Sevoflurane activates ATF4/NSUN7/PRKCD axis to induce neurotoxicity and cognitive impairment by promoting neuron mitochondrial fission.

Nociceptive stimulation activates NR2B-mediated DISC1/GSK-3β and ERK/CREB signaling alleviates sevoflurane induced neurotoxicity in neonatal rats.

Animal studies have shown that early life exposure to general anesthetics may impair brain development. However, the implications of this phenomenon in human patients remain unclear. In this study, we use an induced pluripotent stem cell (iPSC)-derived human brain microphysiological system (bMPS) to investigate the effects of early sevoflurane (SEV) exposure on human brain development. Human iPSCs were cultured and differentiated into neural progenitor cells (NPCs) and then into bMPS. At week 8, bMPSs were exposed to 2.4% SEV for 4 h. Four weeks after exposure, immunofluorescence (IF), Western blotting (WB), and quantitative real-time polymerase chain reaction (qPCR) were conducted to evaluate the alteration of nerve cells in bMPS. After SEV exposure, the number of apoptotic cells increases, and the level of neural differentiation markers decreases. The ratios of mature neurons over NPCs and mature oligodendrocytes over oligodendrocyte progenitor cells (OPCs) are reduced, which leads to a reduction in myelination. SEV also impedes the development of astrocytes and synaptogenesis, especially the formation of excitatory synapses. Meanwhile, SEV increases the expression of molecules in the mammalian target of rapamycin (mTOR) signal pathway. In conclusion, early SEV exposure substantially disrupts the development of human brain tissue, and the mTOR signal pathway is likely to be involved in this alteration.

Diabetes-associated cognitive dysfunction represents a global health challenge, yet the mechanisms by which anesthetics modulate cognitive function in diabetic states remain poorly understood. We systematically compared the effects of 2-hour brief exposure to sevoflurane (SEV) and propofol (PRO) on cognitive function and neuropathology in streptozotocin (STZ) -induced diabetic mice. Morris water maze and Y-maze tests revealed that SEV significantly exacerbated spatial memory and learning deficits in mice, while PRO showed no significant effects. Additionally, diabetic mice exhibited reduced NeuN+ neurons, increased β-amyloid deposition, and decreased SYN expression in the hippocampal CA1 region as examined by Immuno-fluorescence staining. Neither short-term SEV nor PRO exposure aggravated neuronal structural damage. Further transcriptomics revealed both anesthetics affected hippocampal neuron differentiation, but SEV uniquely perturbed fatty acid metabolism pathways. Metabolomics identified SEV-induced disruptions in lipid metabolism, marked by elevated hippocampal free fatty acids, phospholipids, as well as reduced lysophospholipids and acylcarnitine. Integrated multi-omics analysis demonstrated that SEV impaired cognition by suppressing fatty acid oxidation and dysregulating glycerophospholipid metabolism. These findings highlight the critical impact of anesthetic selection in diabetic populations.

Mechanism of lncRNA CYTOR/miR-24-3p in sevoflurane-mediated cardiomyocyte protection against hypoxia/reoxygenation injury in cardiomyocytes.

Evaluation of the ocular cytotoxicity of topical sevoflurane in sirc cells: An in vitro study.

Emergence agitation remains a problem that occurs in pediatric anesthesia. As cleft surgeries constitute one of the most common craniofacial surgeries encountered, majority of the children receive general anesthesia using high dose opioids and inhalation anesthetics and experience emergence agitation. Dexmedetomidine (DEX), an alpha-2 adrenoreceptor agonist possesses anxiolytic, sedative and analgetic properties and have been documented to reduce the incidence of postoperative agitation. Hence, this study aims to compare the incidence of emergence agitation between the use of intravenous DEX versus Sevoflurane (SEVO) anesthesia. This study selected one hundred twenty-one patients ages 3 months to 10 years with ASA 1 and 2 physical status scheduled to undergo elective cleft lip or cleft palate repair with general anesthesia. Before surgery, all patients were assessed preoperatively and subjects were divided into two groups using a computer-generated randomizer with 59 subjects selected as Dexmedetomidine group; and 62 subjects as Sevoflurane group. Extubation time, recovery time and emergence agitation scale were compared between the two groups. This study found no significant difference in the extubation time between DEX and SEVO group (p = 0.317). The recovery time or time to attain full consciousness was statistically longer in the DEX group: 60 minutes as compared to 52 minutes in the SEVO group (p = 0.007). Emergence agitation assessed using Cravero score found that subjects from DEX group had an average Cravero score of 2.5; while SEVO group had an average Cravero score of 3.9 (p = < 0.001). The incidence of agitation was significantly higher in the SEVO group compared to the DEX group: 82% as compared to 10% (p = < 0.001) with an OR of 40.955 CI 95% (14.098-118.9). Dexmedetomidine significantly reduces the incidence of emergence agitation without prolonging extubation time in pediatric patients undergoing cleft lip and cleft palate surgery.

IntroductionEmergence agitation remains a problem that occurs in pediatric anesthesia. As cleft surgeries constitute one of the most common craniofacial surgeries encountered, majority of the children receive general anesthesia using high dose opioids and inhalation anesthetics and experience emergence agitation. Dexmedetomidine (DEX), an alpha-2 adrenoreceptor agonist possesses anxiolytic, sedative and analgetic properties and have been documented to reduce the incidence of postoperative agitation. Hence, this study aims to compare the incidence of emergence agitation between the use of intravenous DEX versus Sevoflurane (SEVO) anesthesia.MethodsThis study selected one hundred twenty-one patients ages 3 months to 10 years with ASA 1 and 2 physical status scheduled to undergo elective cleft lip or cleft palate repair with general anesthesia. Before surgery, all patients were assessed preoperatively and subjects were divided into two groups using a computer-generated randomizer with 59 subjects selected as Dexmedetomidine group; and 62 subjects as Sevoflurane group. Extubation time, recovery time and emergence agitation scale were compared between the two groups.ResultsThis study found no significant difference in the extubation time between DEX and SEVO group (p = 0.317). The recovery time or time to attain full consciousness was statistically longer in the DEX group: 60 minutes as compared to 52 minutes in the SEVO group (p = 0.007). Emergence agitation assessed using Cravero score found that subjects from DEX group had an average Cravero score of 2.5; while SEVO group had an average Cravero score of 3.9 (p = < 0.001). The incidence of agitation was significantly higher in the SEVO group compared to the DEX group: 82% as compared to 10% (p = < 0.001) with an OR of 40.955 CI 95% (14.098–118.9).ConclusionsDexmedetomidine significantly reduces the incidence of emergence agitation without prolonging extubation time in pediatric patients undergoing cleft lip and cleft palate surgery.

To determine the effect of premedication followed by isoflurane (ISO) versus sevoflurane (SEVO), length of general anesthesia (GA), and the amount of IV fluid administered on plasma endocannabinoid arachidonoyl ethanolamide (anandamide; AEA) concentrations in dogs undergoing GA. This study was an analysis of samples collected during a previously designed prospective, randomized, single-blinded experimental study involving 21 client-owned dogs undergoing GA. Samples were collected from March through October 2021. Dogs were randomized to ISO or SEVO as the inhalant anesthetic. Blood samples collected before and after GA were used to measure plasma AEA concentrations using HPLC-MS-MS. Data included signalment, length of GA (minutes), surgery performed, fluid volume administered (milliliters per kilogram), and treatment with NSAIDs or steroids. Statistical analyses included power analysis, normality testing, and adjusted linear mixed models. Plasma AEA concentrations significantly decreased after GA in both groups. Least squares mean AEA concentration decreased from 29 to 12.3 ng/mL in the ISO group and from 26.6 to 11.1 ng/mL in the SEVO group. There were no significant differences between groups or associations with anesthesia duration, fluid volume, surgery, or NSAID/steroid use. Plasma AEA concentrations were significantly reduced after GA in both the ISO and SEVO groups. This reduction may be influenced by other anesthesia agents, such as dexmedetomidine, hydromorphone, and propofol. This study is the first to highlight a potential interaction between premedication, GA, and endocannabinoid signaling. Further research is needed to explore these findings and their implications for pain management and neuroprotection.

The neurotoxicity caused by inhaled anesthetics has attracted more attention. Sevoflurane (SEV), a common general anesthetic, has a wide range of clinical applications. However, the underlying molecular mechanism of SEV-induced neurotoxicity is blurry.Cell viability and apoptosis were evaluated using CCK-8 and flow cytometry. The abundances of targeted molecules were measured using RT-qPCR, western blot and IF assay. SEV induction reduced cell viability, promoted cell apoptosis and autophagy of HT22 cells, which was positively related with gradually increasing concentrations of SEV. In addition, Glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) expression was evidently decreased by SEV induction and its overexpression abolished SEV-mediated influences on cell viability, apoptosis and autophagy of HT22 cells. Furthermore, the autophagy inducer rapamycin reversed GRIA1 overexpression-mediated promotion of cell viability and suppression of cell apoptosis and autophagy of HT22 cells upon SEV induction. GRIA1 improved SEV-induced neurotoxicity by suppressing autophagy.

The present study aimed to investigate how sevoflurane (SEV) regulated the apoptosis of glioma cells through the mitochondrial apoptosis pathway. First, an evaluation was performed on the viability, apoptosis, mitochondrial reactive oxygen species levels, mitochondrial membrane potential and apoptosis and autophagy‑related protein expression of glioma cells according to experimental groups. Next, the expression of microRNA‑211‑5p (miR‑211‑5p), silent information regulator 1 (SIRT1) and phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (AKT) signaling pathway was detected by reverse transcription‑quantitative PCR or western blotting. Dual luciferase reporter gene assay confirmed the targeting relationship between miR‑211‑5p and SIRT1. In addition, SEV suppressed the proliferation and induced the apoptosis in human glioma cell line cells via the mitochondrial apoptosis pathway. In mechanistic analysis, the miR‑211‑5p level in glioma cells was low, while following SEV treatment, it was increased. Furthermore, SEV regulated SIRT1 by upregulating miR‑211‑5p expression, thereby blocking the PI3K/AKT signaling pathway activation. Moreover, functional rescue experiments showed that downregulation of SIRT1 or miR‑211‑5p could reverse the effects of SEV on glioma cells. Collectively, SEV promoted apoptosis in glioma cells by inducing miR‑211‑5p, which regulated SIRT1/PI3K/AKT pathway, mediating mitochondria‑dependent apoptosis pathway. This finding may open new possibilities for SEV as a potential treatment for glioma in the future.

Histone lactylation protects against sevoflurane-induced cognitive impairment by regulating YTHDF3/PRDX3 mediated microglial pyroptosis in neonatal mice.

In recent years, the cardioprotective effects of the volatile anesthetic sevoflurane (SEV) have been confirmed, yet its underlying molecular mechanisms remain incompletely elucidated. Notably, lncRNA LINC00265 has been identified as dysregulated in damaged cardiomyocytes, potentially contributing to disease progression. However, limited research has focused on the interplay between SEV and lncRNA LINC00265. The main objective of this study was to explore the mechanism and role of lncRNA LINC00265 in mediating the cardioprotective effects of SEV against myocardial injury. An in vitro hypoxia/reoxygenation (H/R) model was created in AC16 cells following pretreatment with varying concentrations of SEV. RT-qPCR was used to evaluate the levels of lncRNA LINC00265, miR-370-3p, IL-6, and TNF-α. The concentrations of CK-MB and cTnI were determined using ELISA. Cell viability was evaluated using CCK-8, and apoptosis was quantified by flow cytometry. Additionally, the relationship between lncRNA LINC00265 and miR-370-3p was confirmed using a dual-luciferase reporter assay. Prolonged hypoxia gradually rose in lncRNA LINC00265 levels, which was reversed by SEV pretreatment. SEV pretreatment mitigated H/R-induced decreases in cell viability, increases in apoptosis, and excessive production of IL-6, TNF-α, CK-MB, and cTnI. However, the protective effects of SEV were counteracted by lncRNA LINC00265 overexpression. A negative regulatory relationship between lncRNA LINC00265 and miR-370-3p was discovered. miR-370-3p overexpression mitigated diminished protective effects of SEV by elevated lncRNA LINC00265 in myocardial injury. lncRNA LINC00265 could diminish the protective effects of SEV against myocardial injury by functioning as a sponge for miR-370-3p.

ObjectiveThis study aims to compare the effects of sevoflurane (SEV) and propofol (PRO) on postoperative cognitive dysfunction (POCD) in patients undergoing cardiac surgery (CS) under cardiopulmonary bypass (CPB), with a focus on evaluating the efficacy of these anesthetic agents in preventing POCD.MethodsA total of 113 patients undergoing CS with CPB were grouped into two: PRO group (n = 58) and SEV group (n = 55). Baseline data, anesthesia effects (CPB duration, anesthesia time, respiratory recovery time, and anesthesia recovery time), Montreal Cognitive Assessment (MoCA) scores, POCD incidence, neurological function markers (NSE, S-100β, MMP9), and serum inflammatory markers (IL-6, IL-8, TNF-α) were analyzed. The study was conducted between March 2018 and May 2021.ResultsThe PRO group showed significantly shorter anesthesia time (P < 0.05), respiratory recovery time (P < 0.05), and anesthesia recovery time (P < 0.05) compared to the SEV group. The postoperative MoCA score in the PRO group reduced markedly compared with the baseline, but still higher than that in the SEV group (P < 0.05). The incidence of POCD was significantly lower in the PRO group (5.17% vs. 27.27%, P = 0.001). The levels of NSE, S-100β, MMP9, IL-6, IL-8, and TNF-α were significantly elevated compared to baseline values, but still lower than those in the SEV group (P < 0.05 for all comparisons).ConclusionPRO is more effective than SEV in preventing POCD in patients undergoing CS with CPB. It provides superior anesthetic effects and offers better protection against neuronal damage and serum inflammation compared to SEV.Clinical trial numberNot applicable.

The purpose of this study was to investigate the impact of sevoflurane (SEV) on cardiomyocyte (CM) pyroptosis following myocardial ischemia (MI). Reverse validation was performed by pharmacologically activating NLRP3 with monosodium urate (MSU) to confirm that SEV's cardioprotective effects were specifically mediated through the NLRP3 inflammasome pathway. Sprague Dawley rats were randomly assigned to sham (sham), model (conventional anesthesia + MI-reperfusion [MIR] injury modeling), SEV (SEV inhalation anesthesia + MIR injury modeling), and SEV + NLRP3 (SEV inhalation anesthesia + MIR injury modeling + NLRP3) groups. The myocardial area at risk (MAAR) and the myocardial infarct size (MIS) were evaluated in each experimental group, and cardiac tissue was examined using hematoxylin-eosin (H&E), Masson trichrome, and TUNEL staining. The concentrations of creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), oxidative stress (OS), and pyroptosis-associated proteins and various inflammatory markers in the serum and cardiac tissue were quantified. Results showed that compared to the sham group, both model and SEV groups exhibited a significant increase in MAAR and MIS, accompanied by severe histopathological damage and noticeable OS (p < 0.05). Elevated levels of inflammatory factors, enhanced CM apoptosis, and increased expression of pyroptosis-associated proteins were also observed in these groups. Notably, the SEV intervention in the SEV group demonstrated evident mitigation of heart injury, reduced MAAR and MIS, diminished CM apoptosis and inflammatory factors, and suppressed pyroptosis-associated proteins. Additionally, we observed that NLRP3 activation significantly diminished the protective effects of SEV on MIR rats. This study uncovers a novel mechanism through which SEV suppresses CM pyroptosis by inhibiting NLRP3, as confirmed by pharmacological activation of NLRP3. This was evidenced by worsened histopathological damage, increased CM apoptosis, and higher levels of inflammatory factors, cardiac injury markers, and pyroptosis-associated proteins. Overall, SEV inhibits CM pyroptosis and mitigates OS and inflammation through the NLRP3 inflammasome.

Aims/Purpose: To assess the antiseptic properties of Sevoflurane (SF) when topically applied to the ocular surface in an animal model, and to compare the results with that of 5% Povidone Iodine (PY), a commonly used ophthalmic antiseptic.Methods: This randomized clinical trial involved 24 eyes from 12 New Zealand white rabbits, which were divided into two groups: SF (n = 12) and PY (n = 12), based on the substance administered. Prior to the application of any agent, baseline samples were collected from the conjunctival sac of each eye to determine the normal conjunctival flora. Subsequently, a single dose of 0.1 mL of either SF or PY was administered according to the group allocation. Conjunctival sac samples were then taken at 5 and 30 minutes post‐application. The collected samples were subjected to microbiological analysis.Results: At the commencement of the study, Moraxella cuniculi was identified as the predominant species, with a statistically significant higher colony‐forming units per milliliter (CFU/mL) compared to other species (p &lt; 0.001). In the SF group, there was a statistically significant reduction in CFU/mL for both Moraxella cuniculi and Staphylococcus aureus following treatment. Conversely, in the PY group, a significant reduction was observed only for Moraxella cuniculi. Comparative analysis between the SF and PY groups revealed no statistically significant differences in the reduction of CFU/mL for Moraxella cuniculi at any time point during the study (p &gt; 0.05).Conclusions: Topical application of SF effectively reduces the CFU/mL of predominant germs on the ocular surface of albino rabbits, yielding results comparable to those achieved with PY.

Introduction: Sevoflurane is an extensively used anesthetic for pediatric patients; however, numerous studies showed that sevoflurane (SEVO) may cause long-term neurodevelopmental toxicity. Dexmedetomidine (DEX) has been shown to be protective against SEVO-induced neurotoxicity, but the mechanism remains unclear. The effects and mechanisms of different DEX administration routes on SEVO-induced neurotoxicity and long-term cognitive defects were determined and further investigated the role of sex in these processes. Methods: Male and female Sprague Dawley rats at postnatal day 7 (PND7) received an intraperitoneal injection of DEX (10 μg/kg) before or after exposure to 2.5% SEVO for 6 h, or before and after SEVO exposure. The respiratory and mortality rates of the pups were recorded during anesthesia. Neuroapoptosis was evaluated by TdT-mediated dUTP nick-end labeling staining. Immunohistochemistry and immunofluorescence were employed to detect the expression of caspase-3 in neuronal cells and neurons. The expression of GSK-3β and DISC1 was determined by Western blotting or RT-qPCR. Morris water maze (MWM) test was used to evaluate the learning and memory ability of rats until they were 3 weeks and 5 weeks old. Results: Compared with the control group, exposure to 2.5% SEVO resulted in increased neuroapoptosis and decreased the expression of DISC1 at levels of mRNA and protein and phosphorylated GSK-3β in the developing brain. SEVO exposure during critical neurodevelopmental periods could cause persistent cognitive defects in adolescent male and female rats and inhibited DISC1 and phosphorylated GSK-3β protein expression. The neurotoxic impacts of SEVO were lessened by the administration of DEX (10 μg/kg) before or after exposure. Conclusion: Our findings suggest that DEX (10 μg/kg) mitigates the neurotoxic effects of SEVO on the developing rat brain as well as postnatal cognitive defects by regulating the DISC1/GSK-3β signaling.

Effects of Cohabitation on Neurodevelopmental Outcomes in Rats Discordant for Neonatal Exposure to Sevoflurane

Children of parents with traumatic brain injury (TBI) are more likely to develop psychiatric disorders. This association is usually attributed to TBI-induced changes in parents' personality and families' social environment. We tested the hypothesis that offspring of young adult male rats with TBI develop neurodevelopmental abnormalities in the absence of direct social contact with sires. Male Sprague-Dawley rats (F0 generation) in the TBI group underwent moderate TBI via a midline fluid percussion injury that involved craniectomy under sevoflurane (SEVO) anesthesia for 40 min on post-natal Day 60 (P60), while F0 rats in the control group were placed in a new cage, one per cage, for the equivalent time duration. A subset of F0 rats was sacrificed on P66 to assess acute changes in hypothalamic-pituitary-adrenal (HPA) axis and inflammation markers. The remaining F0 males were mated with naive females on P90 to generate offspring (F1 generation). The F0 males and F1 males and females were sequentially evaluated in the elevated plus maze, for pre-pulse inhibition of acoustic startle, in the Morris water maze, and for resting and stress levels of serum corticosterone starting on ∼P105 (F0) and ∼P60 (F1), followed by tissue collection for further analyses. Acutely, the F0 TBI males had messenger RNA (mRNA) transcripts altered to support an increased hypothalamic and hippocampal Na+-K+-Cl- (Slc12a2) Cl- importer / K+-2Cl- (Slc12a5) Cl- exporter ratio and decreased hippocampal glucocorticoid receptors (Nr3c1), as well as increased serum levels of corticosterone, interleukin-1β (IL-1β), and biomarkers of activated hippocampal microglia and astrocytes. Long-term, F0 TBI rats exhibited increased corticosterone concentrations at rest and under stress, anxiety-like behavior, impaired sensory-motor gating, and impaired spatial memory. These abnormalities were underpinned by reduced mRNA levels of hypothalamic and hippocampal mineralocorticoid receptors (Nr3c2), hippocampal Nr3c1, and hypothalamic brain-derived neurotrophic factor (Bdnf), as well as elevated serum levels of IL-1β, and biomarkers of activated hippocampal microglia and astrocytes. F1 male offspring of TBI sires exhibited abnormalities in all behavioral tests, while their F1 female counterparts had abnormal pre-pulse inhibition responses only. F1 male offspring of TBI sires also had reduced mRNA levels of hippocampal Nr3c1 and Nr3c2, as well as hypothalamic and hippocampal Bdnf, whereas increases in inflammatory markers were more profound in F1 females. These findings suggest that offspring of sires with a history of a moderate TBI that involved craniectomy under SEVO anesthesia for 40 min, develop sex-dependent neurobehavioral abnormalities in the absence of direct social interaction between the sire and the offspring.

ABSTRACT Objectives This study tried to evaluate the impact of dexmedetomidine (DXM) infusion provided during sevoflurane (SEV) anesthesia on cognitive function (CF) of elderly patients undergoing elective arthroscopic shoulder surgeries. Patients & Methods A total of 140 patients were randomly allocated into Groups S and D. All patients received SEV (0.5–1 MAC) with placebo or DXM (0.6 µg/kg/h) infusions, respectively. CF was evaluated preoperatively, 48-h, 1-wk, and 2-wk postoperative (PO) using the Montreal Cognitive Assessment Test and Mini-Mental State Examination (MMSE). The study outcome is the frequency and severity of PO cognitive dysfunction (POCD). Results At 48-h PO, the frequency of normal CF and scorings were significantly decreased compared to preoperative findings, but were significantly higher in group D. At 1-wk PO, the frequency of normal CF and scores increased in both groups with significant difference in favor of group D, but differences were significantly lower than in preoperative measures. At 2-wk PO, 79.3% of patients regained their normal CF, with significantly higher frequency and score for group D, and the difference compared to preoperative data was insignificant in group D, but it was significant in group S. At 48-h, scorings were positively related to using DXM but were negatively related to age, obesity, and PO analgesia. Regression analysis defined old age as negative and the use of DXM as positive predictor for high scores. Conclusion SEV anesthesia induced reversible short-term POCD. Coupling of DXM infusion with SEV anesthesia decreased the frequency and scores of POCF and fastened resumption of normal CF.