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Background: The effects of a solitary neonatal exposure to anesthesia plus surgery (anesthesia/surgery) on cognitive function and the underlying mechanism in developing brains remains largely undetermined. We, therefore, set out to investigate the impact of single exposure to anesthesia/surgery in neonatal mice., Methods: Six-day-old male and female mice received abdominal surgery under 3% sevoflurane plus 50% oxygen for 2 h. The new object recognition (NOR) and Morris water maze (MWM) were used to evaluate cognitive function in young adult mice. Western blot, ELISA and RT-PCR were used to measure levels of NR2B and IL-6 in medial prefrontal cortex and IL-6 in blood of the mice. We employed NR2B siRNA and IL-6 antibody in the interaction studies., Results: The anesthesia/surgery decreased the ratio of novel time to novel plus familiar time in NOR and the number of platform crossings, but not escape latency, in MWM compared to sham condition. The mice in anesthesia/surgery group had increased NR2B expression in medial prefrontal cortex, and IL-6 amounts in blood and medial prefrontal cortex. Local injection of NR2B siRNA in medial prefrontal cortex alleviated the anesthesia/surgery-induced cognitive impairment. IL-6 antibody mitigated the anesthesia/surgery-induced upregulation of NR2B and cognitive impairment in young adult mice., Conclusions: These results suggest that a single neonatal exposure to anesthesia/surgery causes impairment of memory, but not learning, in young adult mice through IL-6-regulated increases in NR2B concentrations in medial prefrontal cortex, highlighting the need for further research on the underlying mechanisms of anesthesia/surgery's impact on cognitive function in developing brains., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Anesthesia often exacerbates memory recall difficulties in individuals with Alzheimer's disease (AD), but the underlying mechanisms remain unclear., Methods: We used in vivo Ca 2+ imaging, viral-based circuit tracing, and chemogenetic approaches to investigate anesthesia-induced remote memory impairment in mouse models of presymptomatic AD., Results: Our study identified pyramidal neuron hyperactivity in the anterior cingulate cortex (ACC) as a significant contributor to anesthesia-induced remote memory impairment. This ACC hyperactivation arises from the disinhibition of local inhibitory circuits and increased excitatory inputs from the hippocampal CA1 region. Inhibiting hyperactivity in the CA1-ACC circuit improved memory recall after anesthesia. Moreover, anesthesia led to increased tau phosphorylation in the hippocampus, and inhibiting this hyperphosphorylation prevented ACC hyperactivity and subsequent memory impairment., Discussion: Hippocampal-cortical hyperactivity plays a role in anesthesia-induced remote memory impairment. Targeting tau hyperphosphorylation shows promise as a therapeutic strategy to mitigate anesthesia-induced neural network dysfunction and retrograde amnesia in AD., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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 GSK3β 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 GSK3β, 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., (Copyright © 2023 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Introduction: Blood phosphorylated tau at threonine 217 (tau-PT217) is a newly established biomarker for Alzheimer's disease and postoperative delirium in patients. However, the mechanisms and consequences of acute changes in blood tau-PT217 remain largely unknown., Methods: We investigated the effects of anesthesia/surgery on blood tau-PT217 in aged mice, and evaluated the associated changes in B cell populations, neuronal excitability in anterior cingulate cortex, and delirium-like behavior using positron emission tomography imaging, nanoneedle technology, flow cytometry, electrophysiology, and behavioral tests., Results: Anesthesia/surgery induced acute increases in blood tau-PT217 via enhanced generation in the lungs and release from B cells. Tau-PT217 might cross the blood-brain barrier, increasing neuronal excitability and inducing delirium-like behavior. B cell transfer and WS635, a mitochondrial function enhancer, mitigated the anesthesia/surgery-induced changes., Discussion: Acute increases in blood tau-PT217 may contribute to brain dysfunction and postoperative delirium. Targeting B cells or mitochondrial function may have therapeutic potential for preventing or treating these conditions., (© 2023 the Alzheimer's Association.)

Objective: To determine the association between olfactory function and cognition in patients and rodents., Background: Perioperative neurocognitive disorders include delayed neurocognitive recovery (dNCR). The contribution of olfactory function to dNCR remains undetermined. It is unknown whether odor enrichment could mitigate dNCR., Methods: We performed a prospective observational cohort study to determine potential association between olfactory impairment and dNCR in patients. We assessed the effects of anesthesia/surgery on olfactory and cognitive function in mice using the block test and Barnes maze. We measured interleukin-6 (IL-6), olfactory mature protein, growth-associated protein 43, mature and premature olfactory neurons, postsynaptic density 95, and synaptophysin in blood, nasal epithelium, and hippocampus of mice. Odor enrichment, IL-6 antibody, and knockout of IL-6 were used in the interaction experiments., Results: Patients with dNCR had worse odor identification than the patients without dNCR [preoperative: 7 (1.25, 9) vs 10 (8, 11), median (interquartile range), P <0.001; postoperative: 8 (2.25, 10) vs 10 (8, 11), P <0.001]. Olfactory impairment associated with dNCR in patients before and after adjusting age, sex, education, preoperative mini-mental state examination score, and days of the neuropsychological tests. Anesthesia/surgery induced olfactory and cognitive impairment, increased levels of IL-6 in blood and nasal epithelium, decreased amounts of olfactory receptor neurons and their markers in the nasal epithelium, and reduced amounts of synapse markers in the hippocampus of mice. These changes were attenuated by odor enrichment and IL-6 antibody., Conclusion: The anesthesia/surgery-induced olfactory impairment may contribute to dNCR in patients and postoperative cognitive impairment in mice. Odor enrichment could be a potential intervention., Competing Interests: Z.X. provided consulting services to Shanghai 9th and 10th hospital and Baxter (invited speaker) in the last 36 months. The remaining authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Delirium is the most common postoperative complication in older patients after prolonged anesthesia and surgery and is associated with accelerated cognitive decline and dementia. The neuronal pathogenesis of postoperative delirium is largely unknown. The unfolded protein response (UPR) is an adaptive reaction of cells to perturbations in endoplasmic reticulum function. Dysregulation of UPR has been implicated in a variety of diseases including Alzheimer's disease and related dementias. However, whether UPR plays a role in anesthesia-induced cognitive impairment remains unexplored. By performing in vivo calcium imaging in the mouse frontal cortex, we showed that exposure of aged mice to the inhalational anesthetic sevoflurane for 2 hours resulted in a marked elevation of neuronal activity during recovery, which lasted for at least 24 hours after the end of exposure. Concomitantly, sevoflurane anesthesia caused a prolonged increase in phosphorylation of PERK and eIF2α, the markers of UPR activation. Genetic deletion or pharmacological inhibition of PERK prevented neuronal hyperactivity and memory impairment induced by sevoflurane. Moreover, we showed that PERK suppression also reversed various molecular and synaptic changes induced by sevoflurane anesthesia, including alterations of synaptic NMDA receptors, tau protein phosphorylation, and dendritic spine loss. Together, these findings suggest that sevoflurane anesthesia causes abnormal UPR in the aged brain, which contributes to neuronal hyperactivity, synapse loss and cognitive decline in aged mice., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

The neuropathogenesis of postoperative delirium remains mostly unknown. The gut microbiota is implicated in the pathogenesis of neurological disorders. We, therefore, set out to determine whether anesthesia/surgery causes age-dependent gut microbiota dysbiosis, changes in brain IL-6 level and mitochondrial function, leading to postoperative delirium-like behavior in mice. Female 9 or 18 months old mice received abdominal surgery under 1.4% isoflurane for two hours. The postoperative delirium-like behavior, gut microbiota, levels of brain IL-6, PSD-95 and synaptophysin, and mitochondrial function were determined by a battery of behavioral tests, 16s rRNA sequencing, ELISA, Western blot and Seahorse XFp Extracellular Flux Analyzer. Intragastric administration of Lactobacillus (10 days) and probiotic (20 days) were used to mitigate the anesthesia/surgery-induced changes. Anesthesia/surgery caused different alterations in gut microbiota, including change rate of reduction in the levels of gut lactobacillus, between the 18 and 9 months old mice. The anesthesia/surgery induced greater postoperative delirium-like behavior, increased brain IL-6 levels, decreased PSD-95 and synaptophysin levels, and mitochondrial dysfunction in 18 than 9 months old mice. Treatments with Lactobacillus and probiotic mitigated the anesthesia/surgery-induced changes. These data suggest that microbiota dysbiosis may contribute to neuropathogenesis of postoperative delirium and treatment with Lactobacillus or a probiotic could mitigate postoperative delirium.

The mechanism of anesthesia neurotoxicity remains largely to be determined. The effects of long noncoding RNAs (LncRNAs) on neural differentiation and the underlying mechanisms are unknown. We thus identified LncRNA Rik-203 (C130071C03Rik) and studied its role on neural differentiation and its interactions with anesthetic sevoflurane, miRNA and GSK-3β. We found that levels of Rik-203 were higher in hippocampus than other tissues and increased during neural differentiation. Sevoflurane decreased the levels of Rik-203. Rik-203 knockdown reduced mRNA levels of Sox1 and Nestin, the markers of neural progenitor cells, and decreased the count of Sox1 positive cells. RNA-RNA pull-down showed that miR-101a-3p was highly bound to Rik-203. Finally, sevoflurane, knockdown of Rik-203, and miR-101a-3p overexpression all decreased GSK-3β levels. These data suggest that Rik-203 facilitates neural differentiation by inhibiting miR-101a-3p's ability to reduce GSK-3β levels and that LncRNAs would serve as the mechanism of the anesthesia neurotoxicity.

Background: Exposure to anesthetics during early life may impair cognitive functions. However, the underlying mechanisms remain largely unknown. We set out to determine effects of sevoflurane anesthesia on folate metabolism and myelination in young non-human primates, mice and children., Methods: Young rhesus macaque and mice received 2.5 to 3% sevoflurane daily for three days. DNA and RNA sequencing and immunohistochemistry among others were used in the studies. We performed unbiased transcriptome profiling in prefrontal cortex of rhesus macaques and mice after the sevoflurane anesthesia. We constructed a brain blood barrier-crossing AAV-PHP.EB vector to harbor ERMN expression in rescue studies. We measured blood folate levels in children after anesthesia and surgery., Findings: We found that thymidylate synthase (TYMS) gene was downregulated after the sevoflurane anesthesia in both rhesus macaque and mice. There was a reduction in blood folate levels in children after the anesthesia and surgery. Combined with transcriptome and genome-wide DNA methylation analysis, we identified that ERMN was the primary target of the disrupted folate metabolism. Myelination was compromised by the anesthesia in the young mice, which was rescued by systematic administration of folic acid or expression of ERMN in the brain through brain-specific delivery of the adeno-associated virus. Moreover, folic acid and expression of ERMN alleviated the cognitive impairment caused by the sevoflurane anesthesia in the mice., Interpretation: General anesthesia leads to disrupted folate metabolism and subsequently defects in myelination in the developmental brain, and ERMN is the important target affected by the anesthesia via epigenetic mechanisms., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

In order to review the current status of the potential relationship between anesthesia and Alzheimer's disease, a group of scientists recently met in Philadelphia for a full day of presentations and discussions. This special article represents a consensus view on the possible link between Alzheimer's disease and anesthesia and the steps required to test this more definitively.

Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions. Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).

INTRODUCTION: Anesthesia often exacerbates memory recall difficulties in individuals with Alzheimer's disease (AD), but the underlying mechanisms remain unclear. METHODS: We used in vivo Ca2+ imaging, viral‐based circuit tracing, and chemogenetic approaches to investigate anesthesia‐induced remote memory impairment in mouse models of presymptomatic AD. RESULTS: Our study identified pyramidal neuron hyperactivity in the anterior cingulate cortex (ACC) as a significant contributor to anesthesia‐induced remote memory impairment. This ACC hyperactivation arises from the disinhibition of local inhibitory circuits and increased excitatory inputs from the hippocampal CA1 region. Inhibiting hyperactivity in the CA1‐ACC circuit improved memory recall after anesthesia. Moreover, anesthesia led to increased tau phosphorylation in the hippocampus, and inhibiting this hyperphosphorylation prevented ACC hyperactivity and subsequent memory impairment. DISCUSSION: Hippocampal‐cortical hyperactivity plays a role in anesthesia‐induced remote memory impairment. Targeting tau hyperphosphorylation shows promise as a therapeutic strategy to mitigate anesthesia‐induced neural network dysfunction and retrograde amnesia in AD. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Blood phosphorylated tau at threonine 217 (tau‐PT217) is a newly established biomarker for Alzheimer's disease and postoperative delirium in patients. However, the mechanisms and consequences of acute changes in blood tau‐PT217 remain largely unknown. METHODS: We investigated the effects of anesthesia/surgery on blood tau‐PT217 in aged mice, and evaluated the associated changes in B cell populations, neuronal excitability in anterior cingulate cortex, and delirium‐like behavior using positron emission tomography imaging, nanoneedle technology, flow cytometry, electrophysiology, and behavioral tests. RESULTS: Anesthesia/surgery induced acute increases in blood tau‐PT217 via enhanced generation in the lungs and release from B cells. Tau‐PT217 might cross the blood–brain barrier, increasing neuronal excitability and inducing delirium‐like behavior. B cell transfer and WS635, a mitochondrial function enhancer, mitigated the anesthesia/surgery‐induced changes. DISCUSSION: Acute increases in blood tau‐PT217 may contribute to brain dysfunction and postoperative delirium. Targeting B cells or mitochondrial function may have therapeutic potential for preventing or treating these conditions. [ABSTRACT FROM AUTHOR]

Inhalation anesthetics isoflurane and sevoflurane have been widely used in clinical practice for anesthesia. However, the molecular mechanisms underlying the faster recovery from sevoflurane anesthesia than isoflurane anesthesia remain largely undetermined. Herein, we use RNA-seq, RNA interference, quantitative real-time PCR and western blotting to explore the mechanisms of recovery from isoflurane and sevoflurane anesthesia in the migratory locusts. Although the migratory locusts show similar anesthetic responses to these two chemicals in corresponding half-maximal effective concentrations (EC50s), the recovery from sevoflurane anesthesia is significantly faster than that for isoflurane anesthesia after 30 min of anesthetic exposure. Transcriptome analysis shows that those transcripts involved in cytoskeletal components, Janus kinase (JAK) pathway and cuticle protein are differentially expressed in locust brains in response to isoflurane and sevoflurane. RNAi knockdown confirms that Actin , Myosin-like protein 84B (Mlp84B), JAK and cuticle protein NCP56 do not affect anesthetic response of the locusts to these two chemical anesthetics. Moreover, actin , Mlp84B and NCP56 do not affect differential recovery from isoflurane and sevoflurane anesthesia, whereas RNAi knockdown of JAK and its partner STAT5B does not affect anesthetic recovery from isoflurane but elongates recovery duration from sevoflurane anesthesia. Thus, JAK may mediate faster recovery from sevoflurane anesthesia than from isoflurane anesthesia in the migratory locust. This finding provides novel insights into the molecular mechanism underlying faster recovery from sevoflurane anesthesia than isoflurane anesthesia. [ABSTRACT FROM AUTHOR]

Background: Postoperative delirium is associated with adverse postoperative outcomes. However, whether intravenous and inhalation anesthetics are associated with different risks of postoperative delirium remains unknown.Objective: We set up to determine the incidence and duration of postoperative delirium in older patients who had surgery under the intravenous anesthetic propofol or the inhalational anesthetic sevoflurane.Methods: Participants were patients who had total hip/knee replacements and were randomized to propofol (N = 106) or sevoflurane (N = 103) anesthesia group. The Confusion Assessment Method was employed by investigators who were blinded to the anesthesia regimen to assess the incidence and duration (days of postoperative delirium per person) of postoperative delirium on postoperative days 1, 2, and 3.Results: A total of 209 participants (71.2±6.7 years old, 29.2% male) were included in the final data analysis. The incidence of postoperative delirium was 33.0% with propofol anesthesia and 23.3% with sevoflurane anesthesia (p = 0.119, Chi-square test), and we estimated that we would need 316 participants in each arm to detect a potential statistically significant difference. Days of postoperative delirium per person were higher in the propofol (0.5±0.8) anesthesia group compared to the sevoflurane anesthesia group (0.3±0.5, p = 0.049, Student's t-test).Conclusion: This pilot study established a system to compare effects of different anesthetics and generated a hypothesis that propofol trended to have a higher incidence and had longer duration of postoperative delirium than sevoflurane. Additional studies with a larger sample size are needed to test this hypothesis. [ABSTRACT FROM AUTHOR]

Clinical observations show emergence of agitation and hyperactivity during the anesthesia induction and/or recovery period post-anesthesia. However, an animal model to illustrate this clinical phenomenon has not yet been established. We therefore set out to investigate whether sevoflurane, a commonly used anesthetic, could alter locomotion in mice during the anesthesia induction and recovery period post-anesthesia. The activity of the mice was recorded 5 minutes before, during (for 30 minutes), and 40 minutes after the administration of the anesthetic sevoflurane [1-, 1.5- and 2-fold minimum alveolar concentration] at 370 C. The total walking distance and velocity of movement were measured and quantified as the indexes of locomotion. We found that the anesthetic sevoflurane increased the locomotion of the mice during the induction period of the anesthesia. During the recovery phase after anesthesia, the mice exhibited increased locomotion for a short period of time (about 5 minutes) and then displayed a sharp decrease in mobility for up to 60 minutes following the end of anesthesia administration. The anesthetic sevoflurane did not significantly alter the food intake and body weight of the mice. Furthermore, we found that Alzheimer’s disease transgenic mice exhibited a greater degree of sevoflurane-induced hyperactivity than the wild-type mice did. Our results showed that inhalation of the anesthetic sevoflurane induced an acute hyperactivity in mice, particularly among Alzheimer’s disease transgenic mice. These findings from the pilot studies have established an animal model to promote further studies into postoperative emergence agitation, hyperactivity and the underlying mechanisms into these conditions. [ABSTRACT FROM AUTHOR]

Background: Anesthesia may induce neurotoxicity and neurocognitive impairment in young mice. However, the underlying mechanism remains largely to be determined. Meanwhile, autophagy is involved in brain development and contributes to neurodegenerative diseases. We, therefore, set out to determine the effects of sevoflurane on autophagy in the hippocampus of young mice and on cognitive function in the mice. Methods: Six day-old mice received 3% sevoflurane, for two hours daily, on postnatal days (P) 6, 7 and 8. We then decapitated the mice and harvested the hippocampus of the young mice at P8. The level of LC3, the ratio of LC3-II to LC3-I, and SQSTM1/p62 level associated with the autophagy in the hippocampus of the mice were assessed by using Western blotting. We used different groups of mice for behavioral testing via the Morris Water Maze from P31 to P37. Results: The anesthetic sevoflurane increased the level of LC3-II and ratio of LC3-II/LC3-I, decreased the p62 level in the hippocampus of the young mice, and induced cognitive impairment in the mice. 3-Methyladenine, the inhibitor of autophagy, attenuated the activation of autophagy and ameliorated the cognitive impairment induced by sevoflurane in the young mice. Conclusion: These data showed that sevoflurane anesthesia might induce cognitive impairment in the young mice via activation of autophagy in the hippocampus of the young mice. These findings from the proof of concept studies have established a system and suggest the role of autophagy in anesthesia neurotoxicity and cognitive impairment in the young mice, pending further investigation. [ABSTRACT FROM AUTHOR]

Early postnatal anesthesia causes long-lasting learning and memory impairment in rodents, however, evidence for a specific neurotoxic effect on early synaptogenesis has not been demonstrated. Drebrin A is an actin binding protein whose localization in dendritic protrusions serves an important role in dendritic spine morphogenesis, and is a marker for early synaptogenesis. We therefore set out to investigate whether clinically-relevant concentrations of anesthetic sevoflurane, widely- used in infants and children, alters dendritic morphology in cultured fetal day 16 mouse hippocampal neurons. After 7 days in vitro, mouse hippocampal neurons were exposed to four hours of 3% sevoflurane in 95% air/5% CO2 or control condition (95% air/5% CO2). Neurons were fixed in 4% paraformaldehyde and stained with Alexa Fluor555-Phalloidin, and/or rabbit anti-mouse drebrin A/E antibodies which permitted subcellular localization of filamentous (F)-actin and/or drebrin immunoreactivity, respectively. Sevoflurane caused acute significant length-shortening in filopodia and thin dendritic spines in days-in-vitro 7 neurons, an effect which was completely rescued by co-incubating neurons with ten micromolar concentrations of the selective Rho kinase inhibitor Y27632. Filopodia and thin spine recovered in length two days after sevoflurane exposure. Yet cluster-type filopodia (a precursor to synaptic filopodia) were persistently significantly decreased in number on day-in-vitro 9, in part owing to preferential localization of drebrin immunoreactivity to dendritic shafts versus filopodial stalks. These data suggest that sevoflurane induces F-actin depolymerization leading to acute, reversible length-shortening in dendritic protrusions through a mechanism involving (in part) activation of RhoA/Rho kinase signaling and impairs localization of drebrin A to filopodia required for early excitatory synapse formation. [ABSTRACT FROM AUTHOR]

There is a need to seek new treatment(s) for Alzheimer's disease (AD). A recent study showed that AD patients may have decreased levels of functional GABA receptors. Propofol, a commonly used anesthetic, is a GABA receptor agonist. We therefore set out to perform a proof of concept study to determine whether chronic treatment with propofol (50 mg/kg/week) can improve cognitive function in both aged wild-type (WT) and AD transgenic (Tg) mice. Propofol was administrated to the WT and AD Tg mice once a week for 8 or 12 weeks, respectively. Morris water maze was used to assess the cognitive function of the mice following the propofol treatment. Activation of caspase-3, caspase-9, and caspase-8 was investigated using western blot analysis at the end of the propofol treatment. In the mechanistic studies, effects of propofol, amyloid-β protein (Aβ), and GABA receptor antagonist flumazenil on caspase-3 activation and opening of the mitochondrial permeability transition pore were assessed in H4 human neuroglioma and mouse neuroblastoma cells by western blot analysis and flow cytometry. Here we showed that the propofol treatment improved cognitive function and attenuated brain caspase-3 and caspase-9 activation in both aged WT and AD Tg mice. Propofol attenuated Aβ-induced caspase-3 activation and opening of the mitochondrial permeability transition pore in the cells, and flumazenil inhibited the propofol's effects. These results suggested that propofol might improve cognitive function via attenuating the Aβ-induced mitochondria dysfunction and caspase activation, which explored the potential that anesthetic propofol could improve cognitive function in elderly and AD patients. [ABSTRACT FROM AUTHOR]

The commonly used inhalation anesthetic isoflurane has been reported to induce DNA damage and cytotoxicity. However, the methods to attenuate these effects remain largely to be determined. Mild hypothermia has neuroprotective effects. We therefore set out to assess whether mild hypothermia could protect the isoflurane-induced DNA damage and cytotoxicity. Moreover, we investigated the underlying mechanisms by assessing the effects of mild hypothermia on the isoflurane-induced changes in ATP levels. H4 human neuroglioma cells were treated with 2% isoflurane for 3 or 6 h with and without mild hypothermia (35°C). We assessed the cell viability by using 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) and lactate dehydrogenase (LDH) assay. We determined DNA damage by measuring levels of phosphorylation of the histone protein H2A variant X at Ser139 (γH2A.X), the marker of DNA damage. We also measured ATP levels in the cells. Here we showed that the treatment with 2% isoflurane for 6 h induced cytotoxicity and DNA damage in the cells. Moreover, the treatment with 2% isoflurane for 3 h decreased ATP levels without inducing cytotoxicity. Mild hypothermia attenuated the isoflurane-induced cytotoxicity, DNA damage, and ATP reduction in the cells. Taken together, these data suggest that the isoflurane-induced reduction in ATP levels occurred before the isoflurane-induced cytotoxicity. Isoflurane may induce DNA damage and cause cytotoxicity through reducing ATP levels. Mild hypothermia would ameliorate isoflurane-induced DNA damage and cytotoxicity by attenuating the isoflurane-induced reduction in ATP levels. These pilot studies have established a system and will promote the future investigations of anesthesia neurotoxicity.

Abstract: Alzheimer''s disease (AD), an insidious and progressive neurodegenerative disorder accounting for the vast majority of dementia, is characterized by global cognitive decline and the robust accumulation of amyloid deposits and neurofibrillary tangles in the brain. This review article is based on the currently published literature regarding molecular studies of AD and the potential involvement of AD neuropathogenesis in post-operative cognitive dysfunction (POCD). Genetic evidence, confirmed by neuropathological and biochemical studies, indicates that excessive β-amyloid protein (Aβ) generated from amyloidogenic processing of the β-amyloid precursor protein (APP) plays a fundamental role in the AD neuropathogenesis. Aβ is produced from APP by β-secretase, and then γ-secretase complex, consisting of presenilins, nicastrin (NCSTN), APH-1 and PEN-2. Additionally, Aβ clearance and APP adaptor proteins can contribute to AD neuropathogenesis via affecting Aβ levels. Finally, cellular apoptosis may also be involved in AD neuropathogenesis. Surgery and anesthesia can cause cognitive disorders, especially in elderly patients. Even the molecular mechanisms underlying these disorders are largely unknown; several perioperative factors such as hypoxia, hypocapnia and anesthetics may be associated with AD and render POCD via trigging AD neuropathogenesis. More studies to assess the potential relationship between anesthesia/surgery and AD dementia are, therefore, urgently needed. [Copyright &y& Elsevier]

There is a need to develop animal models to study postoperative delirium. Inattention is one of the symptoms of delirium. Increases in the levels of α-synuclein and S100β have been reported to be associated with delirium. Therefore, we set out to determine the effects of surgery plus general anesthesia on the behavioral changes (including loss of attention) in mice and on the levels of α-synuclein and S100β in the brain tissues of these mice. C57BL/6J mice (2- to 8-months-old) had a simple laparotomy plus isoflurane anesthesia. The behavioral changes, including attention level and the speed of movements, were determined 12, 24, and 48 h after the surgery plus anesthesia in the mice. The levels of α-synuclein and S100β in the cortex of these mice following the surgery plus anesthesia were determined by Western blot analysis. We found that there was a loss of attention at 24, but not 12 or 48 h following the surgery plus anesthesia (49% ± 5 vs. 33% ± 2.9, P = 0.011, N = 12) in the mice without significantly affecting the speed of their movements. There were increases in the levels of total α-synuclein (139% ± 33.5 vs. 100% ± 13.7, P = 0.037, N = 6) and S100β (142% ± 7.7 vs. 100% ± 6, P = 0.002, N = 6) in the cortex of the mice 12 h following the surgery plus anesthesia. These findings suggested that the surgery plus isoflurane anesthesia might induce behavioral and biochemical/cellular changes associated with delirium. We could use the surgery plus anesthesia in mice to develop an animal model to study postoperative delirium.

Alzheimer’s disease (AD) is the most common form of dementia. At the present time, however, AD still lacks effective treatments. Our recent studies showed that chronic treatment with anesthetic propofol attenuated brain caspase-3 activation and improved cognitive function in aged mice. Accumulation of β-amyloid protein (Aβ) is a major component of the neuropathogenesis of AD dementia and cognitive impairment. We therefore set out to determine the effects of chronic treatment with propofol on Aβ levels in brain tissues of aged mice. Propofol (50 mg/kg) was administrated to aged (18 month-old) wild-type mice once a week for 8 weeks. The brain tissues of mice were harvested one day after the final propofol treatment. The harvested brain tissues were then subjected to enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Here we report that the propofol treatment reduced Aβ (Aβ40 and Aβ42) levels in the brain tissues of the aged mice. Moreover, the propofol treatment decreased the levels of β-site amyloid precursor protein cleaving enzyme (the enzyme for Aβ generation), and increased the levels of neprilysin (the enzyme for Aβ degradation) in the brain tissues of the aged mice. These results suggested that the chronic treatment with propofol might reduce brain Aβ levels potentially via decreasing brain levels of β-site amyloid precursor protein cleaving enzyme, thus decreasing Aβ generation; and via increasing brain neprilysin levels, thus increasing Aβ degradation. These preliminary findings from our pilot studies have established a system and postulated a new hypothesis for future research.

Commonly used anesthetic isoflurane has been reported to promote Alzheimer’s disease (AD) neuropathogenesis by inducing caspase-3 activation. However, the up-stream mechanisms of isoflurane’s effects remain largely to be determined. Specifically, there is a lack of a good model/system to elucidate the underlying mechanism of the isoflurane-induced caspase-3 activation. We therefore set out to assess and compare the effects of isoflurane on caspase-3 activation in neural progenitor cells (NPCs) and in primary neurons from wild-type (WT) and AD transgenic (Tg) mice. The NPCs and neurons were obtained, cultured and then treated with either 2% isoflurane or under control condition for 6 h. The NPCs or neurons were harvested at the end of the treatment and were subjected to Western blot analysis. Here we showed for the first time that the isoflurane treatment induced caspase-3 activation in neurons, but not in NPCs, from either WT or AD Tg mice. Consistently, the isoflurane treatment increased cytosol levels of cytochrome c, a potential up-stream mechanism of isoflurane-induced caspase-3 activation in the mice neurons, but not NPCs. Finally, the isoflurane treatment induced a greater casapse-3 activation in the neurons, but not the NPCs, from AD Tg mice as compared to the WT mice. These data demonstrated that investigation and comparison of isoflurane’s effects between mice NPCs and neurons would serve as a model/system to determine the underlying mechanism by which isoflurane induces caspase-3 activation. These findings would promote more research to investigate the effects of anesthetics on AD neuropathogenesis and the underlying mechanisms.

Hearing impairment is an established independent risk factor for delirium.Whether preoperative hearing impairment is associated with postoperative emergence agitation (POEA) in elderly patients remains unknown. This study aimed to investigate the association between preoperative hearing impairment and POEA in elderly patients undergoing ear surgery. This prospective observational study was carried out at an otologic centre in a tertiary hospital between July 15, 2020, and February 28, 2021. Data of 417 elderly patients who underwent microscopic and endoscopic middle ear surgery were analyzed. Pure tone average was used to assess preoperative hearing function, with a PTA ≥ 50 dB indicating severe hearing impairment. POEA was measured using the Richmond Agitation–Sedation Scale. Multiple logistic regression was used to determine the association between preoperative hearing function and POEA. Of the 417 participants, 45.8% were men, and the median age was 64 (interquartile range: 62–67) years old. Severe preoperative hearing impairment was present in 113 patients (27.1%), and POEA occurred in 42 patients (10.1%). Multiple logistic regression analysis indicated that severe preoperative hearing impairment was associated with an increased risk of POEA (odds ratio: 2.031; 95% confidence interval: 1.044–3.954, P = 0.037). Pending confirmative studies, these findings suggest that severe preoperative hearing impairment could serve as an independent predictor of POEA in older patients undergoing middle ear surgery. These results highlight the need for further research to better understand the biomarker and pathogenesis of POEA, leading to identification of targeted interventions of POEA and improvement of postoperative outcomes in patients. [ABSTRACT FROM AUTHOR]

Abstract: Anesthetics have been reported to promote Alzheimer''s disease (AD) neuropathogenesis by inducing β-amyloid protein accumulation and apoptosis. Neuroinflammation is associated with the emergence of AD. We therefore set out to determine the effects of the common anesthetic isoflurane on the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β, the proinflammatory cytokines, in vitro and in vivo, employing Western blot, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and reverse transcriptase polymerase chain reaction (RT-PCR). Here, we show that a clinically relevant isoflurane anesthesia increased the protein and messenger ribonucleic acid (mRNA) levels of TNF-α, IL-6, and IL-1β in the brain tissues of mice. The isoflurane anesthesia increased the amounts of TNF-α immunostaining positive cells in the brain tissues of mice, the majority of which were neurons. Furthermore, isoflurane increased TNF-α levels in primary neurons, but not microglia cells, of mice. Finally, isoflurane induced a greater degree of TNF-α increase in the AD transgenic mice than in the wild-type mice. These results suggest that isoflurane may increase the levels of proinflammatory cytokines, which may cause neuroinflammation, leading to promotion of AD neuropathogenesis. [Copyright &y& Elsevier]