Ketamine modulates disrupted in schizophrenia-1/glycogen synthase kinase-3ß interaction.

Introduction: Disrupted in schizophrenia-1 (DISC1) is a scaffolding protein whose mutated form has been linked to schizophrenia, bipolar affective disorders, and recurrent major depression. DISC1 regulates multiple signaling pathways involved in neurite outgrowth and cortical development and binds directly to glycogen synthase kinase-3ß (GSK-3ß). Since ketamine activates GSK-3ß, we examined the impact of ketamine on DISC1 and GSK-3ß expression. Methods: Postnatal day 7 rat pups were treated with ketamine with and without the non-specific GSK-3ß antagonist, lithium. Cleaved-caspase-3, GSK-3ß and DISC1 levels were measured by immunoblots and DISC1 co-localization in neurons by immunofluorescence. Binding of DISC1 to GSK-3ß was determined by co-immunoprecipitation. Neurite outgrowth was determined by measuring dendrite and axon length in primary neuronal cell cultures treated with ketamine and lithium. Results: Ketamine decreased DISC1 in a dose and time-dependent manner. This corresponded to decreases in phosphorylated GSK-3ß, which implicates increased GSK-3ß activity. Lithium significantly attenuated ketamine-induced decrease in DISC1 levels. Ketamine decreased co-immunoprecipitation of DISC1 with GSK-3ß and axonal length. Conclusion: These findings confirmed that acute administration of ketamine decreases in DISC1 levels and axonal growth. Lithium reversed this effect. This interaction provides a link between DISC1 and ketamine-induced neurodegeneration.

Sevoflurane anaesthesia induces cognitive impairment in young mice through sequential tau phosphorylation.

BACKGROUND: The volatile anaesthetic sevoflurane induces time (single or multiple exposures)-dependent effects on tau phosphorylation and cognitive function in young mice. The underlying mechanism for this remains largely undetermined. METHODS: Mice received 3% sevoflurane for 0.5 h or 2 h daily for 3 days on postnatal day (P) 6, 9, and 12. Another group of mice received 3% sevoflurane for 0.5 h or 1.5 h (3 × 0.5) on P6. We investigated effects of sevoflurane anaesthesia on tau phosphorylation on P6 or P12 mice, on cognitive function from P31 to P37, and on protein interactions, using in vivo studies, in vitro phosphorylation assays, and nanobeam single-molecule level interactions in vitro. RESULTS: An initial sevoflurane exposure induced CaMKIIα phosphorylation (132 [11]% vs 100 [6]%, P<0.01), leading to tau phosphorylation at serine 262 (164 [7]% vs 100 [26]%, P<0.01) and tau detachment from microtubules. Subsequent exposures to the sevoflurane induced GSK3ß activation, which phosphorylated detached or free tau (tau phosphorylated at serine 262) at serine 202 and threonine 205, resulting in cognitive impairment in young mice. In vitro phosphorylation assays also demonstrated sequential tau phosphorylation. Nanobeam analysis of molecular interactions showed different interactions between tau or free tau and CaMKIIα or GSK3ß, and between tau and tubulin at a single-molecule level. CONCLUSIONS: Multiple exposures to sevoflurane can induce sequential tau phosphorylation, leading to cognitive impairment in young mice, highlighting the need to investigate the underlying mechanisms of anaesthesia-induced tau phosphorylation in developing brain.

Focal drug-resistant temporal lobe epilepsy associated with an ipsilateral anterior choroidal artery aneurysm: illustrative case.

BACKGROUND: The occurrence of both an intracranial aneurysm and epilepsy, especially drug-resistant epilepsy (DRE), is rare. Although the overall incidence of aneurysms associated with DRE is unclear, it is thought to be particularly infrequent in the pediatric population. Surgical ligation of the offending aneurysm has been reported in conjunction with resolving seizure activity, although few cases have cited a combined approach of aneurysm ligation and resection of an epileptogenic focus. OBSERVATIONS: We present the case of a 14-year-old female patient with drug-resistant temporal lobe epilepsy and an ipsilateral supraclinoid internal carotid artery aneurysm. Seizure semiology, electroencephalography monitoring, and magnetic resonance imaging all indicated a left temporal epileptogenic focus, in addition to an incidental aneurysm. The authors recommended a combined surgery involving resection of the temporal lesion and surgical clip ligation of the aneurysm. Near-total resection and successful ligation were achieved, and the patient has remained seizure free since surgery at 1 year postoperatively. LESSONS: In patients with focal DRE and an adjacent intracranial aneurysm, a combined surgical approach involving both resection and surgical ligation can be used. Several surgical timing and neuroanesthetic considerations should be made to ensure the overall safety and efficacy of this procedure.

Differential effects of dexmedetomidine on Gram-positive and Gram-negative bacterial killing and phagocytosis.

Dexmedetomidine is a commonly used sedative in perioperative and intensive care settings with purported immunomodulatory properties. Since its effects on immune functions against infections have not been extensively studied, we tested the effects of dexmedetomidine on Gram-positive [Staphylococcus aureus and Enterococcus faecalis] and Gram-negative bacteria [Escherichia coli], and on effector functions of human monocytes THP-1 cells against them. We evaluated phagocytosis, reactive oxygen species (ROS) formation, and CD11b activation, and performed RNA sequencing analyses. Our study revealed that dexmedetomidine improved Gram-positive but mitigated Gram-negative bacterial phagocytosis and killing in THP-1 cells. The attenuation of Toll-like receptor 4 (TLR4) signaling by dexmedetomidine was previously reported. Thus, we tested TLR4 inhibitor TAK242. Similar to dexmedetomidine, TAK242 reduced E. coli phagocytosis but enhanced CD11b activation. The reduced TLR4 response potentially increases CD11b activation and ROS generation and subsequently enhances Gram-positive bacterial killing. Conversely, dexmedetomidine may inhibit the TLR4-signaling pathway and mitigate the alternative phagocytosis pathway induced by TLR4 activation through LPS-mediated Gram-negative bacteria, resulting in worsened bacterial loads. We also examined another α2 adrenergic agonist, xylazine. Because xylazine did not affect bacterial clearance, we proposed that dexmedetomidine may have an off-target effect on bacterial killing process, potentially involving crosstalk between CD11b and TLR4. Despite its potential to attenuate inflammation, we provide a novel insight into potential risks of dexmedetomidine use during Gram-negative infections, highlighting the differential effect of dexmedetomidine on Gram-positive and Gram-negative bacteria.

2023 American Society of Anesthesiologists Practice Guidelines for Preoperative Fasting: Carbohydrate-containing Clear Liquids with or without Protein, Chewing Gum, and Pediatric Fasting Duration-A Modular Update of the 2017 American Society of Anesthesiologists Practice Guidelines for Preoperative Fasting.

These practice guidelines are a modular update of the "Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration: Application to healthy patients undergoing elective procedures." The guidance focuses on topics not addressed in the previous guideline: ingestion of carbohydrate-containing clear liquids with or without protein, chewing gum, and pediatric fasting duration.

Testosterone attenuates sevoflurane-induced tau phosphorylation and cognitive impairment in neonatal male mice.

BACKGROUND: Sevoflurane anaesthesia induces phosphorylation of the microtubule-associated protein tau and cognitive impairment in neonatal, but not adult, mice. The underlying mechanisms remain largely to be determined. Sex hormones can be neuroprotective, but little is known about the influence of testosterone on age-dependent anaesthesia effects. METHODS: Six- and 60-day-old male mice received anaesthesia with sevoflurane 3% for 2 h daily for 3 days. Morris water maze, immunoassay, immunoblotting, co-immunoprecipitation, nanobeam technology, and electrophysiology were used to assess cognition; testosterone concentrations; tau phosphorylation; glycogen synthase kinase-3ß (GSK3ß) activation; binding or interaction between tau and GSK3ß; and neuronal activation in mice, cells, and neurones. RESULTS: Compared with 60-day-old male mice, 6-day-old male mice had lower testosterone concentrations (3.03 [0.29] vs 0.44 [0.12] ng ml-1; P<0.01), higher sevoflurane-induced tau phosphorylation in brain (133 [20]% vs 100 [6]% in 6-day-old mice, P<0.01; 103 [8]% vs 100 [13]% in 60-day-old mice, P=0.77), and sevoflurane-induced cognitive impairment. Testosterone treatment increased brain testosterone concentrations (1.76 [0.10] vs 0.39 [0.05] ng ml-1; P<0.01) and attenuated the sevoflurane-induced tau phosphorylation and cognitive impairment in neonatal male mice. Testosterone inhibited the interaction between tau and GSK3ß, and attenuated sevoflurane-induced inhibition of excitatory postsynaptic currents in hippocampal neurones. CONCLUSIONS: Lower brain testosterone concentrations in neonatal compared with adult male mice contributed to age-dependent tau phosphorylation and cognitive impairment after sevoflurane anaesthesia. Testosterone might attenuate the sevoflurane-induced tau phosphorylation and cognitive impairment by inhibiting the interaction between tau and GSK3ß.

Risk factors for pediatric surgical site infection following neurosurgical procedures for hydrocephalus: a retrospective single-center cohort study.

BACKGROUND: Infection is a major complication following cerebral spinal fluid (CSF) diversion procedures for hydrocephalus. However, pediatric risk factors for surgical site infection (SSI) are currently not well defined. Because a SSI prevention bundle is increasingly introduced, the purpose of this study was to evaluate risk factors associated with SSIs following CSF diversion surgeries following a SSI bundle at a single quaternary care pediatric hospital. METHODS: We performed a retrospective cohort study of patients undergoing CSF diversion procedures from 2017 to 2019. SSIs were identified prospectively through continuous surveillance. We performed unadjusted logistic regression analyses and univariate analyses to determine an association between SSIs and patient demographics, comorbidities and perioperative factors to identify independent risk factors for SSI. RESULTS: We identified a total of 558 CSF diversion procedures with an overall SSI rate of 3.4%. The SSI rates for shunt, external ventricular drain (EVD) placement, and endoscopic third ventriculostomy (ETV) were 4.3, 6.9 and 0%, respectively. Among 323 shunt operations, receipt of clindamycin as perioperative prophylaxis and presence of cardiac disease were significantly associated with SSI (O.R. 4.99, 95% C.I. 1.27-19.70, p = 0.02 for the former, and O.R. 7.19, 95% C.I. 1.35-38.35, p = 0.02 for the latter). No risk factors for SSI were identified among 72 EVD procedures. CONCLUSION: We identified receipt of clindamycin as perioperative prophylaxis and the presence of cardiac disease as risk factors for SSI in shunt procedures. Cefazolin is recommended as a standard antibiotic for perioperative prophylaxis. Knowing that unsubstantiated beta-lactam allergy label is a significant medical problem, efforts should be made to clarify beta-lactam allergy status to maximize the number of patients who can receive cefazolin for prophylaxis before shunt placement. Further research is needed to elucidate the mechanism by which cardiac disease may increase SSI risk after shunt procedures.

Anesthetics isoflurane and sevoflurane attenuate flagellin-mediated inflammation in the lung.

Isoflurane and sevoflurane are volatile anesthetics (VA) widely used in clinical practice to provide general anesthesia. We and others have previously shown that VAs have immunomodulatory effects and may have a significant impact on the progression of disease states. Flagellin is a component of Gram negative bacteria and plays a significant role in the pathophysiology of bacterial pneumonia through its binding to Toll-like Receptor 5 (TLR5). Our results showed that VAs, not an intravenous anesthetic, significantly attenuated the activation of TLR5 and the release of the neutrophil chemoattractant IL-8 from lung epithelial cells. Furthermore, flagellin-induced lung injury was significantly attenuated by VAs by inhibiting neutrophil migration to the bronchoalveolar space. The lungs of cystic fibrosis (CF) patients are highly colonized by Pseudomonas aeruginosa, which causes inflammation. The retrospective study of oxygenation in patients with CF who had received VA versus intravenous anesthesia suggested that VAs might have the protective effect for gas exchange. To understand the interaction between VAs and TLR5, a docking simulation was performed, which indicated that isoflurane and sevoflurane docked into the binding interphase between TLR5 and flagellin.

Vaping and E-Cigarette Use in Children and Adolescents: Implications on Perioperative Care From the American Society of Anesthesiologists Committee on Pediatric Anesthesia, Society for Pediatric Anesthesia, and American Academy of Pediatrics Section on Anesthesiology and Pain Medicine.

Electronic cigarettes (e-cigarettes) or vaping use in adolescents has emerged as a public health crisis that impacts the perioperative care of this vulnerable population. E-cigarettes have become the most commonly used tobacco products among youth in the United States. Fruit and mint flavors and additives such as marijuana have enticed children and adolescents. E-cigarette, or vaping, product use-associated lung injury (EVALI) is a newly identified lung disease linked to vaping. Clinical presentation of EVALI can be varied, but most commonly includes the respiratory system, gastrointestinal (GI) tract, and constitutional symptoms. Clinical management of EVALI has consisted of vaping cessation and supportive therapy, including supplemental oxygen, noninvasive ventilation, mechanical ventilation, glucocorticoids, and empiric antibiotics, until infectious causes are eliminated, and in the most severe cases, extracorporeal membrane oxygenation (ECMO). Currently, although there is an insufficient evidence to determine the safety and the efficacy of e-cigarettes for perioperative smoking cessation, EVALI clearly places these patients at an increased risk of perioperative morbidity. Given the relatively recent introduction of e-cigarettes, the long-term impact on adolescent health is unknown. As a result, the paucity of postoperative outcomes in this potentially vulnerable population does not support evidence-based recommendations for the management of these patients. Clinicians should identify "at-risk" individuals during preanesthetic evaluations and adjust the risk stratification accordingly. Our societies encourage continued education of the public and health care providers of the risks associated with vaping and nicotine use and encourage regular preoperative screening and postoperative outcome studies of patients with regard to smoking and vaping use.

Mechanistic consideration of the effect of perioperative volatile anesthetics on phagocytes.

A growing literature has shown that volatile anesthetics are promiscuous molecules targeting multiple molecules, some of which are critical for immunological functions. We focused on studies that delineated target molecules of volatile anesthetics on immune cells and summarized the effects of volatile anesthetics on immune functions. We also presented the perspectives of studying volatile anesthetics-mediated immunomodulation.

Dexmedetomidine and Clonidine Attenuate Sevoflurane-Induced Tau Phosphorylation and Cognitive Impairment in Young Mice via α-2 Adrenergic Receptor.

BACKGROUND: Anesthetic sevoflurane induces tau phosphorylation and cognitive impairment in young mice. The underlying mechanism and the targeted interventions remain largely unexplored. We hypothesized that dexmedetomidine and clonidine attenuated sevoflurane-induced tau phosphorylation and cognitive impairment by acting on α-2 adrenergic receptor. METHODS: Six-day-old mice received anesthesia with 3% sevoflurane 2 hours daily on postnatal days 6, 9, and 12. Alpha-2 adrenergic receptor agonist dexmedetomidine and clonidine were used to treat the mice with and without the α-2 adrenergic receptor antagonist yohimbine. Mouse hippocampi were harvested and subjected to western blot analysis. The New Object Recognition Test and Morris Water Maze were used to measure cognitive function. We analyzed the primary outcomes by using 2- and 1-way analysis of variance (ANOVA) and Mann-Whitney U test to determine the effects of sevoflurane on the amounts of phosphorylated tau, postsynaptic density-95, and cognitive function in young mice after the treatments with dexmedetomidine, clonidine, and yohimbine. RESULTS: Both dexmedetomidine and clonidine attenuated the sevoflurane-induced increase in phosphorylated tau amount (94 ± 16.3% [dexmedetomidine plus sevoflurane] versus 240 ± 67.8% [vehicle plus sevoflurane], P < .001; 125 ± 13.5% [clonidine plus sevoflurane] versus 355 ± 57.6% [vehicle plus sevoflurane], P < .001; mean ± standard deviation), sevoflurane-induced reduction in postsynaptic density-95 (82 ± 6.6% [dexmedetomidine plus sevoflurane] versus 31 ± 12.4% [vehicle plus sevoflurane], P < .001; 95 ± 6.4% [clonidine plus sevoflurane] versus 62 ± 18.4% [vehicle plus sevoflurane], P < .001), and cognitive impairment in the young mice. Interestingly, yohimbine reversed the effects of dexmedetomidine and clonidine on attenuating the sevoflurane-induced changes in phosphorylated tau, postsynaptic density-95, and cognitive function. CONCLUSIONS: Dexmedetomidine and clonidine could inhibit the sevoflurane-induced tau phosphorylation and cognitive impairment via activation of α-2 adrenergic receptor. More studies are needed to confirm the results and to determine the clinical relevance of these findings.

Is Anesthesia Bad for the Brain? Current Knowledge on the Impact of Anesthetics on the Developing Brain.

There are compelling preclinical data that common general anesthetics cause increased neuroapoptosis in juvenile animals. Retrospective studies demonstrate that young children exposed to anesthesia have school difficulties, which could be caused by anesthetic neurotoxicity, perioperative hemodynamic and homeostatic instability, underlying morbidity, or the neuroinflammatory effects of surgical trauma. Unnecessary procedures should be avoided. Baseline measures of blood pressure are important in determining perioperative blood pressure goals. Inadvertent hypocapnia or moderate hypercapnia and hyperoxia or hypoxia should be avoided. Pediatric patients should be maintained in a normothermic, euglycemic state with neutral positioning. Improving outcomes of infants and children requires the collaboration of anesthesiologists, surgeons, pediatricians and neonatologists.

Interaction of Tau, IL-6 and mitochondria on synapse and cognition following sevoflurane anesthesia in young mice.

Tau phosphorylation is associated with cognitive impairment in young mice. However, the underlying mechanism and targeted interventions remain mostly unknown. We set out to determine the potential interactions of Tau, interleukin 6 (IL-6) and mitochondria following treatment of anesthetic sevoflurane and to assess their influences on synapse number and cognition in young mice. Sevoflurane (3% for 2 â€‹h) was given to wild-type, Tau knockout, IL-6 knockout, and cyclophilin D (CypD) knockout mice on postnatal (P) day 6, 7 and 8. We measured amounts of phosphorylated Tau, IL-6, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), ATP, postsynaptic density 95 (PSD-95), synaptophysin, N-cadherin, synapse number, and cognitive function in the mice, employing Western blot, electron microscope and Morris water maze among others. Here we showed that sevoflurane increased Tau phosphorylation and caused IL-6 elevation, mitochondrial dysfunction, synaptic loss and cognitive impairment in young wild-type, but not Tau knockout, mice. In young IL-6 knockout mice, sevoflurane increased Tau phosphorylation but did not cause mitochondrial dysfunction, synaptic loss or cognitive impairment. Finally, sevoflurane increased Tau phosphorylation and IL-6 amount, but did not induce synaptic loss and cognitive impairment, in young CypD knockout mice or WT mice pretreated with idebenone, an analog of co-enzyme Q10. In conclusion, sevoflurane increased Tau phosphorylation, which caused IL-6 elevation, leading to mitochondrial dysfunction in young mice. Such interactions caused synaptic loss and cognitive impairment in the mice. Idebenone mitigated sevoflurane-induced cognitive impairment in young mice. These studies would promote more research to study Tau in young mice.

Does general anesthesia affect neurodevelopment in infants and children?

General anesthesia has been unequivocally linked to abnormal development of the central nervous system, leading to neurocognitive impairments in laboratory models. In vitro and in vivo studies have consistently shown that exposure to GABA agonists (eg, volatile anesthetics, midazolam, and propofol) or NMDA antagonists (eg, ketamine, isoflurane, and nitrous oxide) produces dose dependent and developmental age dependent effects on various neuronal transmission systems. Exposure to these drugs increases neuronal cell death in juvenile animals including rats, mice, and non-human primates. The possibility of anesthetic induced neurotoxicity occurring in children has led to concerns about the safety of pediatric anesthesia. A spectrum of behavioral changes has been documented after general anesthetic exposure in young children, including emergence delirium, which may be evidence of toxicity. Most clinical studies are retrospective; specifics about medications or monitoring are unavailable and many of the outcomes may not be sensitive to detect small neurocognitive deficits. Some of these retrospective studies have shown an association between anesthesia exposure at a young age and neurocognitive deficits, but others have not. Practitioners and families should be reassured that although general anesthetics have the potential to induce neurotoxicity, very little clinical evidence exists to support this.

The volatile anesthetic sevoflurane reduces neutrophil apoptosis via Fas death domain-Fas-associated death domain interaction.

Sepsis remains a significant health care burden, with high morbidities and mortalities. Patients with sepsis often require general anesthesia for procedures and imaging studies. Knowing that anesthetic drugs can pose immunomodulatory effects, it would be critical to understand the impact of anesthetics on sepsis pathophysiology. The volatile anesthetic sevoflurane is a common general anesthetic derived from ether as a prototype. Using a murine sepsis model induced by cecal ligation and puncture surgery, we examined the impact of sevoflurane on sepsis outcome. Different from volatile anesthetic isoflurane, sevoflurane exposure significantly improved the outcome of septic mice. This was associated with less apoptosis in the spleen. Because splenic apoptosis was largely attributed to the apoptosis of neutrophils, we examined the effect of sevoflurane on FasL-induced neutrophil apoptosis. Sevoflurane exposure significantly attenuated apoptosis. Sevoflurane did not affect the binding of FasL to the extracellular domain of Fas receptor. Instead, in silico analysis suggested that sevoflurane would bind to the interphase between Fas death domain (DD) and Fas-associated DD (FADD). The effect of sevoflurane on Fas DD-FADD interaction was examined using fluorescence resonance energy transfer (FRET). Sevoflurane attenuated FRET efficiency, indicating that sevoflurane hindered the interaction between Fas DD and FADD. The predicted sevoflurane binding site is known to play a significant role in Fas DD-FADD interaction, supporting our in vitro and in vivo apoptosis results.-Koutsogiannaki, S., Hou, L., Babazada, H., Okuno, T., Blazon-Brown, N., Soriano, S. G., Yokomizo, T., Yuki, K. The volatile anesthetic sevoflurane reduces neutrophil apoptosis via Fas death domain-Fas-associated death domain interaction.

A Summary of Preclinical Poster Presentations at the Sixth Biennial Pediatric Anesthesia Neurodevelopment Assessment (PANDA) Symposium.

The potential for long-term neurotoxic effects of anesthetics on the developing human brain has led to intensified research in this area. To date, the human evidence has been inconclusive, but a large body of animal evidence continues to demonstrate cause for concern. On April 14 and 15, 2018 the sixth biennial Pediatric Anesthesia and Neurodevelopmental Assessment (PANDA) study symposium was held at Morgan Stanley Children's Hospital of New York. This symposium brought together clinicians and researchers and served as a platform to review preclinical and clinical data related to anesthesia and neurotoxicity in developing brains. The program participants included many active investigators in the field of anesthesia neurotoxicity as well as stakeholders from different backgrounds with the common interest of potential anesthetic neurotoxicity in children. The moderated poster session included presentations of preclinical animal research studies. These studies focused on defining the anesthetic-induced neurotoxicity phenotype, understanding the mechanism of injury and discovering potential inhibitors of neurotoxic effects.

Sevoflurane Acts on Ubiquitination-Proteasome Pathway to Reduce Postsynaptic Density 95 Protein Levels in Young Mice.

BACKGROUND: Children with multiple exposures to anesthesia and surgery may have an increased risk of developing cognitive impairment. Sevoflurane, a commonly used anesthetic in children, has been reported to decrease levels of postsynaptic density 95 protein. However, the upstream mechanisms and downstream consequences of the sevoflurane-induced reduction in postsynaptic density 95 protein levels remains largely unknown. We therefore set out to assess whether sevoflurane acts on ubiquitination-proteasome pathway to facilitate postsynaptic density 95 protein degradation. METHODS: Six-day-old wild-type mice received anesthesia with 3% sevoflurane 2 h daily for 3 days starting on postnatal day 6. We determined the effects of the sevoflurane anesthesia on mRNA, protein and ubiquitinated levels of postsynaptic density 95 protein in neurons, and synaptosomes and hippocampus of young mice. Cognitive function in the mice was determined at postnatal day 31 by using a Morris water maze. Proteasome inhibitor MG132 and E3 ligase mouse double mutant 2 homolog inhibitor Nutlin-3 were used for the interaction studies. RESULTS: The sevoflurane anesthesia decreased protein, but not mRNA, levels of postsynaptic density 95, and reduced ubiquitinated postsynaptic density 95 protein levels in neurons, synaptosomes, and hippocampus of young mice. Both MG132 and Nutlin-3 blocked these sevoflurane-induced effects. Sevoflurane promoted the interaction of mouse double mutant 2 homolog and postsynaptic density 95 protein in neurons. Finally, MG132 and Nutlin-3 ameliorated the sevoflurane-induced cognitive impairment in the mice. CONCLUSIONS: These data suggest that sevoflurane acts on the ubiquitination-proteasome pathway to facilitate postsynaptic density 95 protein degradation, which then decreases postsynaptic density 95 protein levels, leading to cognitive impairment in young mice. These studies would further promote the mechanistic investigation of anesthesia neurotoxicity in the developing brain.