Sevoflurane impedes neuropathic pain by maintaining endoplasmic reticulum stress and oxidative stress homeostasis through inhibiting the activation of the PLCγ/CaMKII/IP3R signaling pathway.

OBJECTIVE: To investigate the effect of sevoflurane on neuropathic pain induced by chronic constriction injury (CCI) of sciatic nerve in mice, and to elucidate its mechanism by animal experiments. METHODS AND RESULTS: Thirty-two C57BL/6 mice were randomly divided into four groups: Sham group, Model group, Control group and Sevoflurane group. First, a mouse model of neuropathic pain was established. Then, the mice in each group were killed on Day 14 after operation to harvest the enlarged lumbosacral spinal cord. In contrast with the Model group, the Sevoflurane group displayed a significantly increased paw withdrawal mechanical threshold (PWMT) and significantly prolonged paw withdrawal thermal latency (PWTL) from Day 5 after operation. The morphological changes of lumbosacral spinal cord were observed by hematoxylin-eosin (HE) staining and transmission electron microscopy. Pathological results showed that sevoflurane reduced nuclear pyknosis in lumbosacral spinal cord tissue, with a large number of mitochondrial crista disappearance and mitochondrial swelling. The results of Western blotting showed that sevoflurane significantly decreased the protein expressions of phosphorylated phospholipase Cγ (p-PLCγ), phosphorylated calcium/calmodulin-dependent protein kinase II (p-CaMKII) and phosphorylated inositol 1,4,5-triphosphate receptor (p-IP3R), and reduced the protein expressions of endoplasmic reticulum (ER) stress proteins glucose-regulated protein 78 (GRP78) and GRP94, oxidative stress-related proteins P22 and P47 and inflammatory factors nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), interleukin-1 ß (IL-1ß), and tumor necrosis factor-α (TNF-α). CONCLUSIONS: Sevoflurane inhibits neuropathic pain by maintaining ER stress and oxidative stress homeostasis through inhibiting the activation of the PLCγ/CaMKII/IP3R signaling pathway.

The effect of remimazolam-based total intravenous anesthesia versus sevoflurane-based inhalation anesthesia on emergence delirium in children undergoing tonsillectomy and adenoidectomy: study protocol for a prospective randomized controlled trial.

Background: Remimazolam, a new ultrashort-acting benzodiazepine, is becoming increasingly applied in general anesthesia. This study is designed to investigate the effect of remimazolam-based total intravenous anesthesia and sevoflurane-based inhalation anesthesia on emergence delirium in pediatric tonsillectomy and adenoidectomy. Methods and analysis: This is a monocentric, prospective, randomized, double-blind clinical trial. A total of 90 pediatric patients will be randomized to receive remimazolam-based total intravenous anesthesia (remimazolam group, n = 45) or sevoflurane-based inhalation anesthesia (sevoflurane group, n = 45). The primary outcome will be the incidence of emergence delirium, which will be evaluated using the Pediatric Anesthesia Emergence Delirium (PAED) scale. The secondary outcomes include the extubation time, recovery time, behavior change using the post-hospitalization behavior questionnaire for ambulatory surgery (PHBQ-AS), and adverse events. Ethics and dissemination: This study has been approved by the Institutional Review Board (IRB) of the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University (2023-K-262-02). Clinical trial registration: ClinicalTrials.gov, identifier NCT06214117.

Sevoflurane-induced regulation of NKCC1/KCC2 phosphorylation through activation of Spak/OSR1 kinase and cognitive impairment in ischemia-reperfusion injury in rats.

The occurrence of excitotoxic damage caused by cerebral ischemia-reperfusion (I/R) injury is closely linked to a decrease in central inhibitory function, in which the concentration of chloride inside the cells ([Cl-]i) plays a crucial role. The outflow and inflow of [Cl-]i are controlled by KCC2 and NKCC1, which are cellular cotransporters for K+/Cl- and Na+/K+/Cl-, respectively. NKCC1/KCC2 is regulated by upstream regulators such as SPAK and OSR1, whose activity is influenced by I/R. Sevoflurane is the most commonly used and controversial general anesthetic. To elucidate the impact of sevoflurane on cerebral ischemia-reperfusion (I/R) injury and its underlying mechanism, we investigated its influence on cognitive function and the mechanism of action utilizing a rat model of I/R. By activating the kinase Spak/OSR1, we discovered that I/R damage enhanced the function of NKCC1 and inhibited the function of KCC2, which triggered an imbalance of [Cl-]i concentration, leading to neurological dysfunction and cognitive dysfunction. At the beginning of reperfusion, administration of 1.3 MAC sevoflurane for 3 h increased activation of Spak/OSR1 kinases on day 7 post-perfusion, resulting in an additional dysregulation of NKCC1 and KCC2 activity, which disappeared on day 14. Administration of Closantel, a Spak/OSR1 kinase inhibitor, to animals treated with sevoflurane reverses the additional stimulation. The research revealed that sevoflurane modified the functioning of NKCC1 and KCC2, resulting in cognitive decline by activating Spak/OSR1 kinase. However, this issue could be resolved by inhibiting Spak/OSR1. The research revealed that sevoflurane transiently alters the function of NKCC1 and KCC2, resulting in exacerbating cognitive decline. However, this can be fixed by suppressing Spak/OSR1.

Sevoflurane augments neuroinflammation by regulating DUSP6 via YTHDF1 in postoperative cognitive dysfunction.

Background: Postoperative cognitive dysfunction (POCD) is a generally recognized complication experienced by patients who receive anesthesia during surgery. Sevoflurane, the most commonly used inhaled anesthetic, has been shown to trigger neuroinflammation that promotes to POCD. Objective: This study examined the pathological mechanism by which sevoflurane causes neuroinflammation, participating in POCD. Methods: To establish a neurocyte injury model, the human neuroblastoma cell lines SH-SY5Y and SK-N-SH were treated with sevoflurane. Cell viability was determined using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assays. The reactive oxygen species (ROS) level was evaluated by DCFH-DA assays. A lactate dehydrogenase (LDH) Cytotoxicity Assay Kit was used to measure LDH levels. Inflammatory cytokine levels were measured using enzyme-linked immunosorbent assay assays. Gene expression densities and protein abundance were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR) or western blotting. The interaction between YTHDF1 and dual specific phosphatase 6 (DUSP6) was validated using RNA immunoprecipitation (RIP)-qPCR and methylated RIP (MeRIP)-qPCR assays. Flow cytometry was performed to determine apoptosis. Results: Sevoflurane promoted apoptosis, oxidative stress, and neuroinflammation and repressed the expression levels of YTHDF1 and DUSP6. Furthermore, YTHDF1 overexpression reversed sevoflurane-induced neuroinflammation in neurocytes. DUSP6 overexpression could alleviate the neuroinflammation induced by sevoflurane via regulating the extracellular signal-regulated kinase (ERK)1/2 signaling pathway. Moreover, YTHDF1 enhanced DUSP6 expression. Conclusion: Sevoflurane-stimulated neuroinflammation by regulating DUSP6 via YTHDF1. Sevoflurane promoted neuroinflammation by regulating DUSP6 via YTHDF1 in an in vitro model of POCD.

Efficiency of passive activated carbon anaesthetic gas capturing systems during simulated ventilation.

BACKGROUND: Interest in passive flow filter systems to remove sevoflurane from anaesthetic machine exhaust have increased recently to mitigate the environmental impact of volatile anaesthetics. These filter systems consist of chemically activated carbon, with limited evidence on their performance characteristics. We hypothesised that their efficiency depends on filter material. METHODS: Binding capacity was tested for three carbon filter materials (CONTRAfluran®, FlurAbsorb®, and Anaesthetic Agent Filter AAF633). Adsorption efficiency and resistive pressure were determined during simulated ventilation at different stages of filter saturation and fresh gas flow. In addition, sevoflurane concentration in filtered gas was measured at randomly selected anaesthesia workstations. RESULTS: Sevoflurane concentration in filtered gas exceeded 10 ppm when saturated with 184 ml sevoflurane each for CONTRAfluran and FlurAbsorb and 276 ml for AAF633. During simulated ventilation, sevoflurane concentration >10 ppm passed through CONTRAfluran and AAF633 at fresh gas flow 10 L min-1 only at maximum saturation, but through FlurAbsorb at all stages of saturation. The resistance pressure of all filters was negligible during simulated ventilation, but increased up to 5.2 (0.2) cm H2O during simulated coughing. At two of seven anaesthesia workstations, sevoflurane concentration in filtered exhaust gas was >10 ppm. CONCLUSIONS: Depending on the filter material and saturation, the likelihood of sevoflurane passing through passive flow carbon filters depends on the filter material and fresh gas flow. Combining the filter systems with anaesthetic gas scavenging systems could protect from pollution of ambient air with sevoflurane.

Mechanism research on microRNA-669f-5p/deoxycytidylate deaminase axis mediating sevoflurane-induced cognitive dysfunction in aged mice.

OBJECTIVE: To investigate the role of the microRNA (miRNA)-669f-5p/deoxycytidylate deaminase (Dctd) axis in sevoflurane inducing cognitive dysfunction in aged mice. METHODS: Sixty-six C57BL/6J mice were used in the experiment model and were randomly divided into the sevoflurane group and the control group. The mice in the sevoflurane group were anesthetised with 3.4% sevoflurane, whereas those in the control group were air-treated for the same period. The study was then performed using bioinformatics sequencing, as well as in vitro and in vivo validation. RESULTS: The mice in the sevoflurane group showed significant cognitive impairments in terms of a decrease in both spatial learning and memory abilities. Experimental doses of miR-669f-5p agonist exhibited no obvious effect on cognitive function following sevoflurane inhalation, but inhibiting the expression of miR-669f-5p could alleviate the impairments. Based on the results of the bioinformatics sequencing, miR-669f-5p/Dctd and the toll-like receptor (TLR) signalling pathway could be the key miRNA, gene and pathway leading to postoperative cognitive dysfunction following sevoflurane inhalation. The aged mice showed significantly increased expression of miR-669f-5p in the hippocampus following sevoflurane inhalation, and upregulating/inhibiting its expression could increase/decrease TLR expression in the hippocampus. Furthermore, miR-669f-5p could reduce the expression of the Dctd gene by binding to its 3'untranslated region. CONCLUSION: The miR-669f-5p/Dctd axis plays an important role in sevoflurane inducing cognitive dysfunction in aged mice, providing a new direction for further development of therapeutic strategies concerning the prevention and treatment of cognitive dysfunction associated with sevoflurane anaesthesia.

Dorsal raphe nucleus to basolateral amygdala 5-HTergic neural circuit modulates restoration of consciousness during sevoflurane anesthesia.

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.

Microglial EPOR Contribute to Sevoflurane-induced Developmental Fine Motor Deficits Through Synaptic Pruning in Mice.

Clinical researches including the Mayo Anesthesia Safety in Kids (MASK) study have found that children undergoing multiple anesthesia may have a higher risk of fine motor control difficulties. However, the underlying mechanisms remain elusive. Here, we report that erythropoietin receptor (EPOR), a microglial receptor associated with phagocytic activity, was significantly downregulated in the medial prefrontal cortex of young mice after multiple sevoflurane anesthesia exposure. Importantly, we found that the inhibited erythropoietin (EPO)/EPOR signaling axis led to microglial polarization, excessive excitatory synaptic pruning, and abnormal fine motor control skills in mice with multiple anesthesia exposure, and those above-mentioned situations were fully reversed by supplementing EPO-derived peptide ARA290 by intraperitoneal injection. Together, the microglial EPOR was identified as a key mediator regulating early synaptic development in this study, which impacted sevoflurane-induced fine motor dysfunction. Moreover, ARA290 might serve as a new treatment against neurotoxicity induced by general anesthesia in clinical practice by targeting the EPO/EPOR signaling pathway.

Early and late effects of volatile sedation with sevoflurane on respiratory mechanics of critically ill COPD patients.

BACKGROUND: The objective was to compare sevoflurane, a volatile sedation agent with potential bronchodilatory properties, with propofol on respiratory mechanics in critically ill patients with COPD exacerbation. METHODS: Prospective study in an ICU enrolling critically ill intubated patients with severe COPD exacerbation and comparing propofol and sevoflurane after 1:1 randomisation. Respiratory system mechanics (airway resistance, PEEPi, trapped volume, ventilatory ratio and respiratory system compliance), gas exchange, vitals, safety and outcome were measured at inclusion and then until H48. Total airway resistance change from baseline to H48 in both sevoflurane and propofol groups was the main endpoint. RESULTS: Sixteen patients were enrolled and were sedated for 126 h(61-228) in the propofol group and 207 h(171-216) in the sevoflurane group. At baseline, airway resistance was 21.6cmH2O/l/s(19.8-21.6) in the propofol group and 20.4cmH2O/l/s(18.6-26.4) in the sevoflurane group, (p = 0.73); trapped volume was 260 ml(176-290) in the propofol group and 73 ml(35-126) in the sevoflurane group, p = 0.02. Intrinsic PEEP was 1.5cmH2O(1-3) in both groups after external PEEP optimization. There was neither early (H4) or late (H48) significant difference in airway resistance and respiratory mechanics parameters between the two groups. CONCLUSIONS: In critically ill patients intubated with COPD exacerbation, there was no significant difference in respiratory mechanics between sevoflurane and propofol from inclusion to H4 and H48.

Post-operative vomiting after pediatric strabismus surgery: A comparison of propofol versus sevoflurane anaesthesia.

Background and Aims: Squint surgery is a risk factor for postoperative vomiting (POV) in children. This study was designed to compare the incidence of POV in children undergoing strabismus surgery under balanced anesthesia with sevoflurane versus intravenous anesthesia with propofol. Material and Methods: In this prospective randomized controlled study conducted in a tertiary care ophthalmology hospital, 70 ASA I-II children aged 1-12 years undergoing strabismus surgery were randomized to two groups -Group S (sevoflurane-based anesthesia) and Group P (propofol-based anesthesia) for maintenance. The surgical details, intraoperative hemodynamic parameters, recovery characteristics, and emergence delirium were recorded. Any episode of postoperative vomiting in the 0-2 hours, 2-6 hours, and 6-24 hours period was noted. Rescue antiemetic was administered if there was more than one episode of vomiting. Results: Both the groups were similar with respect to demographic and surgical details. The average duration of surgery was 118.2 ± 41.88 min in group S and 137.32 ± 39.09 min in group P (P = .05). Four children in group S (11.4%) and one child in group P (2.9%) had POV in the first 24 hours but this was not statistically significant (P = .36). The median time to discharge from post anesthesia care unit was significantly less (P = .02) in the P group (50 min) than in the S group (60 min). Conclusion: Propofol-based anesthesia does not offer advantage over sevoflurane, in reducing POV after squint surgery, when dual prophylaxis with dexamethasone and ondansetron is administered. It, however, reduces the duration of stay in the post anesthesia care unit.

Unveiling the protective role of sevoflurane in video-assisted thoracoscopic surgery associated-acute lung injury: Inhibition of ferroptosis.

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), Fe2+, 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 Fe2+ 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.

Current status of sevoflurane anesthesia in association with microglia inflammation and neurodegenerative diseases.

Sevoflurane is one of the most commonly used volatile anesthetics in clinical practice and is often used in pediatric anesthesia and intraoperative maintenance. Microglia exist in the central nervous system and are innate immune cells in the central nervous system. Under external stimulation, microglia are divided into two phenotypes: proinflammatory (M1 type) and anti-inflammatory (M2 type), maintaining the stability of the central nervous system through induction, housekeeping, and defense functions. Sevoflurane can activate microglia, increase the expression of inflammatory factors through various inflammatory signaling pathways, release inflammatory mediators to cause oxidative stress, damage nerve tissues, and eventually develop into neurodegenerative diseases. In this article, the relationship between sevoflurane anesthesia and microglia inflammation expression and the occurrence of neurodegenerative diseases is reviewed as follows.

Sevoflurane and Propofol Co-affect the Development of Colorectal Cancer by Regulating TM2D1.

AIMS: Sevoflurane and propofol are the most commonly used anesthetics in surgery. In this study, we aim to explore and clarify the function of sevoflurane and propofol in colorectal cancer. METHODS: Cell counting kit-8, colony formation, western blot, and transwell assays were performed to determine cell proliferation, apoptosis, ferroptosis, invasion, and migration. We performed overexpression experiments to detect the underlying molecular mechanism of sevoflurane and propofol. The genes related to epithelial-mesenchymal transition were measured by western blot. RESULTS: We discovered that sevoflurane and propofol co-treatment exerted more anti-tumor activities than just sevoflurane or propofol treatment in colorectal cancer cells in vitro. Mechanistically, our data showed that sevoflurane and propofol-induced apoptosis and ferroptosis and inhibited cell proliferation, invasion, and migration. Additionally, TM2D1 was considered a target of sevoflurane and propofol, and TM2D1 overexpression reversed the effect of sevoflurane and propofol on colorectal cancer cell biology behaviors. CONCLUSION: Our results showed a novel anti-tumor mechanism of sevoflurane and propofol in colorectal cancer cells, and TM2D1 might be an underlying therapeutic target for treating colorectal cancer patients.

Autophagic degradation of DHCR7 activates AKT3 and promotes sevoflurane-induced hippocampal neuroinflammation in neonatal mice.

Repeated sevoflurane exposure in neonatal mice triggers neuroinflammation with detrimental effects on cognitive function. Yet, the mechanism of the sevoflurane-induced cytokine response is largely unknown. In this study, we reveal that 3-MA, an autophagy inhibitor, attenuated the sevoflurane-induced neuroinflammation and cognitive dysfunction, including the decreased freezing time and fewer platform crossings, in the neonate mice. 3-Methyladenine (3-MA) suppressed sevoflurane-induced expression of interleukin-6 and tumor necrosis factor-alpha in vitro. Moreover, sevoflurane activates IRF3, facilitating cytokine transcription in an AKT3-dependent manner. Mechanistically, sevoflurane-induced autophagic degradation of dehydrocholesterol-reductase-7 (DHCR7) resulted in accumulations of its substrate 7-dehydrocholesterol (7-DHC), mimicking the effect of sevoflurane on AKT3 activation and IRF3-driven cytokine expression. 3-MA significantly reversed sevoflurane-induced DHCR7 degradation, AKT phosphorylation, IRF3 activation, and the accumulation of 7-DHC in the hippocampal CA1 region. These findings pave the way for additional investigations aimed at developing novel strategies to mitigate postoperative cognitive impairment in pediatric patients.

The Impact of the Combined Effect of Inhalation Anesthetics and Iron Dextran on Rats' Systemic Toxicity.

Disruption of any stage of iron homeostasis, including uptake, utilization, efflux, and storage, can cause progressive damage to peripheral organs. The health hazards associated with occupational exposure to inhalation anesthetics (IA) in combination with chronic iron overload are not well documented. This study aimed to investigate changes in the concentration of essential metals in the peripheral organs of rats after iron overload in combination with IA. The aim was also to determine how iron overload in combination with IA affects tissue metal homeostasis, hepcidin-ferritin levels, and MMP levels according to physiological, functional, and tissue features. According to the obtained results, iron accumulation was most pronounced in the liver (19×), spleen (6.7×), lungs (3.1×), and kidneys (2.5×) compared to control. Iron accumulation is associated with elevated heavy metal levels and impaired essential metal concentrations due to oxidative stress (OS). Notably, the use of IA increases the iron overload toxicity, especially after Isoflurane exposure. The results show that the regulation of iron homeostasis is based on the interaction of hepcidin, ferritin, and other proteins regulated by inflammation, OS, free iron levels, erythropoiesis, and hypoxia. Long-term exposure to IA and iron leads to the development of numerous adaptation mechanisms in response to toxicity, OS, and inflammation. These adaptive mechanisms of iron regulation lead to the inhibition of MMP activity and reduction of oxidative stress, protecting the organism from possible damage.

The effect of N-acetylcysteine on the neurotoxicity of sevoflurane in developing hippocampus cells.

Sevoflurane, a common pediatric anesthetic, has been linked to neurodegeneration, raising safety concerns. This study explored N-acetylcysteine's protective potential against sevoflurane-induced neurotoxicity in rat hippocampi. Four groups were examined: Control: Received 6 hours of 3 l/min gas (air and 30 % O2) and intraperitoneal saline. NAC: Received 6 hours of 3 l/min gas and 150 mg/kg NAC intraperitoneally. Sev: Exposed to 6 hours of 3 l/min gas and 3 % sevoflurane. Sev+NAC: Received 6 hours of 3 l/min gas, 3 % sevoflurane, and 150 mg/kg NAC. Protein levels of NRF-2, NLRP3, IL-1ß, caspase-1, Beclin 1, p62, LC3A, and apoptosis markers were assessed. Sevoflurane and NAC alone reduced autophagy, while Sev+NAC group maintained autophagy levels. Sev group had elevated NRF-2, NLRP3, pNRF2, Caspase-1, and IL-1ß, which were reduced in Sev+NAC. Apoptosis was higher in Sev, but Sev+NAC showed reduced apoptosis compared to the control. In summary, sevoflurane induced neurotoxicity in developing hippocampus, which was mitigated by N-acetylcysteine administration.

Sevoflurane-induced overexpression of extrasynaptic α5-GABAAR via the RhoA/ROCK2 pathway impairs cognitive function in aged mice.

Perioperative neurocognitive disorder (PND) is a serious neurologic complication in aged patients and might be associated with sevoflurane exposure. However, the specific pathogenesis is still unclear. The distribution of α5-GABAAR, a γ-aminobutyric acid type A receptor (GABAAR) subtype, at extrasynaptic sites is influenced by the anchor protein radixin, whose phosphorylation is regulated via the RhoA/ROCK2 signaling pathway and plays a crucial role in cognition. However, whether sevoflurane affects the ability of radixin phosphorylation to alter extrasynaptic receptor expression is unknown. Aged mice were exposed to sevoflurane to induce cognitive impairment. Both total proteins and membrane proteins were extracted for analysis. Cognitive function was evaluated using the Morris water maze and fear conditioning test. Western blotting was used to determine the expression of ROCK2 and the phosphorylation of radixin. Furthermore, the colocalization of p-radixin and α5-GABAAR was observed. To inhibit ROCK2 activity, either an adeno-associated virus (AAV) or fasudil hydrochloride was administered. Aged mice treated with sevoflurane exhibited significant cognitive impairment accompanied by increased membrane expression of α5-GABAAR. Moreover, the colocalization of α5-GABAAR and p-radixin increased after treatment with sevoflurane, and this change was accompanied by an increase in ROCK2 expression and radixin phosphorylation. Notably, inhibiting the RhoA/ROCK2 pathway significantly decreased the distribution of extrasynaptic α5-GABAAR and improved cognitive function. Sevoflurane activates the RhoA/ROCK2 pathway and increases the phosphorylation of radixin. Excess α5-GABAAR is anchored to extrasynaptic sites and impairs cognitive ability in aged mice. Fasudil hydrochloride administration improves cognitive function.

Uncovering essential anesthetics-induced exosomal miRNAs related to hepatocellular carcinoma progression: a bioinformatic investigation.

BACKGROUND: Anesthetic drugs may alter exosomal microRNA (miRNA) contents and mediate cancer progression and tumor microenvironment remodeling. Our study aims to explore how the anesthetics (sevoflurane and propofol) impact the miRNA makeup within exosomes in hepatocellular carcinoma (HCC), alongside the interconnected signaling pathways linked to the tumor immune microenvironment. METHODS: In this prospective study, we collected plasma exosomes from two groups of HCC patients (n = 5 each) treated with either propofol or sevoflurane, both before anesthesia and after hepatectomy. Exosomal miRNA profiles were assessed using next-generation sequencing (NGS). Furthermore, the expression data from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) was used to pinpoint the differentially expressed exosomal miRNAs (DEmiRNAs) attributed to the influence of propofol or sevoflurane in the context of HCC. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were used to dissect the signaling pathways and biological activities associated with the identified DEmiRNAs and their corresponding target genes. RESULTS: A total of 35 distinct DEmiRNAs were exclusively regulated by either propofol (n = 9) or sevoflurane (n = 26). Through TCGA-LIHC database analysis, 8 DEmiRNAs were associated with HCC. These included propofol-triggered miR-452-5p and let-7c-5p, as well as sevoflurane-induced miR-24-1-5p, miR-122-5p, miR-200a-3p, miR-4686, miR-214-3p, and miR-511-5p. Analyses revealed that among these 8 DEmiRNAs, the upregulation of miR-24-1-5p consistently demonstrated a significant association with lower histological grades (p < 0.0001), early-stage tumors (p < 0.05) and higher survival (p = 0.029). Further analyses using GSEA and GSVA indicated that miR-24-1-5p, along with its target genes, were involved in governing the tumor immune microenvironment and potentially inhibiting tumor progression in HCC. CONCLUSIONS: This study provided bioinformatics evidence suggesting that sevoflurane-induced plasma exosomal miRNAs may have a potential impact on the immune microenvironment of HCC. These findings established a foundation for future research into mechanistic outcomes in cancer patients.