes neural injury by promoting apoptosis and oxidative stress. Reactive oxygen species modulator 1 (ROMO1) regulates apoptosis and oxidative stress, while its role in sevoflurane-induced neural injury remains unclear. This study intended to investigate the effect of ROMO1 knockdown on viability, apoptosis, and oxidative stress in sevoflurane-treated HT22 cells and its downstream pathway. HT22 cells were untreated (blank control), or treated with 1%, 2%, and 4% sevoflurane, respectively. Moreover, HT22 cells were transfected with siROMO1 small interfering RNA (siROMO1) or negative control siRNA (siNC) and then stimulated with 4% sevoflurane for further assays. Sevoflurane dose-dependently decreased cell viability and increased apoptosis rate versus blank control in HT22 cells. Sevoflurane elevated reactive oxygen species (ROS) fluorescence intensity, malondialdehyde (MDA), and lactate dehydrogenase (LDH) release, while reducing superoxide dismutase (SOD) activity in a dose-dependent manner versus blank control in HT22 cells. It also dose-dependently increased the relative mRNA and protein expressions of ROMO1 versus blank treatment in HT22 cells. Moreover, siROMO1 plus 4% sevoflurane increased cell viability, while decreasing apoptosis rate, ROS fluorescence intensity, MDA, and LDH release versus siNC plus 4% sevoflurane in HT22 cells. siROMO1 plus 4% sevoflurane elevated the phosphorylation of protein kinase B (AKT) versus siNC plus 4% sevoflurane in HT22 cells. ROMO1 inhibition reverses sevoflurane-induced neural injury by reducing apoptosis and oxidative stress in HT22 cells. The results indicate that ROMO1 may be a potential target for the management of sevoflurane-induced neural injury., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The common marmoset is an essential model for understanding social cognition and neurodegenerative diseases. This study explored the structural and functional brain connectivity in a marmoset under isoflurane anesthesia, aiming to statistically overcome the effects of high inter-individual variability and noise-related confounds such as physiological noise, ensuring robust and reliable data. Similarities and differences in individual subject data, including assessments of functional and structural brain connectivities derived from resting-state functional MRI and diffusion tensor imaging were meticulously captured. The findings highlighted the high consistency of structural neural connections within the species, indicating a stable neural architecture, while functional connectivity under anesthesia displayed considerable variability. Through independent component and dual regression analyses, several distinct brain connectivities were identified, elucidating their characteristics under anesthesia. Insights into the structural and functional features of the marmoset brain from this study affirm its value as a neuroscience research model, promising advancements in the field through fundamental and translational studies., Competing Interests: Declaration of competing interest None, (Copyright © 2024. Published by Elsevier Inc.)

Background: Cognitive dysfunction, encompassing perioperative psychological distress and cognitive impairment, is a prevalent postoperative complication within the elderly population, and in severe cases, it may lead to dementia. Building upon our prior research that unveiled a connection between postoperative mood fluctuations and cognitive dysfunction with the phosphorylation of P38, this present investigation aims to delve deeper into the involvement of the P38 MAPK/NLRP3 pathway in perioperative neurocognitive disorders (PND) in an abdominal exploratory laparotomy (AEL) aged mice model., Methods: C57BL/6 mice (male, 18-month-old) underwent AEL with 3 % anesthesia. Then, inhibitors targeting P38 MAPK (SB202190, 1 mg/kg) and GSK3β (TWS119, 10 mg/kg) were administered multiple times daily for 7 days post-surgery. The NLRP3-cKO AEL and WT AEL groups only underwent the AEL procedure. Behavioral assessments, including the open field test (OFT), novel object recognition (NOR), force swimming test (FST), and fear conditioning (FC), were initiated on postoperative day 14. Additionally, mice designated for neuroelectrophysiological monitoring had electrodes implanted on day 14 before surgery and underwent novel object recognition while their local field potential (LFP) was concurrently recorded on postoperative day 14. Lastly, after they were euthanasized, pathological analysis and western blot were performed., Results: SB202190, TWS119, and astrocyte-conditional knockout NLRP3 all ameliorated the cognitive impairment behaviors induced by AEL in mice and increased mean theta power during novel location exploration. However, it is worth noting that SB202190 may exacerbate postoperative depressive and anxiety-like behaviors in mice, while TWS119 may induce impulsive behaviors., Conclusions: Our study suggests that anesthesia and surgical procedures induce alterations in mood and cognition, which may be intricately linked to the P38 MAPK/NLRP3 pathway., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

An aortic aneurysm (AA) is a life-threatening condition. Oxidative stress may be a common pathway linking multiple mechanisms of an AA, including vascular inflammation and metalloproteinase activity. Endovascular aneurysm repair (EVAR) is the preferred surgical approach for AA treatment. During surgery, inflammation and ischemia-reperfusion injury occur, and reactive oxygen species (ROS) play a key role in their modulation. Increased perioperative oxidative stress is associated with higher postoperative complications. The use of volatile anesthetics during surgery has been shown to reduce oxidative stress. Individual biomarkers only partially reflect the oxidative status of the patients. A global indicator of oxidative stress (OXY-SCORE) has been validated in various pathologies. This study aimed to compare the effects of the main volatile anesthetics, sevoflurane and desflurane, on oxidative status during EVAR. Eighty consecutive patients undergoing EVAR were randomized into two groups: sevoflurane and desflurane. Plasma biomarkers of oxidative damage (protein carbonylation and malondialdehyde) and antioxidant defense (total thiols, glutathione, nitrates, superoxide dismutase, and catalase activity) were measured before surgery and 24 h after EVAR. The analysis of individual biomarkers showed no significant differences between the groups. However, the OXY-SCORE was positive in the desflurane group (indicating a shift towards antioxidants) and negative in the sevoflurane group (favoring oxidants) ( p < 0.044). Compared to sevoflurane, desflurane had a positive effect on oxidative stress during EVAR. The OXY-SCORE could provide a more comprehensive perspective on oxidative stress in this patient population.

Background: Repeated exposure to sevoflurane during early developmental stages is a risk factor for social behavioural disorders, but the underlying neuropathological mechanisms remain unclear. As the hippocampal cornu ammonis area 2 subregion (CA2) is a critical centre for social cognitive functions, we hypothesised that sevoflurane exposure can lead to social behavioural disorders by disrupting neuronal activity in the CA2., Methods: Neonatal mice were anaesthetised with sevoflurane 3 vol% for 2 h on postnatal day (PND) 6, 8, and 10. Bulk RNA sequencing of CA2 tissue was conducted on PND 12. Social cognitive function was assessed by behavioural experiments, and in vivo CA2 neuronal activity was recorded by multi-channel electrodes on PND 60-65., Results: Repeated postnatal exposure to sevoflurane impaired social novelty recognition in adulthood. It also caused a decrease in the synchronisation of neuronal spiking, gamma oscillation power, and spike phase-locking between GABAergic spiking and gamma oscillations in the CA2 during social interaction. After sevoflurane exposure, we observed a reduction in the density and dendritic complexity of CA2 GABAergic neurones, and decreased expression of transcription factors critical for GABAergic neuronal development after., Conclusions: Repeated postnatal exposure to sevoflurane disturbed the development of CA2 GABAergic neurones through downregulation of essential transcription factors. This resulted in impaired electrophysiological function in adult GABAergic neurones, leading to social recognition deficits. These findings reveal a potential electrophysiological mechanism underlying the long-term social recognition deficits induced by sevoflurane and highlight the crucial role of CA2 GABAergic neurones in social interactions., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Volatile sedation is still used with caution in patients with acute brain injury because of safety concerns. We analyzed the effects of sevoflurane sedation on systemic and cerebral parameters measured by multimodal neuromonitoring in patients after aneurysmal subarachnoid hemorrhage (aSAH) with normal baseline intracranial pressure (ICP)., Methods: In this prospective observational study, we analyzed a 12-h period before and after the switch from intravenous to volatile sedation with sevoflurane using the Sedaconda Anesthetic Conserving Device with a target Richmond Agitation Sedation Scale score of - 5 to - 4. ICP, cerebral perfusion pressure (CPP), brain tissue oxygenation (PBrO 2 ), metabolic values of cerebral microdialysis, systemic cardiopulmonary parameters, and the administered drugs before and after the sedation switch were analyzed., Results: We included 19 patients with a median age of 61 years (range 46-78 years), 74% of whom presented with World Federation of Neurosurgical Societies grade 4 or 5 aSAH. We observed no significant changes in the mean ICP (9.3 ± 4.2 vs. 9.7 ± 4.2 mm Hg), PBrO 2 (31.0 ± 13.2 vs. 32.2 ± 12.4 mm Hg), cerebral lactate (5.0 ± 2.2 vs. 5.0 ± 1.9 mmol/L), pyruvate (136.6 ± 55.9 vs. 134.1 ± 53.6 µmol/L), and lactate/pyruvate ratio (37.4 ± 8.7 vs. 39.8 ± 9.2) after the sedation switch to sevoflurane. We found a significant decrease in mean arterial pressure (MAP) (88.6 ± 7.6 vs. 86.3 ± 5.8 mm Hg) and CPP (78.8 ± 8.5 vs. 76.6 ± 6.6 mm Hg) after the initiation of sevoflurane, but the decrease was still within the physiological range requiring no additional hemodynamic support., Conclusions: Sevoflurane appears to be a feasible alternative to intravenous sedation in patients with aSAH without intracranial hypertension, as our study did not show negative effects on ICP, cerebral oxygenation, or brain metabolism. Nevertheless, the risk of a decrease of MAP leading to a consecutive CPP decrease should be considered., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background: The perioperative administration of low-dose ketamine has shown potential in postoperative pain management, opioid sparing, and enhancing pain control. This study aimed to investigate the impact of low-dose ketamine on processed electroencephalography (EEG) signals during anesthesia., Methods: Forty patients with American Society of Anesthesiologists physical status I-II undergoing elective gynecological surgery were enrolled. EEG monitoring was initiated upon induction of anesthesia. Anesthesia was maintained with desflurane and alfentanil immediately after induction. Fifteen minutes after induction, the ketamine group received a 0.3 mg/kg bolus followed by 0.05 mg/kg/h infusion until completion of surgery. The control group received equivalent saline. Postoperative assessments included pain score (visual analog scale), morphine usage, and quality of recovery., Results: The ketamine group had significantly higher Patient State Index (PSi) values at 10, 20, and 30 minutes after ketamine administration compared to the controls. Ketamine administration led to significant alterations in EEG patterns, including reduced relative power in delta and theta frequency bands, and increased relative power in beta and gamma frequency bands at 10 minutes post-administration. Relative power in the alpha frequency band significantly decreased at 10, 20, and 30 minutes post-administration. However, there were no differences in intraoperative alfentanil consumption, postoperative morphine usage, and pain scores between the two groups., Conclusion: Low-dose ketamine administration during desflurane anesthesia led to notable changes in EEG patterns and PSi values. These findings provide valuable insights into the impact of ketamine on brain activity, and offer essential information for clinical anesthesiologists., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)

Elderly individuals undergoing surgical procedures are often confronted with the peril of experiencing postoperative cognitive dysfunction (POCD). Prior research has demonstrated the exacerbating effect of sevoflurane anesthesia on neuroinflammation, which can further deteriorate the condition of POCD in elderly patients. Intermittent fasting (IF) restricts food consumption to a specific time window and has been demonstrated to ameliorate cognitive dysfunction induced by neuropathic inflammation. We subjected 18-month-old male mice to 16 hours of fasting and 8 hours of unrestricted eating over a 24-hour period for 0, 1, 2, and 4 weeks, followed by abdominal exploration under sevoflurane anesthesia. In this study, we aim to explore the potential impact of IF on postoperative cognitive function in aged mice undergoing sevoflurane surgery through the preoperative implementation of IF measures. The findings indicate two weeks of IF leads to a significant enhancement of learning and memory capabilities in mice following surgery. The cognitive performance, as determined by the novel object recognition and Morris water maze tests, as well as the synaptic plasticity, as measured by in vivo electrophysiological recordings, has demonstrated marked improvements. Furthermore, the administration of IF markedly enhances the expression of synaptic-associated proteins in hippocampal neurons, concomitant with a decreasing expression of pro-inflammatory factors and a reduced density of microglial cells within the hippocampal brain region. To summarize, the results of this study indicate that IF may mitigate inflammation in the hippocampal area of the brain. Furthermore, IF appears to provide a safeguard against cognitive impairment and synaptic plasticity impairment brought on by sevoflurane anesthesia., Competing Interests: Declaration of Competing Interest The authors assert that the study was carried out without any commercial or financial affiliations that could be interpreted as a possible conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Vitamin D (VD) is a neuroactive steroid involved in many brain functions, such as neurotrophic, neuroimmune control and neurotransmission, which affects the growth and function of the brain. The purpose of this study is to explore the effect of VD on motor and cognitive function of aged mice after sevoflurane anesthesia., Method: We established sevoflurane anesthesia model and VD(-) and VD(+) mice model. The VD concentration of mice in each group was determined by enzyme-linked immunosorbent assay (ELISA). An open-field test was used to evaluate the mice's capacity for movement and exploration. A Y-maze test was used to gauge the mice's short-term memory. The primary purpose of the water-maze experiment was to examine mice's long-term spatial memory., Results: The ELISA results showed that the model was successfully constructed. In the open-field test, VD increased the exercise distance of mice ( P  < .05). In the Y-maze experiment, VD improved short-term memory impairment in mice ( P  < .05). In the water-maze test, VD increased the activity time and platform crossing number of mice in the target quadrant. ( P  < .05)., Conclusion: Sevoflurane anesthesia caused cognitive dysfunction in aged mice, including reduced learning ability, memory loss, lower motor and exploratory abilities and depression, and VD deficiency aggravated these impairments. By supplementing with VD, learning ability and long-term memory were enhanced, motor and exploratory abilities were improved, and depression levels were reduced. Anxiety was also improved.

Background: Dopaminergic psychostimulants can restore arousal in anaesthetised animals, and dopaminergic signalling contributes to hippocampal-dependent memory formation. We tested the hypothesis that dopaminergic psychostimulants can antagonise the amnestic effects of isoflurane on visuospatial working memory., Methods: Sixteen adult Sprague-Dawley rats were trained on a trial-unique nonmatching-to-location (TUNL) task which assessed the ability to identify a novel touchscreen location after a fixed delay. Once trained, the effects of low-dose isoflurane (0.3 vol%) on task performance and activity, assessed by infrared beam breaks, were assessed. We attempted to rescue deficits in performance and activity with a dopamine D1 receptor agonist (chloro-APB), a noradrenergic reuptake inhibitor (atomoxetine), and a mixed dopamine/norepinephrine releasing agent (dextroamphetamine). Anaesthetic induction, emergence, and recovery from anaesthesia were also investigated., Results: Low-dose isoflurane impaired working memory in a sex-independent and intra-trial delay-independent manner as assessed by task performance, and caused an overall reduction in activity. Administration of chloro-APB, atomoxetine, or dextroamphetamine did not restore visuospatial working memory, but chloro-APB and dextroamphetamine recovered arousal to levels observed in the baseline awake state. Performance did not differ between induction and emergence. Animals recovered to baseline performance within 15 min of discontinuing isoflurane., Conclusions: Low-dose isoflurane impairs visuospatial working memory in a nondurable and delay-independent manner that potentially implicates non-hippocampal structures in isoflurane-induced memory deficits. Dopaminergic psychostimulants counteracted sedation but did not reverse memory impairments, suggesting that isoflurane-induced amnesia and isoflurane-induced sedation have distinct underlying mechanisms that can be antagonised independently., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: To examine whether isoflurane preconditioning (IsoP) has a protective effect against renal ischemia/reperfusion injury (I/RI) in diabetic conditions and to further clarify the underlying mechanisms., Methods: Control and streptozotocin-induced diabetic rats were randomly assigned to five groups, as follows: normal sham, normal I/R, diabetic sham, diabetic I/R, and diabetic I/R + isoflurane. Renal I/RI was induced by clamping renal pedicle for 45 min followed by reperfusion for 24 h. IsoP was achieved by exposing the rats to 2% isoflurane for 30 min before vascular occlusion. Kidneys and blood were collected after reperfusion for further analysis. Renal histology, blood urea nitrogen, serum creatinine, oxidative stress, inflammatory cytokines, and renal cell apoptosis were assessed. Furthermore, the expression of brahma related gene 1 (Brg1), nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and nuclear factor-κB (NF-κB) were determined., Results: Compared with control, diabetic rats undergoing I/R presented more severe renal injury, oxidative stress, inflammatory reaction, and apoptosis with the impairment of Brg1/Nrf2/HO-1 signaling. All these alterations were significantly attenuated by pretreatment with isoflurane., Conclusions: These findings suggest that isoflurane could alleviate renal I/RI in diabetes, possibly through improving Brg1/Nrf2/HO-1 signaling.

Introduction: The use of volatile anaesthetic agents for the sedation of patients requiring critical care treatment offers several theoretical advantages over intravenous sedation, which may be of benefit in neurocritical care. However, there are concerns that they may increase intracranial pressure. The objective of this systematic review is to assess whether, and if so, to what extent volatile anaesthetic agents affect intracranial pressure, cerebral blood flow (CBF), cerebral oximetry and cerebrovascular autoregulation. If sufficient data exist, subgroup analyses will be conducted in traumatic brain injury and decompressive craniectomy patients., Methods and Analysis: A database search of PubMed, Medline (including Medline plus), CINAHL (including CINAHL Plus), Embase databases and the Cochrane Central Controlled Trials Register without time limits will be conducted. The search results will be screened by title and abstract by two independent researchers on a rule-in basis against predetermined criteria-controlled studies in humans of contemporary fluorinated volatile anaesthetic agents against a control, which measures intracranial pressure, CBF, cerebral oximetry or cerebrovascular autoregulation. Articles responsive to screening will then be reviewed in full text by two independent researchers, requiring consensus or a tie-break by a third independent researcher. Reference lists and a non-generative AI tool will be examined for missed articles, with all identified articles being reviewed in full text by two independent researchers. The included articles will be assessed for risk of bias and will have data extracted by two independent researchers. If sufficient data exist, a meta-analysis will be performed; otherwise, a narrative description of outcomes will be performed., Ethics and Dissemination: No ethics approval will be sought for this systematic review. This study has no explicit funding. The results of this study will be disseminated in a peer-reviewed journal, in a conference presentation and on PROSPERO., Trial Registration Number: PROSPERO number CRD42023474587., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Isoflurane is a commonly used general anesthetic widely employed in clinical surgeries. Recent studies have indicated that isoflurane might induce negative impacts on the nervous system, notably by triggering neuronal apoptosis. This process is pivotal to the development and emergence of neurological disorders; its misregulation could result in functional deficits and the initiation of diseases within nervous system. However, the potential molecular mechanism of isoflurane on the neuronal apoptosis remains fully unexplored. This study aims to investigate the regulatory role of the sirtuin 1-mechanistic target of rapamycin (SIRT1-mTOR) signaling pathway in autophagy during isoflurane-induced apoptosis of fetal rat brain neuronal cells., Methods: Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, real-time quantitative polymerase chain reaction (qPCR), and Western blot were utilized to evaluate the apoptotic status of hippocampal tissue cells in fetal mice after sevoflurane exposure. Our further investigation was commenced with flow cytometry, immunofluorescence, qPCR, and Western blot to determine the impact of autophagy on sevoflurane-induced apoptosis in these neurons. On the other hand, we conducted an additional set of analyses, including flow cytometric analysis, qPCR, and Western blot, to further elucidate the neuroprotective potential of autophagy in neural cells of fetal mice subjected to sevoflurane-induced apoptosis., Results: Our findings indicated that a 3% sevoflurane treatment led to a significant rise in apoptosis among fetal rat hippocampal tissue cells and neurons. Levels of apoptosis-associated proteins, cleaved-caspase-3 and Bcl-2 associated X protein (Bax), were found to be markedly higher, coinciding with an enhancement in autophagy as evidenced by increased microtubule-associated proteins 1A/1B-light chain 3 (LC3) and decreased p62 expression. Concurrently, there was a notable up-regulation of sirtuin 1 (SIRT1) and a down-regulation of mechanistic target of rapamycin (mTOR) expression. In conclusion, our research elucidated the pivotal function of cellular autophagy in an apoptosis induced by sevoflurane in fetal rat nerve cells. Through experimental manipulation, we observed that interference with SIRT1 resulted in a reduction of both cleaved-caspase-3 and Bax levels. This intervention also beget a diminished expression of the autophagy-associated factor LC3 and an up-regulation of p62. Furthermore, inhibition against mTOR reversed the effects induced by SIRT1 interference, suggesting a complex interplay amid these regulatory pathways., Conclusions: SIRT1 possesses a capacity to modulate apoptosis in the hippocampal neurons of fetal rats triggered by sevoflurane, with mTOR functioning as an inhibitory factor within this signaling pathway., (© 2024 The Author(s). Published by IMR Press.)

Inhalation anesthesia stands as a pivotal modality within clinical anesthesia practices. Beyond its primary anesthetic effects, inhaled anesthetics have non-anesthetic effects, exerting bidirectional influences on the physiological state of the body and disease progression. These effects encompass impaired cognitive function, inhibition of embryonic development, influence on tumor progression, and so forth. For many years, inhaled anesthetics were viewed as inhibitors of stem cell fate regulation. However, there is now a growing appreciation that inhaled anesthetics promote stem cell biological functions and thus are now regarded as a double-edged sword affecting stem cell fate. In this review, the effects of inhaled anesthetics on self-renewal and differentiation of neural stem cells (NSCs), embryonic stem cells (ESCs), and cancer stem cells (CSCs) were summarized. The mechanisms of inhaled anesthetics involving cell cycle, metabolism, stemness, and niche of stem cells were also discussed. A comprehensive understanding of these effects will enhance our comprehension of how inhaled anesthetics impact the human body, thus promising breakthroughs in the development of novel strategies for innovative stem cell therapy approaches.

Background: The lateral hypothalamus (LHA) is an evolutionarily conserved structure that regulates basic functions of an organism, particularly wakefulness. To clarify the function of LHA GABA neurons and their projections on regulating general anesthesia is crucial for understanding the excitatory and inhibitory effects of anesthetics on the brain. The aim of the present study is to investigate whether LHA GABA neurons play either an inhibitory or a facilitatory role in sevoflurane-induced anesthetic arousal regulation., Methods: We used fiber photometry and immunofluorescence staining to monitor changes in neuronal activity during sevoflurane anesthesia. Opto-/chemogenetic modulations were employed to study the effect of neurocircuit modulations during the anesthesia. Anterograde tracing was used to identify a GABAergic projection from the LHA to a periaqueductal gray (PAG) subregion., Results: c-Fos staining showed that LHA GABA activity was inhibited by induction of sevoflurane anesthesia. Anterograde tracing revealed that LHA GABA neurons project to multiple arousal-associated brain areas, with the lateral periaqueductal gray (LPAG) being one of the dense projection areas. Optogenetic experiments showed that activation of LHA GABA neurons and their downstream target LPAG reduced the burst suppression ratio (BSR) during continuous sevoflurane anesthesia. Chemogenetic experiments showed that activation of LHA GABA and its projection to LPAG neurons prolonged the anesthetic induction time and promoted wakefulness., Conclusions: In summary, we show that an inhibitory projection from LHA GABA to LPAG GABA neurons promotes arousal from sevoflurane-induced loss of consciousness, suggesting a complex control of wakefulness through intimate interactions between long-range connections., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Aims: Ischemic stroke is a major cause of disability and mortality worldwide. Transcranial direct current stimulation (tDCS) and isoflurane (ISO) preconditioning exhibit neuroprotective properties. However, it remains unclear whether tDCS enhances the protective effect of ISO preconditioning on ischemic stroke, and the underlying mechanisms are yet to be clarified., Method: A model of middle cerebral artery occlusion (MCAO), a rat ischemia-reperfusion (I/R) injury model, and an in vitro oxygen-glucose deprivation/re-oxygenation (O/R) model of ischemic injury were developed. ISO preconditioning and tDCS were administered daily for 7 days before MCAO modeling. Triphenyltetrazolium chloride staining, modified neurological severity score, and hanging-wire test were conducted to assess infarct volume and neurological outcomes. Untargeted metabolomic experiments, adeno-associated virus, lentiviral vectors, and small interfering RNA techniques were used to explore the underlying mechanisms., Results: tDCS/DCS enhanced the protective effects of ISO pretreatment on I/R injury-induced brain damage. This was evidenced by reduced infarct volume and improved neurological outcomes in rats with MCAO, as well as decreased cortical neuronal death after O/R injury. Untargeted metabolomic experiments identified oxidative phosphorylation (OXPHOS) as a critical pathological process for ISO-mediated neuroprotection from I/R injury. The combination of tDCS/DCS with ISO preconditioning significantly inhibited I/R injury-induced OXPHOS. Mechanistically, Akirin2, a small nuclear protein that regulates cell proliferation and differentiation, was found to decrease in the cortex of rats with MCAO and in cortical primary neurons subjected to O/R injury. Akirin2 functions upstream of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). tDCS/DCS was able to further upregulate Akirin2 levels and activate the Akirin2/PTEN signaling pathway in vivo and in vitro, compared with ISO pretreatment alone, thereby contributing to the improvement of cerebral I/R injury., Conclusion: tDCS treatment enhances the neuroprotective effects of ISO preconditioning on ischemic stroke by inhibiting oxidative stress and activating Akirin2-PTEN signaling pathway, highlighting potential of combination therapy in ischemic stroke., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

This paper introduces an efficient methodology for conducting rat anesthesia experiments, aimed at enhancing the quality of raw brain signals obtained. The proposed approach enables the acquisition of animal brain signals during experiments without the confounding influence of muscle noise. Initially, the use of alpha-chloralose (a-c) in conjunction with Isoflurane is introduced to induce anesthesia in rats. Subsequently, Dexdomitor is administered to prevent muscular movements during the collection of brain signals, further refining the signal quality. Experimental outcomes conclusively demonstrate that our anesthesia method produces cleaner raw signals and exhibits improved robustness during data acquisition, outperforming existing methods that rely solely on Isoflurane or the Ketamine-Xylazine combination. Notably, this improved performance is achieved with minimal alterations to vital physiological parameters, including body temperature, respiration, and heart rates. Moreover, the efficacy of a-c in maintaining anesthesia for up to 7 h stands in contrast to the shorter durations achievable with continuous Isoflurane administration or the 30-min window offered by Ketamine-Xylazine, highlighting the practical advantages of our proposed method. Finally, post-experiment observations confirmed that the animals gradually returned to normal behavior without any signs of distress or adverse effects, indicating that our method was both effective and safe., Competing Interests: Declaration of competing interest There are no actual or apparent conflict of interest in this study for any of the co-authors., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This review explores the complex interactions between sedation and invasive ventilation and examines the potential of volatile anesthetics for lung- and diaphragm-protective sedation. In the early stages of invasive ventilation, many critically ill patients experience insufficient respiratory drive and effort, leading to compromised diaphragm function. Compared with common intravenous agents, inhaled sedation with volatile anesthetics better preserves respiratory drive, potentially helping to maintain diaphragm function during prolonged periods of invasive ventilation. In turn, higher concentrations of volatile anesthetics reduce the size of spontaneously generated tidal volumes, potentially reducing lung stress and strain and with that the risk of self-inflicted lung injury. Taken together, inhaled sedation may allow titration of respiratory drive to maintain inspiratory efforts within lung- and diaphragm-protective ranges. Particularly in patients who are expected to require prolonged invasive ventilation, in whom the restoration of adequate but safe inspiratory effort is crucial for successful weaning, inhaled sedation represents an attractive option for lung- and diaphragm-protective sedation. A technical limitation is ventilatory dead space introduced by volatile anesthetic reflectors, although this impact is minimal and comparable to ventilation with heat and moisture exchangers. Further studies are imperative for a comprehensive understanding of the specific effects of inhaled sedation on respiratory drive and effort and, ultimately, how this translates into patient-centered outcomes in critically ill patients., (© 2024. The Author(s).)

Inhalation of hydrogen (H 2 ) gas is therapeutically effective for cerebrovascular diseases, neurodegenerative disorders, and neonatal brain disorders including pathologies induced by anesthetic gases. To understand the mechanisms underlying the protective effects of H 2 on the brain, we investigated the molecular signals affected by H 2 in sevoflurane-induced neuronal cell death. We confirmed that neural progenitor cells are susceptible to sevoflurane and undergo apoptosis in the retrosplenial cortex of neonatal mice. Co-administration of 1-8% H 2 gas for 3 h to sevoflurane-exposed pups suppressed elevated caspase-3-mediated apoptotic cell death and concomitantly decreased c-Jun phosphorylation and activation of the c-Jun pathway, all of which are induced by oxidative stress. Anesthesia-induced increases in lipid peroxidation and oxidative DNA damage were alleviated by H 2 inhalation. Phosphoproteome analysis revealed enriched clusters of differentially phosphorylated proteins in the sevoflurane-exposed neonatal brain that included proteins involved in neuronal development and synaptic signaling. H 2 inhalation modified cellular transport pathways that depend on hyperphosphorylated proteins including microtubule-associated protein family. These modifications may be involved in the protective mechanisms of H 2 against sevoflurane-induced neuronal cell death., (© 2024 International Society for Neurochemistry.)

Positron emission tomography (PET) imaging studies in laboratory animals are almost always performed under isoflurane anesthesia to ensure that the subject stays still during the image acquisition. Isoflurane is effective, safe, and easy to use, and it is generally assumed to not have an impact on the imaging results. Motivated by marked differences observed in the brain uptake and metabolism of the PET tracer 3-[ 18 F]fluoro-4-aminopyridine [( 18 F]3F4AP) between human and nonhuman primate studies, this study investigates the possible effect of isoflurane on this process. Mice received [ 18 F]3F4AP injection while awake or under anesthesia and the tracer brain uptake and metabolism was compared between groups. A separate group of mice received the known cytochrome P450 2E1 inhibitor disulfiram prior to tracer administration. Isoflurane was found to largely abolish tracer metabolism in mice (74.8 ± 1.6 vs. 17.7 ± 1.7% plasma parent fraction, % PF) resulting in a 4.0-fold higher brain uptake in anesthetized mice at 35 min post-radiotracer administration. Similar to anesthetized mice, animals that received disulfiram showed reduced metabolism (50.0 ± 6.9% PF) and a 2.2-fold higher brain signal than control mice. The higher brain uptake and lower metabolism of [ 18 F]3F4AP observed in anesthetized mice compared to awake mice are attributed to isoflurane's interference in the CYP2E1-mediated breakdown of the tracer, which was confirmed by reproducing the effect upon treatment with the known CYP2E1 inhibitor disulfiram. These findings underscore the critical need to examine the effect of isoflurane in PET imaging studies before translating tracers to humans that will be scanned without anesthesia., (© 2024 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Background and Purpose: Sevoflurane, a commonly used inhaled anaesthetic known for its favourable safety profile and rapid onset and offset, has not been thoroughly investigated as a potential treatment for depression. In this study, we reveal the mechanism through which sevoflurane delivers enduring antidepressant effects., Experimental Approach: To assess the antidepressant effects of sevoflurane, behavioural tests were conducted, along with in vitro and ex vivo whole-cell patch-clamp recordings, to examine the effects on GluN1-GluN2 incorporated N-methyl-d-aspartate (NMDA) receptors (NMDARs) and neuronal circuitry in the medial prefrontal cortex (mPFC). Multiple-channel electrophysiology in freely moving mice was performed to evaluate sevoflurane's effects on neuronal activity, and GluN2D knockout (grin2d -/- ) mice were used to confirm the requirement of GluN2D for the antidepressant effects., Key Results: Repeated exposure to subanaesthetic doses of sevoflurane produced sustained antidepressant effects lasting up to 2 weeks. Sevoflurane preferentially inhibited GluN2C- and GluN2D-containing NMDARs, causing a reduction in interneuron activity. In contrast, sevoflurane increased action potentials (AP) firing and decreased spontaneous inhibitory postsynaptic current (sIPSC) in mPFC pyramidal neurons, demonstrating a disinhibitory effect. These effects were absent in grin2d -/- mice, and both pharmacological blockade and genetic knockout of GluN2D abolished sevoflurane's antidepressant actions, suggesting that GluN2D is essential for its antidepressant effect., Conclusion and Implications: Sevoflurane directly targets GluN2D, leading to a specific decrease in interneuron activity and subsequent disinhibition of pyramidal neurons, which may underpin its antidepressant effects. Targeting the GluN2D subunit could hold promise as a potential therapeutic strategy for treating depression., (© 2024 British Pharmacological Society.)

Sevoflurane has been shown to increase the incidence of emergence delirium in children; however, the mechanism remains unclear. Sevoflurane increases cytoplasmic calcium concentration which in turn may play a role in emergence delirium. This study aimed to investigate the level of intracellular calcium in rats experiencing hyperexcitatory behavior after exposure to sevoflurane, as well as the role of magnesium in preventing this phenomenon. After ethical approval, 2-5-week-old Sprague-Dawley rats (n = 34) were insufflated with sevoflurane in a modified anesthesia chamber. One group received magnesium sulphate intraperitoneally. After termination of sevoflurane exposure, the occurrence of hyperexcitation was observed. Brain tissue samples from the rats were studied for intracellular calcium levels under a two-channel laser scanning confocal microscope and were quantitatively calculated using ratiometric calculation. The presence of inflammation or oxidative stress reaction was assessed using nuclear factor κB and malondialdehyde. The incidence of hyperexcitatory behavior post sevoflurane exposure was 9 in 16 rats in the observation group and none in the magnesium group. Tests for inflammation and oxidative stress were within normal limits in both groups. The rats showing hyperexcitation had a higher level of cytosol calcium concentration compared to the other groups. To conclude, the calcium concentration of neocortical neurons in Sprague-Dawley rats with hyperexcitatory behavior is increased after exposure to sevoflurane. Administration of magnesium sulphate can prevent the occurrence of hyperexcitation in experimental animals., (Copyright © 2024 Copyright: © 2024 Medical Gas Research.)

Objective: To examine the effect of ketanserin and naloxone on fentanyl-induced motor activity in isoflurane-anaesthetized pigs., Study Design: Randomized, blinded, prospective two-group study., Animals: A group of 12 crossbred pigs weighing 22-31 kg., Methods: Fentanyl was administered to isoflurane-anaesthetized pigs at 7.5 μg kg -1 hour -1 for 40 minutes intravenously, followed by an intravenous injection of naloxone 0.1 mg kg -1 or ketanserin 1 mg kg -1 . Electromyography (EMG) and accelerometry were used to record motor unit activity and tremors, respectively. To test the effect of drug administration on motor activity, data from a 5 minute period at baseline, immediately before and after antagonist injection were compared in a mixed model; p < 0.05., Results: Results are reported with the median difference, 95% confidence intervals and corresponding p-values in brackets. Fentanyl significantly increased EMG activity [30.51 (1.84-81.02) μV, p = 0.004] and induced tremors [0.09 (0.02-0.18) m s -2 , p < 0.001] in 10 of 12 pigs. Ketanserin significantly reduced EMG [32.22 (6.29-136.80) μV, p = 0.001] and tremor [0.10 (0.03-0.15) m s -2 , p = 0.007] activity. No significant effect was found for naloxone on EMG [26.76 (-13.28-91.17) μV, p = 0.4] or tremors [0.08 (-0.01-0.19) m s -2 , p = 0.08]., Conclusions and Clinical Relevance: Fentanyl can induce motor activity in anaesthetized pigs, with a suggested link to the serotonergic system. This study shows that ketanserin can antagonize this activity, which supports the role of serotonin. This knowledge contributes to the general understanding of the motor effects of fentanyl and especially the problem of tremors in anaesthetized pigs., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To compare the effects of propofol, ketamine-propofol and isoflurane, at similar anesthetic depth, on cardiopulmonary variables in unpremedictated chickens., Study Design: Prospective, randomized, crossover experimental trial., Animals: A total of 10 male Leghorn domestic chickens, aged 3 months and body mass 1.4-2.0 kg., Methods: Birds were randomly assigned to each of three anesthetic protocols, 7 days apart: intravenous propofol, intravenous ketamine-propofol or isoflurane. Anesthesia was induced (indicated by loss of righting reflex and tracheal intubation) and maintained with propofol (10 mg kg -1 minute -1 , then 1.1 mg kg -1 minute -1 ), ketamine-propofol (5 mg mL -1 ketamine and 5 mg mL -1 propofol combined; 10 mg kg -1 minute -1 , then 1.1 mg kg -1 minute -1 ) or isoflurane [5% vaporizer setting initially, then end-tidal concentration (Fe'Iso) of 2%] for 65 minutes. Anesthesia was maintained at a similar anesthetic depth based upon positive or negative responses to toe pinch. Heart rate (HR), respiratory rate (f R ), noninvasive arterial blood pressure and arterial blood gases were measured during anesthesia. Propofol or ketamine-propofol infusion rates and Fe'Iso required to prevent movement in response to a noxious stimulus and recovery times were recorded., Results: Anesthesia induction dose was 9.0 ± 0.8 (mean ± SD) and 12.2 ± 0.3 mg kg -1 for propofol and ketamine-propofol, respectively. Propofol and ketamine-propofol infusion rates and Fe'Iso required to prevent movement in response to the noxious stimulus were 0.88 ± 0.14 mg kg -1 minute -1 , 0.92 ± 0.14 mg kg -1 minute -1 and 1.45 ± 0.28%, respectively. Cardiopulmonary variables remained clinically acceptable, but ketamine-propofol was associated with a significantly higher HR (p = 0.0001) and lower f R (p = 0.0001). Time to extubation did not differ among treatments., Conclusions and Clinical Relevance: Cardiovascular and respiratory variables were maintained within normal ranges in all treatments. Coadministration of ketamine with propofol significantly reduced the induction and maintenance dose of propofol., (Copyright © 2024 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Acute lung injury (ALI) frequently occurs after video-assisted thoracoscopic surgery (VATS). Ferroptosis is implicated in several lung diseases. Therefore, the disparate effects and underlying mechanisms of the two commonly used anesthetics (sevoflurane (Sev) and propofol) on VATS-induced ALI need to be clarified. In the present study, enrolled patients were randomly allocated to receive Sev (group S) or propofol anesthesia (group P). Intraoperative oxygenation, morphology of the lung tissue, expression of ZO-1, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), superoxide dismutase (SOD), glutathione (GSH), Fe 2+ , glutathione peroxidase 4 (GPX4), and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in the lung tissue as well as the expression of TNF-α and IL-6 in plasma were measured. Postoperative complications were recorded. Of the 85 initially screened patients scheduled for VATS, 62 were enrolled in either group S (n = 32) or P (n = 30). Compared with propofol, Sev substantially (1) improved intraoperative oxygenation; (2) relieved histopathological lung injury; (3) increased ZO-1 protein expression; (4) decreased the levels of TNF-α and IL-6 in both the lung tissue and plasma; (5) increased the contents of GSH and SOD but decreased Fe 2+ concentration; (6) upregulated the protein expression of p-AKT, Nrf2, HO-1, and GPX4. No significant differences in the occurrence of postoperative outcomes were observed between both groups. In summary, Sev treatment, in comparison to propofol anesthesia, may suppress local lung and systemic inflammatory responses by activating the PI3K/Akt/Nrf2/HO-1 pathway and inhibiting ferroptosis. This cascade of effects contributes to the maintenance of pulmonary epithelial barrier permeability, alleviation of pulmonary injury, and enhancement of intraoperative oxygenation in patients undergoing VATS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The Nociception Level Index has shown benefits in estimating the nociception/antinociception balance in adults, but there is limited evidence in the pediatric population. Evaluating the index performance in children might provide valuable insights to guide opioid administration., Aims: To evaluate the Nociception Level Index ability to identify a standardized nociceptive stimulus and the analgesic effect of a fentanyl bolus. Additionally, to characterize the pharmacokinetic/pharmacodynamic relationship of fentanyl with the Nociception Level Index response during sevoflurane anesthesia., Methods: Nineteen children, 5.3 (4.1-6.7) years, scheduled for lower abdominal or urological surgery, were studied. After sevoflurane anesthesia and caudal block, a tetanic stimulus (50 Hz, 60 mA, 5 s) was performed in the forearm. Following the administration of fentanyl 2 μg/kg intravenous bolus, three similar consecutive tetanic stimuli were performed at 5-, 15-, and 30-min post-fentanyl administration. Changes in the Nociception Level Index, heart rate, mean arterial pressure, and bispectral index were compared in response to the tetanic stimuli. Fentanyl plasma concentrations and the Nociception Level Index data were used to elaborate a pharmacokinetic/pharmacodynamic model using a sequential modeling approach in NONMEM®., Results: After the first tetanic stimulus, both the Nociception Level Index and the heart rate increased compared to baseline (8 ± 7 vs. 19 ± 10; mean difference (CI95) -12(-18--6) and 100 ± 10 vs. 102 ± 10; -2(-4--0.1)) and decrease following fentanyl administration (19 ± 10 vs. 8 ± 8; 12 (5-18) and 102 ± 10 vs. 91 ± 11; 11 (7-16)). In subsequent tetanic stimuli, heart rate remained unchanged, while the Nociception Level Index progressively increased within 15 min to values similar to those before fentanyl. An allometric weight-scaled, 3-compartment model best characterized the pharmacokinetic profile of fentanyl. The pharmacokinetic/pharmacodynamic modeling analysis revealed hysteresis between fentanyl plasma concentrations and the Nociception Level Index response, characterized by plasma effect-site equilibration half-time of 1.69 (0.4-2.9) min. The estimated fentanyl C50 was 1.93 (0.73-4.2) ng/mL., Conclusion: The Nociception Level Index showed superior capability compared to traditional hemodynamic variables in discriminating different nociception-antinociception levels during varying fentanyl concentrations in children under sevoflurane anesthesia., (© 2024 John Wiley & Sons Ltd.)

Background: Individuals with mitochondrial defects, especially those in Complex I of the electron transport chain, exhibit behavioral hypersensitivity and toxicity to volatile anesthetics. In Drosophila melanogaster, mutation of ND23 (NDUFS8 in mammals), which encodes a subunit of the matrix arm of Complex I, sensitizes flies to toxicity from isoflurane but not an equipotent dose of sevoflurane. Also, in ND23 flies, both anesthetics activate expression of stress response genes, but to different extents. Here, we investigated the generality of these findings by examining flies mutant for ND2 (ND2 in mammals), which encodes a subunit of the membrane arm of Complex I., Methods: The serial anesthesia array was used to expose ND2 del1 and ND23 60114 flies to precise doses of isoflurane, sevoflurane, and oxygen. Behavioral sensitivity was assessed by a climbing assay and toxicity by percent mortality within 24 h of exposure. Changes in expression were determined by qRT-PCR of RNA isolated from heads at 0.5 h after anesthetic exposure., Results: Unlike ND23 60114 , ND2 del1 did not affect behavioral sensitivity to isoflurane or sevoflurane. Furthermore, sevoflurane in hyperoxia as well as anoxia caused mortality of ND2 del1 but not ND23 60114 flies. Finally, the mutations had different effects on induction of stress response gene expression by the anesthetics., Conclusion: Mutations in different arms of Complex I resulted in different behavioral sensitivities and toxicities to isoflurane and sevoflurane, indicating that (i) the anesthetics have mechanisms of action that involve arms of Complex I to different extents and (ii) the lack of behavioral hypersensitivity does not preclude susceptibility to anesthetic toxicity., (© 2024 The Author(s). Pediatric Anesthesia published by John Wiley & Sons Ltd.)

The zona incerta (ZI) predominantly consists of gamma-aminobutyric acid (GABAergic) neurons, located adjacent to the lateral hypothalamus. GABA, acting on GABAA receptors, serves as a crucial neuromodulator in the initiation and maintenance of general anesthesia. In this study, we aimed to investigate the involvement of ZI GABAergic neurons in the general anesthesia process. Utilizing in-vivo calcium signal optical fiber recording, we observed a decrease in the activity of ZI GABAergic neurons during isoflurane anesthesia, followed by a significant increase during the recovery phase. Subsequently, we selectively ablated ZI GABAergic neurons to explore their role in general anesthesia, revealing no impact on the induction of isoflurane anesthesia but a prolonged recovery time, accompanied by a reduction in delta-band power in mice under isoflurane anesthesia. Finally, through optogenetic activation/inhibition of ZI GABAergic neurons during isoflurane anesthesia, we discovered that activation of these neurons facilitated emergence without affecting the induction process, while inhibition delayed emergence, leading to fluctuations in delta band activity. In summary, these findings highlight the involvement of ZI GABAergic neurons in modulating the emergence of isoflurane anesthesia., (© 2024. The Author(s).)

In developed countries, stroke is the leading cause of death and disability that affects long-term quality of life and its incidence is increasing. The incidence of ischemic stroke is much higher than that of hemorrhagic stroke. Ischemic stroke often leads to very serious neurological sequelae, which severely reduces the patients' quality of life and becomes a social burden. Therefore, ischemic stroke has received increasing attention. As a new type of anesthetic, sevoflurane has a lower solubility, works faster in the human body, and has less impact on the cardiovascular system than isoflurane. At the same time, studies have shown that preconditioning and postconditioning with sevoflurane have a beneficial effect on stroke. We believe that the role of sevoflurane in stroke may be a key area for future research. Therefore, this review mainly summarizes the relevant mechanisms of sevoflurane preconditioning and postconditioning in stroke in the past 20 years, revealing the bright prospects of sevoflurane in stroke treatment., (Copyright © 2024 Copyright: © 2024 Medical Gas Research.)

Volatile anesthetics are currently believed to cause unconsciousness by acting on one or more molecular targets including neural ion channels, receptors, mitochondria, synaptic proteins, and cytoskeletal proteins. Anesthetic gases including isoflurane bind to cytoskeletal microtubules (MTs) and dampen their quantum optical effects, potentially contributing to causing unconsciousness. This possibility is supported by the finding that taxane chemotherapy consisting of MT-stabilizing drugs reduces the effectiveness of anesthesia during surgery in human cancer patients. In order to experimentally assess the contribution of MTs as functionally relevant targets of volatile anesthetics, we measured latencies to loss of righting reflex (LORR) under 4% isoflurane in male rats injected subcutaneously with vehicle or 0.75 mg/kg of the brain-penetrant MT-stabilizing drug epothilone B (epoB). EpoB-treated rats took an average of 69 s longer to become unconscious as measured by latency to LORR. This was a statistically significant difference corresponding to a standardized mean difference (Cohen's d ) of 1.9, indicating a "large" normalized effect size. The effect could not be accounted for by tolerance from repeated exposure to isoflurane. Our results suggest that binding of the anesthetic gas isoflurane to MTs causes unconsciousness and loss of purposeful behavior in rats (and presumably humans and other animals). This finding is predicted by models that posit consciousness as a property of a quantum physical state of neural MTs., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Khan et al.)

Although anesthesia provides favorable conditions for surgical procedures, recent studies have revealed that the brain remains active in processing noxious signals even during anesthesia. However, whether and how these responses affect the anesthesia effect remains unclear. The ventrolateral periaqueductal gray (vlPAG), a crucial hub for pain regulation, also plays an essential role in controlling general anesthesia. Hence, it was hypothesized that the vlPAG may be involved in the regulation of general anesthesia by noxious stimuli. Here, we found that acute noxious stimuli, including capsaicin-induced inflammatory pain, acetic acid-induced visceral pain, and incision-induced surgical pain, significantly delayed recovery from sevoflurane anesthesia in male mice, whereas this effect was absent in the spared nerve injury-induced chronic pain. Pretreatment with peripheral analgesics could prevent the delayed recovery induced by acute nociception. Furthermore, we found that acute noxious stimuli, induced by the injection of capsaicin under sevoflurane anesthesia, increased c-Fos expression and activity in the GABAergic neurons of the ventrolateral periaqueductal gray. Specific reactivation of capsaicin-activated vlPAG GABA neurons mimicked the effect of capsaicin and its chemogenetic inhibition prevented the delayed recovery from anesthesia induced by capsaicin. Finally, we revealed that the vlPAG GABA neurons regulated the recovery from anesthesia through the inhibition of ventral tegmental area dopaminergic neuronal activity, thus decreasing dopamine (DA) release and activation of DA D 1 -like receptors in the brain. These findings reveal a novel, cell- and circuit-based mechanism for regulating anesthesia recovery by nociception, and it is important to provide new insights for guiding the management of the anesthesia recovery period., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Current anesthetic theory is mostly based on neurons and/or neuronal circuits. A role for astrocytes also has been shown in promoting recovery from volatile anesthesia, while the exact modulatory mechanism and/or the molecular target in astrocytes is still unknown. In this study by animal models in male mice and electrophysiological recordings in vivo and in vitro, we found that activating astrocytes of the paraventricular thalamus (PVT) and/or knocking down PVT astrocytic Kir4.1 promoted the consciousness recovery from sevoflurane anesthesia. Single-cell RNA sequencing of the PVT reveals two distinct cellular subtypes of glutamatergic neurons: PVT GRM and PVT ChAT neurons. Patch-clamp recording results proved astrocytic Kir4.1-mediated modulation of sevoflurane on the PVT mainly worked on PVT ChAT neurons, which projected mainly to the mPFC. In summary, our findings support the novel conception that there is a specific PVT→prefrontal cortex projection involved in consciousness recovery from sevoflurane anesthesia, which is mediated by the inhibition of sevoflurane on PVT astrocytic Kir4.1 conductance., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Aims: The parabrachial nucleus (PBN) promotes wakefulness states under general anesthesia. Recent studies have shown that glutamatergic neurons within the PBN play a crucial role in facilitating emergence from anesthesia. Our previous study indicates that vesicular glutamate transporter 2 (vglut2) expression neurons of the PBN extend into the extended amygdala (EA). However, the modulation of PBN vglut2 -EA in general anesthesia remains poorly understood. This study aims to investigate the role of PBN vglut2 -EA in alterations of consciousness during sevoflurane anesthesia., Methods: We first validated vglut2-expressing neuron projections from the PBN to the EA using anterograde tracing. Then, we conducted immunofluorescence staining of c-Fos to investigate the role of the EA involved in the regulation of consciousness during sevoflurane anesthesia. After, we performed calcium fiber photometry recordings to determine the changes in PBN vglut2 -EA activity. Lastly, we modulated PBN vglut2 -EA activity under sevoflurane anesthesia using optogenetics, and electroencephalogram (EEG) was recorded during specific optogenetic modulation., Results: The expression of vglut2 in PBN neurons projected to the EA, and c-Fos expression in the EA was significantly reduced during sevoflurane anesthesia. Fiber photometry revealed that activity in the PBN vglut2 -EA pathway was suppressed during anesthesia induction but restored upon awakening. Optogenetic activation of the PBN vglut2 -EA delayed the induction of anesthesia. Meanwhile, EEG recordings showed significantly decreased δ oscillations and increased β and γ oscillations compared to the EYFP group. Furthermore, optogenetic activation of the PBN vglut2 -EA resulted in an acceleration of awakening from anesthesia, accompanied by decreased δ oscillations on EEG recordings. Optogenetic inhibition of PBN vglut2 -EA accelerated anesthesia induction. Surprisingly, we found a sex-specific regulation of PBN vglut2 -EA in this study. The activity of PBN vglut2 -EA was lower in males during the induction of anesthesia and decreased more rapidly during sevoflurane anesthesia compared to females. Photoactivation of the PBN vglut2 -EA reduced the sensitivity of males to sevoflurane, showing more pronounced wakefulness behavior and EEG changes than females., Conclusions: PBN vglut2 -EA is involved in the promotion of wakefulness under sevoflurane anesthesia. Furthermore, PBN vglut2 -EA shows sex differences in the changes of consciousness induced by sevoflurane anesthesia., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Perioperative neurocognitive disorders (PND) refer to cognitive deterioration that occurs after surgery or anesthesia. Prolonged isoflurane exposure has potential neurotoxicity and induces PND, but the mechanism is unclear. The glymphatic system clears harmful metabolic waste from the brain. This study sought to unveil the functions of glymphatic system in PND and explore the underlying molecular mechanisms. The PND mice model was established by long term isoflurane anesthesia. The glymphatic function was assessed by multiple in vitro and in vivo methods. An adeno-associated virus was used to overexpress AQP4 and TGN-020 was used to inhibit its function. This research revealed that the glymphatic system was impaired in PND mice and the blunted glymphatic transport was closely associated with the accumulation of inflammatory proteins in the hippocampus. Increasing AQP4 polarization could enhance glymphatic transport and suppresses neuroinflammation, thereby improve cognitive function in the PND model mice. However, a marked impaired glymphatic inflammatory proteins clearance and the more severe cognitive dysfunction were observed when decreasing AQP4 polarization. Therefore, long-term isoflurane anesthesia causes blunted glymphatic system by inducing AQP4 depolarization, enhanced the AQP4 polarization can alleviate the glymphatic system malfunction and reduce the neuroinflammatory response, which may be a potential treatment strategy for PND., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aims: The mechanism underlying the reversible unconsciousness induced by general anesthetics (GA) remains unclear. Recent studies revealed the critical roles of myelin and oligodendrocytes (OLs) in higher functions of the brain. However, it is unknown whether myelin actively participates in the regulation of GA. The aim of this study is to investigate the roles and possible mechanisms of myelin in the regulation of consciousness alterations induced by isoflurane anesthesia., Methods: First, demyelination models for the entire brain and specific neural nuclei were established to investigate the potential role of myelination in the regulation of GA, as well as its possible regional specificity. c-Fos staining was then performed on the demyelinated nuclei to verify the impact of myelin loss on neuronal activity. Finally, the activity of neurons during isoflurane anesthesia in demyelinated mice was recorded by optical fiber photometric calcium signal. The related behavioral indicators and EEG were recorded and analyzed., Results: A prolonged emergence time was observed from isoflurane anesthesia in demyelinated mice, which suggested the involvement of myelin in regulating GA. The demyelination in distinct nuclei by LPC further clarified the region-specific roles of isoflurane anesthesia regulation by myelin. The effect of demyelination on isoflurane anesthesia in the certain nucleus was consistent with that in neurons towards isoflurane anesthesia. Finally, we found that the mechanism of myelin in the modulation of isoflurane anesthesia is possibly through the regulation of neuronal activity., Conclusions: In brief, myelin in the distinct neural nucleus plays an essential role in regulating the process of isoflurane anesthesia. The possible mechanism of myelin in the regulation of isoflurane anesthesia is neuronal activity modification by myelin integrity during GA. Our findings enhanced the comprehension of myelin function, and offered a fresh perspective for investigating the neural mechanisms of GA., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

The lateral parabrachial nucleus (PBL) is implicated in the regulation of respiratory activity. Sodium leak channel (NALCN) mutations disrupt the respiratory rhythm and influence anesthetic sensitivity in both rodents and humans. Here, we investigated whether the NALCN in PBL glutamatergic neurons maintains respiratory function under general anesthesia. Our results showed that chemogenetic activation of PBL glutamatergic neurons increased the respiratory frequency (RF) in mice; whereas chemogenetic inhibition suppressed RF. NALCN knockdown in PBL glutamatergic neurons but not GABAergic neurons significantly reduced RF under physiological conditions and caused more respiratory suppression under sevoflurane anesthesia. NALCN knockdown in PBL glutamatergic neurons did not further exacerbate the respiratory suppression induced by propofol or morphine. Under sevoflurane anesthesia, painful stimuli rapidly increased the RF, which was not affected by NALCN knockdown in PBL glutamatergic neurons. This study suggested that the NALCN is a key ion channel in PBL glutamatergic neurons that maintains respiratory frequency under volatile anesthetic sevoflurane but not intravenous anesthetic propofol., (© 2024. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences.)

Background: Ventral tegmental area (VTA) glutamatergic neurons promote wakefulness in the sleep-wake cycle; however, their roles and neural circuit mechanisms during isoflurane (ISO) anesthesia remain unclear., Methods: Fiber photometry and in vivo electrophysiology were used to observe the changes in neuronal or terminal activity during ISO anesthesia and arousal processes. Optogenetic and anesthesia behaviors were used to investigate the effects of VTA glutamatergic neurons and their projections to the lateral septum (LS) during ISO anesthesia and arousal. Anterograde and retrograde tracings were performed to identify the connections between VTA glutamatergic neurons and the LS., Results: Population activity and firing rates of VTA glutamatergic neurons decreased during ISO anesthesia (ISO: 95% confidence interval [CI], 0.83-2.06 Spikes.s -1 vs wake: 95% CI, 3.53-7.83 Spikes.s -1 ; P =.0001; n = 34 from 4 mice). Optogenetic activation of VTA glutamatergic neurons reduced the burst-suppression ratio in electroencephalography (laser: 95% CI, 13.09%-28.76% vs pre: 95% CI, 52.85%-71.59%; P =.0009; n = 6) and facilitated emergence (ChR2: 95% CI, 343.3-388.0 seconds vs mCherry: 95% CI, 447.6-509.8 seconds; P < .0001; n = 11/12) from ISO anesthesia. VTA glutamatergic neurons monosynaptically innervated LS γ-aminobutyric acid (GABA)-ergic neurons. The activity of VTA glutamatergic terminals in the LS decreased during ISO anesthesia, and optogenetic activation of the VTA glutamatergic terminals in the LS facilitated emergence from ISO anesthesia. Furthermore, optogenetic activation of VTA glutamatergic terminals increased the firing rates of LS γ-aminobutyric acid-ergic (GABAergic) neurons (laser: 95% CI, 0.85-4.03 Spikes.s -1 vs pre: 95% CI, 0.24-0.78 Spikes.s -1 ; P =.008; n = 23 from 4 mice) during ISO anesthesia., Conclusions: VTA glutamatergic neurons facilitated emergence from ISO anesthesia involving excitation of LS GABAergic neurons., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 International Anesthesia Research Society.)

Background and Objectives : Lower-extremity ischemia-reperfusion injury can induce distant organ ischemia, and patients with diabetes are particularly susceptible to ischemia-reperfusion injury. Sevoflurane, a widely used halogenated inhalation anesthetic, and fullerenol C60, a potent antioxidant, were investigated for their effects on heart and lung tissues in lower-extremity ischemia-reperfusion injury in streptozotocin (STZ)-induced diabetic mice. Materials and Methods : A total of 41 mice were divided into six groups: control ( n = 6), diabetes-control ( n = 7), diabetes-ischemia ( n = 7), diabetes-ischemia-fullerenol C60 ( n = 7), diabetes-ischemia-sevoflurane ( n = 7), and diabetes-ischemia-fullerenol C60-sevoflurane ( n = 7). Diabetes was induced in mice using a single intraperitoneal dose of 55 mg/kg STZ in all groups except for the control group. Mice in the control and diabetes-control groups underwent midline laparotomy and were sacrificed after 120 min. The DIR group underwent 120 min of lower-extremity ischemia followed by 120 min of reperfusion. In the DIR-F group, mice received 100 μg/kg fullerenol C60 intraperitoneally 30 min before IR. In the DIR-S group, sevoflurane and oxygen were administered during the IR procedure. In the DIR-FS group, fullerenol C60 and sevoflurane were administered. Biochemical and histological evaluations were performed on collected heart and lung tissues. Results : Histological examination of heart tissues showed significantly higher necrosis, polymorphonuclear leukocyte infiltration, edema, and total damage scores in the DIR group compared to controls. These effects were attenuated in fullerenol-treated groups. Lung tissue examination revealed more alveolar wall edema, hemorrhage, vascular congestion, polymorphonuclear leukocyte infiltration, and higher total damage scores in the DIR group compared to controls, with reduced injury parameters in the fullerenol-treated groups. Biochemical analyses indicated significantly higher total oxidative stress, oxidative stress index, and paraoxonase-1 levels in the DIR group compared to the control and diabetic groups. These levels were lower in the fullerenol-treated groups. Conclusions : Distant organ damage in the lung and heart tissues due to lower-extremity ischemia-reperfusion injury can be significantly reduced by fullerenol C60.

The objective of this investigation was to examine the impact of multiple exposures to general anesthesia (GA) with sevoflurane on the offspring of pregnant mice, as well as to elucidate the underlying mechanism. Neurodevelopmental assessments, including various reflexes and behavioral tests, were conducted on the offspring in the GA group to evaluate neuronal cell development. Furthermore, neonatal mouse neuronal cells were isolated and transfected with a high-expression CREB vector (pcDNA3.1-CREB), followed by treatment with sevoflurane (0.72 mol/L), ZD7288 (50 μmol/L), and KN-62 (10 μmol/L), or a combination of these compounds. The expression of relevant genes was then analyzed using qRT-PCR and western blot techniques. In comparison to the sham group, neonatal mice in the GA group exhibited significantly prolonged latencies in surface righting reflex, geotaxis test, and air righting reflex. Furthermore, there was a notable deceleration in the development of body weight and tail in the GA group. These mice also displayed impairments in social ability, reduced reciprocal social interaction behaviors, diminished learning capacity, and heightened levels of anxious behaviors. Additionally, synaptic trigger malfunction was observed, along with decreased production of c-Fos and neurotrophic factors. Sevoflurane was found to notably decrease cellular c-Fos and neurotrophic factor production, as well as the expression of HCN2 and CaMKII/CREB-related proteins. The inhibitory effects of sevoflurane on HCN2 or CaMKII channels were similar to those observed with ZD7288 or KN-62 inhibition. However, overexpression of CREB mitigated the impact of sevoflurane on neuronal cells. Repetitive exposure to sevoflurane general anesthesia while pregnant suppresses the CaMKII/CREB pathway, leading to the development of autism-like characteristics in offspring mice through the reduction of HCN2 expression., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

General anesthetics may accelerate the neuropathological changes related to Alzheimer's disease (AD), of which amyloid beta (Aβ)-induced toxicity is one of the main causes. However, the interaction of general anesthetics with different Aβ-isoforms remains unclear. In this study, we investigated the effects of sevoflurane (0.4 and 1.2 maximal alveolar concentration (MAC)) on four Aβ species-induced changes on dendritic spine density (DSD) in hippocampal brain slices of Thy1-eGFP mice and multiple epidermal growth factor-like domains 10 (MEGF10)-related astrocyte-mediated synaptic engulfment in hippocampal brain slices of C57BL/6 mice. We found that both sevoflurane and Aβ downregulated CA1-dendritic spines. Moreover, compared with either sevoflurane or Aβ alone, pre-treatment with Aβ isoforms followed by sevoflurane application in general further enhanced spine loss. This enhancement was related to MEGF10-related astrocyte-dependent synaptic engulfment, only in AβpE3 + 1.2 MAC sevoflurane and 3NTyrAβ + 1.2 MAC sevoflurane condition. In addition, removal of sevoflurane alleviated spine loss in Aβ + sevoflurane. In summary, these results suggest that both synapses and astrocytes are sensitive targets for sevoflurane; in the presence of 3NTyrAβ, 1.2 MAC sevoflurane alleviated astrocyte-mediated synaptic engulfment and exerted a lasting effect on dendritic spine remodeling.

The potential long-term effects of anesthesia on cognitive development, especially in neonates and infants, have raised concerns. However, our understanding of its underlying mechanisms and effective treatments is still limited. In this study, we found that early exposure to isoflurane (ISO) impaired fear memory retrieval, which was reversed by dexmedetomidine (DEX) pre-treatment. Measurement of c-fos expression revealed that ISO exposure significantly increased neuronal activation in the zona incerta (ZI). Fiber photometry recording showed that ZI neurons from ISO mice displayed enhanced calcium activity during retrieval of fear memory compared to the control group, while DEX treatment reduced this enhanced calcium activity. Chemogenetic inhibition of ZI neurons effectively rescued the impairments caused by ISO exposure. These findings suggest that the ZI may play a pivotal role in mediating the cognitive effects of anesthetics, offering a potential therapeutic target for preventing anesthesia-related cognitive impairments., (© 2024. The Author(s).)

Introduction: Pregnant women may need to undergo non-obstetric surgery under general anesthesia owing to medical needs, and pregnant women frequently experience sleep disturbances during late gestation. Preclinical studies demonstrated that maternal isoflurane exposure (MISO) or maternal sleep deprivation (MSD) contributed to cognitive impairments in offspring. Research studies in mice have revealed that SD can aggravate isoflurane-induced cognitive deficits. However, it remains unclear whether MSD aggravates MISO-induced cognitive deficits in offspring. The purpose of this research was to explore the combined effects of MSD and MISO on offspring cognitive function and the role of neuroinflammation and synaptic function in the process of MSD + MISO., Methods: Pregnant mice were exposed to 1.4% isoflurane by inhalation for 4 h on gestational day (GD) 14. Dams were then subjected to SD for 6 h (12:00-18:00 h) during GD15-21. At 3 months of age, the offspring mice were subjected to the Morris water maze test to assess cognitive function. Then the levels of inflammatory and anti-inflammatory markers and synaptic function-related proteins were assessed using molecular biology methods., Results: The results of this study demonstrated that MISO led to cognitive dysfunction, an effect that was aggravated by MSD. In addition, MSD exacerbated the maternal isoflurane inhalation, leading to an enhancement in the expression levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha and a reduction in the hippocampal levels of IL-10, synaptophysin, post-synaptic density-95, growth-associated protein-43, and brain-derived neurotrophic factor., Conclusion: Our findings revealed that MSD aggravated the cognitive deficits induced by MISO in male offspring mice, and these results were associated with neuroinflammation and alternations in synaptic function., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Phosphatidylinositol 4,5-bisphosphate (PIP 2 ), as well as other anionic phospholipids, play a pivotal role in various cellular processes, including ion channel regulation, receptor trafficking, and intracellular signaling pathways. The binding of volatile anesthetics and propofol to PIP 2 leads to alterations in PIP 2 -mediated signaling causing modulation of ion channels such as ɣ-aminobutyric acid type A (GABA A ) receptors, voltage-gated calcium channels, and potassium channels through various mechanisms. Additionally, the interaction between anionic phospholipids and G protein-coupled receptors plays a critical role in various anesthetic pathways, with these anesthetic-induced changes impacting PIP 2 levels which cause cascading effects on receptor trafficking, including GABA A receptor internalization. This comprehensive review of various mechanisms of interaction provides insights into the intricate interplay between PIP 2 signaling and anesthetic-induced changes, shedding light on the molecular mechanisms underlying anesthesia., (Published by Elsevier Inc.)

The advent of general anesthesia (GA) has significant implications for clinical practice. However, the exact mechanisms underlying GA-induced transitions in consciousness remain elusive. Given some similarities between GA and sleep, the sleep-arousal neural nuclei and circuits involved in sleep-arousal, including the 5-HTergic system, could be implicated in GA. Herein, we utilized pharmacology, optogenetics, chemogenetics, fiber photometry, and retrograde tracing to demonstrate that both endogenous and exogenous activation of the 5-HTergic neural circuit between the dorsal raphe nucleus (DR) and basolateral amygdala (BLA) promotes arousal and facilitates recovery of consciousness from sevoflurane anesthesia. Notably, the 5-HT1A receptor within this pathway holds a pivotal role. Our findings will be conducive to substantially expanding our comprehension of the neural circuit mechanisms underlying sevoflurane anesthesia and provide a potential target for modulating consciousness, ultimately leading to a reduction in anesthetic dose requirements and side effects., Competing Interests: Declaration of Competing Interest This manuscript has not been submitted for publication elsewhere (other than BioRxiv), and the authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)