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Purpose: We investigated whether short term infusion of propofol, a highly lipophilic agonist at GABA A receptors, which is in widespread clinical use as anesthetic and sedative, affects passive blood-brain barrier (BBB) permeability in vivo., Methods: Mice were anesthetized with an intraperitoneal injection of ketamine/xylazine followed by a continuous IV infusion of propofol in lipid emulsion through a tail vein catheter. Control groups received ketamine/xylazine anesthesia and an infusion of Intralipid, or ketamine/xylazine anesthesia only. [ 13 C 12 ]sucrose as a permeability marker was injected as IV bolus 15 min after start of the infusions. Brain uptake clearance, K in , of sucrose was calculated from the brain concentrations at 30 min and the area under the plasma-concentration time curve. We also measured the plasma and brain concentration of propofol at the terminal time point., Results: The K in value for propofol-infused mice was significantly higher, by a factor of 1.55 and 1.87, compared to the Intralipid infusion and the ketamine/xylazine groups, respectively, while the control groups were not significantly different. No difference was seen in the expression levels of tight junction proteins in brain across all groups. The propofol plasma concentration at the end of infusion (10.7 µM) matched the clinically relevant range of blood concentrations reported in humans, while concentration in brain was 2.5-fold higher than plasma., Conclusions: Propofol at clinical plasma concentrations acutely increases BBB permeability, extending our previous results with volatile anesthetics to a lipophilic injectable agent. This prompts further exploration, potentially refining clinical practices and ensuring safety, especially during extended propofol infusion schemes., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Context: Propofol can induce neuroapoptosis. It has been reported that dexmedetomidine (DEX) has a protective effect on propofol-induced neuroapoptosis, but the specific mechanism needs to be further explored to provide a theoretical basis for their combined use., Objective: We aimed to explore the neuroprotective effect of DEX on primary cortical neurons treated by propofol and to elucidate the underlying mechanistic pathways., Methods: Cortical neurons were isolated from fetal rats and treated with propofol. MTT assays were performed to detect cell viability, α-tubulin immunofluorescent assays were conducted to observe cell abnormalities, and c-caspase3 immunofluorescent assays and flow cytometry were performed to examine cell apoptosis. Further, neurons were cotreated with propofol and DEX to study DEX's neuroprotective effects on propofol-caused neuronal injuries. Finally, the α 2A -adrenoceptor was knocked out and/or the Akt activator (SC-79) was added to cells co-treated with propofol and DEX. The expression levels of Akt-IKK-NF-κB pathway-related proteins were detected by western blot., Results: Propofol decreased cell viability in a dose-dependent manner, triggered apoptosis, caused morphological abnormalities and down-regulated the phosphorylation levels of Akt, IKK, NF-κB and IκB in cortical neurons. DEX ameliorated the decrease of cell viability, alleviated neuronal apoptosis and promoted the downregulated expression levels of p-Akt, IKK, NF-κB, and IκB proteins which had been induced by propofol treatment. Western blot findings following the transfection of α 2A -siRNA and the addition of SC-79 suggested that DEX's neuroprotective functions arose from the stimulation of α 2A -adrenoceptors to activate the Akt-IKK-NF-κB signal pathway., Conclusion: DEX protected neurons against propofol-induced apoptosis via activation of the Akt-IKK-NF-κB signal pathway through α 2A -adrenoceptors., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

General anesthesia in calves is easier to perform under field conditions, total intravenous anesthesia (TIVA) than using inhalation anesthesia. In the present study, cardiopulmonary function, anesthetic effects, quality of arousal, hematology, and blood biochemistry were assessed during continuous infusion of a combination solution of 0.01% xylazine, 0.001% butorphanol, and 0.2% propofol (XBP) at doses of 6 (G6; 10 μg/kg/min xylazine, 1 μg/kg/min butorphanol, 200 μg/kg/min propofol) and 9 mL/kg/h (G9; 15 μg/kg/min xylazine, 1.5 μg/kg/min butorphanol 300 μg/kg/min propofol). For both groups, five castrated Holstein calves received intravenous injections of xylazine (0.2 mg/kg) and propofol (2 mg/kg), followed by a continuous infusion of XBP for 60 min to maintain anesthesia. Respiratory management consisted of tracheal intubation followed by spontaneous inhalation of pure oxygen. Cardiopulmonary, anesthesia, hematology, and blood biochemistry variables were assessed at rest (baseline) and every 5 or 15 min after the start of the XBP infusion. Quality of arousal was assessed based on the swallowing reflex recovery time from the stop of XBP infusion, and the sternal position time and standing time after atipamezole administration. XBP produced adequate sedation, analgesia, and muscle relaxation in all calves and maintained stable anesthesia for 60 min. As XBP infusion time passed, rectal temperature and heart rate became lower, and mean arterial blood pressure increased. In both groups, hematologic and blood biochemical effects were mild. The quality of arousal was not different, and all calves were standing. The results of the present study suggested that XBP is useful for TIVA in calves., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels 1 are essential for pacemaking activity and neural signalling 2,3 . Drugs inhibiting HCN1 are promising candidates for management of neuropathic pain 4 and epileptic seizures 5 . The general anaesthetic propofol (2,6-di-iso-propylphenol) is a known HCN1 allosteric inhibitor 6 with unknown structural basis. Here, using single-particle cryo-electron microscopy and electrophysiology, we show that propofol inhibits HCN1 by binding to a mechanistic hotspot in a groove between the S5 and S6 transmembrane helices. We found that propofol restored voltage-dependent closing in two HCN1 epilepsy-associated polymorphisms that act by destabilizing the channel closed state: M305L, located in the propofol-binding site in S5, and D401H in S6 (refs.  7,8 ). To understand the mechanism of propofol inhibition and restoration of voltage-gating, we tracked voltage-sensor movement in spHCN channels and found that propofol inhibition is independent of voltage-sensor conformational changes. Mutations at the homologous methionine in spHCN and an adjacent conserved phenylalanine in S6 similarly destabilize closing without disrupting voltage-sensor movements, indicating that voltage-dependent closure requires this interface intact. We propose a model for voltage-dependent gating in which propofol stabilizes coupling between the voltage sensor and pore at this conserved methionine-phenylalanine interface in HCN channels. These findings unlock potential exploitation of this site to design specific drugs targeting HCN channelopathies., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Since the clinical introduction of general anesthesia, its underlying mechanisms have not been fully elucidated. The ventral tegmental area (VTA) and parabrachial nucleus (PBN) play pivotal roles in the mechanisms underlying general anesthesia. However, whether dopaminergic (DA) projections from the VTA to the PBN play a role in mediating the effects of general anesthesia is unclear. We microinjected 6-hydroxydopamine into the PBN to damage tyrosine hydroxylase positive (TH+) neurons and found a prolonged recovery time from propofol anesthesia. We used calcium fiber photometry recording to explore the activity of TH + neurons in the PBN. Then, we used chemogenetic and optogenetic approaches either activate the VTA DA -PBN pathway, shortening the propofol anesthesia emergence time, or inhibit this pathway, prolonging the emergence time. These data indicate the crucial involvement of TH + neurons in the PBN in regulating emergence from propofol anesthesia, while the activation of the VTA DA -PBN pathway facilitates the emergence of propofol anesthesia., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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

Background: Sepsis-associated encephalopathy (SAE) develops in 30-70% of hospitalized patients with sepsis. In intensive care units (ICUs), propofol is often administered to ensure an appropriate level of sedation in mechanically ventilated patients. Ferroptosis is a newly identified mode of cellular death characterized by the peroxidation of membrane lipids and excessive iron. This study was conducted to explore the interplay between propofol, sepsis, and ferroptosis., Methods: An acute systemic inflammatory model was constructed via the intraperitoneal administration of lipopolysaccharide (LPS). Nissl and Fluoro-Jade C (FJC) staining were employed to display neuronal damage and degeneration. Western blotting and immunofluorescence (IF) staining of Bax and Bcl-2 were used to confirm the neural apoptosis. QPCR of cytokines and DHE staining were used to indicate neuroinflammation. To validate ferroptosis, we assessed the content of malondialdehyde (MDA), GSH, and tissue iron, accompanied by transcription level of CHAC1, PTGS2 and GPX4. Additionally, we examined the content of acyl-CoA synthetase long-chain family member 4 (ACSL4), xCT (SLC7A11, solute carrier family 7 member 11), and glutathione peroxidase 4 (GPX4). The IF staining of Iba1-labeled microglia and GFAP-marked astrocytes were used to measure the gliosis. Erastin was pre-pretreated to confirm the anti-ferroptotic capability of propofol. ML385 was preconditioned to explore the role of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in propofol-repressed ferroptosis., Results: Propofol dose-dependently inhibited the decrease of Nissl-positive neurons and the increase of FJC-stained neurons in septic hippocampus and cortex. Neural cytokines, oxidative stress, apoptosis and gliosis were reduced by propofol. Propofol repressed the level of MDA, iron, CHAC1, PTGS2, ACLS4 and restored the content of GSH, GPX4, xCT, Nrf2 and HO-1, thus inhibiting sepsis-induced ferroptosis. All protections from propofol could be reversed by eratsin and ML385 pretreatment., Conclusion: Propofol protected against sepsis-induced brain damage, neuroinflammation, neuronal apoptosis and gliosis through the activation of the Nrf2/HO-1 axis to combat ferroptosis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The blood-brain barrier (BBB) is a highly selective semi-permeable barrier that separates circulating blood from the extracellular fluid of the brain and central nervous system, which is crucial for maintaining brain homeostasis. This study aimed to explore the role of propofol in BBB damage and further evaluate the underlying molecular mechanism. Lipopolysaccharide (LPS) was administered to mice to create an in vivo BBB damage mice model. Additionally, hCMEC/D3 cells as brain microvascular endothelial cells (BMECs) were treated with LPS to establish the in vitro BBB damage cell model. Subsequently, propofol was used for the BBB damage model. Evans blue staining and fluorescein sodium were utilized in the in vivo experiments to demonstrate BBB leakage and BBB permeability. Cell counting kit-8 (CCK-8) assay was used to assess cell viability and the trans-endothelial electrical resistance (TEER) value was measured using an epithelial voltmeter. Furthermore, enzyme-linked immunosorbent assay was performed to measure the levels of the inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α). The levels of miR-130a-5p and zonula occludens-1 (ZO-1) in brain tissues and cells were detected using reverse transcription-quantitative polymerase chain reaction, western blot, or immunofluorescence staining. Furthermore, a dual-luciferase reporter assay was used to demonstrate the association between miR-130a-5p and ZO-1. Propofol treatment suppressed BBB leakage, the amount of fluorescein sodium, and the levels of IL-1β and TNF-α in the LPS-induced BBB damage mice model. Meanwhile, propofol treatment increased the TEER value in the LPS-induced hCMEC/D3 cells. Additionally, propofol treatment significantly down-regulated miR-130a-5p and up-regulated ZO-1. More importantly, miR-130a-5p directly targeted ZO-1 and negatively regulated ZO-1 expression in hCMEC/D3 cells. Furthermore, miR-130a-5p mimic partially reversed the effect of propofol on the TEER value and the levels of inflammatory cytokines such as IL-1β and TNF-α in the LPS-induced hCMEC/D3 cells. Propofol suppressed LPS-induced BBB damage by regulating miR-130a-5p/ZO-1 axis. These findings suggested a potentially effective treatment approach for BBB damage., (© 2023. The Author(s).)

Hypotension induced by general anesthesia is associated with postoperative complications, increased mortality, and morbidity, particularly elderly patients. The aim of this study was to investigate the effectiveness of corrected carotid artery flow time (FTc) for predicting hypotension following anesthesia induction in patients over 65 years old. After faculty ethical committee approval and written informed consent, 138 patients (65 years and older, ASA physical status I-III) who scheduled for elective surgery were included in this study. In the pre-operative anesthesia unit, the carotid artery FTc value was measured by ultrasound and hemodynamic values were recorded. Following anesthesia induction with propofol, hemodynamic data were recorded at 1-minute intervals for 3 min. Measurements were terminated prior to endotracheal intubation, as direct laryngoscopy and endotracheal intubation could cause sympathetic stimulation and hemodynamic changes. Hypotension occurred in 52 patients (37.7%). The preoperative FTc value of the patients who developed hypotension was statistically lower (312.5 ms) than the patients who did not (345.0 ms) (p < 0.001). The area under the ROC curve for carotid artery FTc was 0.93 (95% CI for AUC:0.89-0.97; p < 0.001) with an optimal cut-off of value for predicting post-anesthesia hypotension 333 ms, a sensitivity of 90.4% and a specificity of 84.9%. As a result of the multiple logistic regression model, carotid artery FTc emerged as the sole independent risk factor for hypotension following anesthesia induction. Preoperative carotid artery FTc measurement is a simple, bedside, noninvasive, and reliable method for predicting anesthesia-induced hypotension in elderly patients., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Dexmedetomidine and propofol are common sedatives in intensive care units and for interventional procedures. Both may compromise sinus node function and atrioventricular conduction. The objective of this prospective, randomized study is to compare the effect of dexmedetomidine with propofol on sinus node function and atrioventricular conduction., Methods: In a tertiary care center in Switzerland we included from September 2019 to October 2020 160 patients (65 ± 11 years old; 32% female) undergoing first ablation for atrial fibrillation by cryoballoon ablation or by radiofrequency ablation. Patients were randomly assigned to deep sedation with dexmedetomidine (DEX group) versus propofol (PRO group). A standard electrophysiological study was performed after pulmonary vein isolation with the patients still deeply sedated and hemodynamically stable., Results: Eighty patients each were randomized to the DEX and PRO group. DEX group patients had higher baseline sinus cycle length (1022 vs. 1138 ms; p = 0.003) and longer sinus node recovery time (SNRT400; 1597 vs. 1412 ms; p = 0.042). However, both corrected SNRT and normalized SNRT did not differ. DEX group patients had longer PR interval (207 vs. 186 ms; p = 0.002) and AH interval (111 vs. 95 ms, p = 0.008), longer Wenckebach cycle length of the atrioventricular node (512 vs. 456 ms; p = 0.005), and longer atrioventricular node effective refractory period (390 vs. 344 ms; p = 0.009). QRS width and HV interval were not different. An arrhythmia, mainly atrial fibrillation, was induced in 33 patients during the electrophysiological study, without differences among groups (20% vs. 15%, p = 0.533)., Conclusions: Dexmedetomidine has a more pronounced slowing effect on sinus rate and suprahissian AV conduction than propofol, but not on infrahissian AV conduction and ventricular repolarization. These differences need to be taken into account when using these sedatives., Trial Registration: ClinicalTrials.gov number NCT03844841, 19/02/2019., (© 2024. The Author(s).)

Background: Pediatric postoperative cognitive dysfunction (POCD) is a prevalent complication following anesthesia and surgery. Hypoxia and propofol are the primary risk factors contributing to pediatric POCD. Our previous in vivo animal research has demonstrated that cognitive dysfunction in immature Sprague-Dawley (SD) rats, induced by hypoxia combined with propofol (HCWP), is closely associated with hippocampal neuron ferroptosis., Methods and Results: In vivo transcriptome sequencing and KEGG functional analysis revealed significant enrichment of the mitophagy pathway. To further elucidate the relationship between mitophagy and ferroptosis, HT22 cells were selected to construct an in vitro HCWP model. Our findings indicate that HCWP activates excessive mitophagy in HT22 cells, leading to decreased mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS) burst, mitochondrial fragmentation, and the induction of ferroptosis. To explore this causal relationship further, we employed Mdivi-1, a mitophagy inhibitor. Notably, low-dose Mdivi-1 (10 µM) effectively suppressed excessive mitophagy in HT22 cells, improved mitochondrial function and morphology, and mitigated markers associated with ferroptosis. The mechanism by which Mdivi-1 alleviates HCWP-induced ferroptosis in HT22 cells is likely due to its inhibition of excessive mitophagy, thereby promoting mitochondrial homeostasis., Conclusions: Our study suggests that mitophagy may be an upstream event in HCWP-induced ferroptosis in HT22 cells. Consequently, targeted regulation of mitophagy by Mdivi-1 may represent a promising approach to prevent cognitive dysfunction following HCWP exposure., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: This study explored the effects of different doses of remimazolam tosilate (RT) and propofol combined with remifentanil anesthesia on hemodynamic and inflammatory responses in patients undergoing laparoscopic surgery., Subjects and Methods: Ninety patients with a BMI of less than 35 kg/m², classified as ASA II-III and scheduled for laparoscopic surgery, were enrolled in this study. Patients were divided into three groups: low-dose RT group (A), high-dose RT group (B), and propofol group (C). The changes in hemodynamic indices such as SBP, DBP, HR, MAP, and inflammatory response indices such as IL-6, SAA, CRP, and PCT, along with extubation time and doses of sufentanil, remifentanil, urapidil, and phenylephrine, were compared among the three groups., Results: There were no statistically significant differences in extubation time, doses of sufentanil and remifentanil, or the usage rates and average doses of urapidil and phenylephrine between the three groups. The average dose of phenylephrine in group A was lower than in group B and group C, with a statistically significant difference. There were no statistically significant differences among the groups in SBP, DBP, HR, and MAP from T0 to T2, nor in IL-6, SAA, CRP, or PCT levels., Conclusion: Using RT for induction and maintenance of anesthesia in laparoscopic surgery ensures stable hemodynamic and inflammatory responses in patients. Low-dose RT may reduce the usage rate and dose of vasopressors such as phenylephrine during surgery., Competing Interests: The authors declare that they have no competing interests., (© 2024 Deng et al.)

Introduction: Motor-evoked potentials (MEP) are widely used to mitigate the risk of nerve injury resulting from surgical manipulation. Infants are more susceptible to anaesthetics that suppress MEP because of the immaturity of their nervous structures. Current evidence of the impact of the interaction between a small dose of sevoflurane and propofol-based total intravenous anaesthesia (TIVA) on MEP in infants is controversial. This current study aims to evaluate the impact of the coadministration of low-dose sevoflurane with propofol-based TIVA on MEP in infants., Methods and Analysis: A randomised controlled study will be conducted at a single tertiary care children's hospital in Japan between July 2024 and June 2029. Children between 35 and 87 weeks of postconceptual age undergoing spinal surgery requiring MEP under general anaesthesia will be enrolled in this study. The participants will be randomly allocated into two groups: propofol+remifentanil with (intervention group) or without (control group) low-dose sevoflurane (0.10-0.15 age-adjusted minimum alveolar concentration). MEP top-to-bottom amplitudes will be measured at two chronological points: T1 (first transcranial MEP (TcMEP) recording), T2 (second TcMEP recording) in the same patient. The primary and secondary endpoints will be a reduction in MEP amplitudes (T1-T2) in the right upper and lower extremities between the control and intervention groups, respectively. The sample size was calculated to be a total of 40 based on the preliminary data of 10 infants, which showed a 35% reduction in mean values of MEP amplitudes in the right adductor muscle (SD=31) with a 10% assumed dropout rate., Ethics and Dissemination: The study protocol was approved by the Institutional Review Board of the Aichi Children's Health and Medical Center (2022058). The results will be reported in a peer-reviewed journal at the relevant academic conference., Trial Registration Number: jRCT1041230094., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The properties of a potentiator are typically evaluated by measuring its ability to enhance the magnitude of the control response. Analysis of the ability of drugs to potentiate responses from receptor channels takes place in the context of particular models to extract parameters for functional effects. In the often-used coagonist model, the agonist generating control activity and the potentiator enhancing the control activity make additive energetic contributions to stabilize the active state of the receptor. The energetic contributions are fixed and, once known, enable calculation of predicted receptor behavior at any concentration combination of agonist and potentiator. Here, we have examined the applicability of the coagonist model by measuring the relationship between the magnitude of receptor potentiation and the level of background activity. Ternary αβγ GABA A receptors were activated by GABA or the allosteric agonist propofol, or by a gain-of-function mutation, and etiocholanolone- or propofol-mediated potentiation of peak responses was measured. We show that the free energy change contributed by the modulators etiocholanolone or propofol is reduced at higher levels of control activity, thereby being in disagreement with basic principles of the coagonist model. Possible mechanisms underlying this discrepancy are discussed., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Despite their frequent use across many clinical settings, general anesthetics are medications with lethal side effects and no reversal agents. A fluorinated analogue of propofol has previously been shown to antagonize propofol anesthesia in tadpoles and zebrafish, but little further investigation of this class of molecules as anesthetic antagonists has been conducted. A 13-member library of alkyl-fluorobenzene derivatives was tested in an established behavioral model of anesthesia in zebrafish at 5 days post fertilization. These compounds were examined for their ability to antagonize propofol and two volatile anesthetics, as well as their interaction with the anesthetic-binding model protein apoferritin. Two compounds provided significant antagonism of propofol, and when combined, were synergistic, suggesting more than one antagonist sensitive target site. These compounds did not antagonize the volatile anesthetics, indicating some selectivity amongst general anesthetics. For the compounds with the most antagonistic potency, similarities in structure and binding to apoferritin may be suggestive of competitive antagonism; however, this was not supported by a Schild analysis. This is consistent with multiple targets contributing to general anesthesia, but whether these are physiologic antagonists or are antagonists at only some subset of the many anesthetic potential targets remains unclear, and will require additional investigation., (© 2024. The Author(s).)

Background: Sedatives are commonly used to promote sleep in intensive care unit patients. However, it is not clear whether sedation-induced states are similar to the biological sleep. We explored if sedative-induced states resemble biological sleep using multichannel electroencephalogram (EEG) recordings., Methods: Multichannel EEG datasets from two different sources were used in this study: (1) sedation dataset consisting of 102 healthy volunteers receiving propofol (N = 36), sevoflurane (N = 36), or dexmedetomidine (N = 30), and (2) publicly available sleep EEG dataset (N = 994). Forty-four quantitative time, frequency and entropy features were extracted from EEG recordings and were used to train the machine learning algorithms on sleep dataset to predict sleep stages in the sedation dataset. The predicted sleep states were then compared with the Modified Observer's Assessment of Alertness/ Sedation (MOAA/S) scores., Results: The performance of the model was poor (AUC = 0.55-0.58) in differentiating sleep stages during propofol and sevoflurane sedation. In the case of dexmedetomidine, the AUC of the model increased in a sedation-dependent manner with NREM stages 2 and 3 highly correlating with deep sedation state reaching an AUC of 0.80., Conclusions: We addressed an important clinical question to identify biological sleep promoting sedatives using EEG signals. We demonstrate that propofol and sevoflurane do not promote EEG patterns resembling natural sleep while dexmedetomidine promotes states resembling NREM stages 2 and 3 sleep, based on current sleep staging standards., Competing Interests: M. M. R. F. Struys: His research group/department received (over the last 3 years) research grants and consultancy fees from Masimo (Irvine, CA, USA), Becton Dickinson (Eysins, Switzerland), Fresenius (Bad Homburg, Germany), Paion (Aachen, Germany), Medcaptain Europe (Andelst, The Netherlands), Baxter (Chicago, Il, USA), HanaPharm (Seoul, Republic of Korea). He receives royalties on intellectual property from Demed Medical (Sinaai, Belgium) and the Ghent University (Gent, Belgium). This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Ramaswamy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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

Pain, a comorbidity of anxiety disorders, causes substantial clinical, social, and economic burdens. Emerging evidence suggests that propofol, the most commonly used general anesthetic, may regulate psychological disorders; however, its role in pain-associated anxiety is not yet described. This study investigates the therapeutic potential of a single dose of propofol (100 mg kg -1 ) in alleviating pain-associated anxiety and examines the underlying neural mechanisms. In acute and chronic pain models, propofol decreased anxiety-like behaviors in the elevated plus maze (EPM) and open field (OF) tests. Propofol also reduced the serum levels of stress-related hormones including corticosterone, corticotropin-releasing hormone (CRH), and norepinephrine. Fiber photometry recordings indicated that the calcium signaling activity of CRH neurons in the paraventricular nucleus (PVN CRH ) is reduced after propofol treatment. Interestingly, artificially activating PVN CRH neurons through chemogenetics interfered with the anxiety-reducing effects of propofol. Electrophysiological recordings indicated that propofol decreases the activity of PVN CRH neurons by increasing spontaneous inhibitory postsynaptic currents (sIPSCs). Further, reducing the levels of γ-aminobutyric acid type A receptor β3 (GABA A β3) subunits in PVN CRH neurons diminished the anxiety-relieving effects of propofol. In conclusion, this study provides a mechanistic and preclinical rationale to treat pain-associated anxiety-like behaviors using a single dose of propofol., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Background: Sleep deprivation (SD) is a growing global health problem with many deleterious effects, such as cognitive impairment. Microglia activation-induced neuroinflammation may be an essential factor in this. Propofol has been shown to clear sleep debt after SD in rats. This study aims to evaluate the effects of propofol-induced sleep on ameliorating sleep quality impairment and cognitive decline after 48 h SD., Methods: Almost 8-12-week-old rats were placed in the SD system for 48 h of natural sleep or continuous SD. Afterwards, rats received propofol (20 mg·kg -1 ·h -1 , 6 h) via the tail or slept naturally. The Morris water maze (MWM) and Y-maze test assessed spatial learning and memory abilities. Rat EEG/EMG monitored sleep. The expression of brain and muscle Arnt-like protein 1 (BMAL1), brain-derived neurotrophic factor (BDNF) in the hippocampus and BMAL1 in the hypothalamus were assessed by western blot. Enzyme-linked immunosorbent assay detected IL-6, IL-1β, arginase 1 (Arg1), and IL-10 levels in the hippocampus. Immunofluorescence was used to determine microglia expression as well as morphological changes., Results: Compared to the control group, the sleep-deprived rats showed poor cognitive performance on both the MWM test and the Y-maze test, accompanied by disturbances in sleep structure, including increased total sleep time, and increased time spent and delta power in non-rapid eye movement sleep. In addition, SD induces abnormal expression of the circadian rhythm protein BMAL1, activates microglia, and causes neuroinflammation and nerve damage. Propofol reversed these changes and saved sleep and cognitive impairment. Furthermore, propofol treatment significantly reduced hippocampal IL-1β and IL-6 levels, increased BDNF, Arg1, and IL-10 levels, and switched microglia surface markers from the inflammatory M1 type to the anti-inflammatory M2 type., Conclusion: Propofol reduces SD-induced cognitive impairment and circadian rhythm disruption, possibly by lowering neuronal inflammation and switching the microglia phenotype from an M1 to an M2 activated state, thus exerting neuroprotective effects., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background: Reversible loss of consciousness is the primary therapeutic endpoint of general anesthesia; however, the drug-invariant mechanisms underlying anesthetic-induced unconsciousness are still unclear. This study aimed to investigate the static, dynamic, topological and organizational changes in functional brain network induced by five clinically-used general anesthetics in the rat brain., Method: Male Sprague-Dawley rats (n = 57) were randomly allocated to received propofol, isoflurane, ketamine, dexmedetomidine, or combined isoflurane plus dexmedetomidine anesthesia. Resting-state functional magnetic resonance images were acquired under general anesthesia and analyzed for changes in dynamic functional brain networks compared to the awake state., Results: Different general anesthetics induced distinct patterns of functional connectivity inhibition within brain-wide networks, resulting in multi-level network reorganization primarily by impairing the functional connectivity of cortico-subcortical networks as well as by reducing information transmission capacity, intrinsic connectivity, and network architecture stability of subcortical regions. Conversely, functional connectivity and topological properties were preserved within cortico-cortical networks, albeit with fewer dynamic fluctuations under general anesthesia., Conclusions: Our findings highlighted the effects of different general anesthetics on functional brain network reorganization, which might shed light on the drug-invariant mechanism of anesthetic-induced unconsciousness., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Propofol is a clinically common intravenous general anesthetic and is widely used for anesthesia induction, maintenance and intensive care unit (ICU) sedation in children. Hypoxemia is a common perioperative complication. In clinical work, we found that children with hypoxemia who received propofol anesthesia experienced significant postoperative cognitive changes. To explore the causes of this phenomenon, we conducted the study. In this study, our in vivo experiments found that immature rats exposed to hypoxia combined with propofol (HCWP) could develop cognitive impairment. We performed the RNA-seq analysis of its hippocampal tissues and found that autophagy and ferroptosis may play a role in our model. Next, we verified the participation of the two modes of death by detecting the expression of autophagy-related indexes Sequestosome 1 (SQSTM1) and Beclin1, and ferroptosis-related indicators Fe 2+ , reactive oxygen species (ROS) and glutathione peroxidase 4 (GPX4). Meanwhile, we found that ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, could improve cognitive impairment in immature rats caused by HCWP. In addition, we found that nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy, which acted as a key junction between autophagy and ferroptosis, was also involved. Finally, our in vitro experiments concluded that autophagy activation was an upstream factor in HCWP-induced hippocampus ferroptosis through the intervention of autophagy inhibitor 3-methyladenine (3-MA). Our study was expected to provide an attractive therapeutic target for cognitive impairment that occurred after HCWP exposures., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Ciprofol is a recently developed short-acting gamma-aminobutyric acid receptor agonist with a higher potency than that of propofol. As a new sedative drug, there are few clinical studies on ciprofol. We sought to examine the safety and efficacy of ciprofol use for general anesthesia in neurosurgical individuals undergoing neurosurgical surgery with intraoperative neurophysiological monitoring (IONM)., Patients and Methods: This single-center, non-inferiority, single-blind, randomized controlled trial was conducted from September 13, 2022 to September 22, 2023. 120 patients undergoing elective microvascular decompression surgery (MVD) with IONM were randomly assigned to receive either ciprofol or propofol. The primary outcome of this study was the amplitude of intraoperative compound muscle action potential decline, and the secondary outcome included the indexes related to neurophysiological monitoring and anesthesia outcomes., Results: The mean values of the primary outcome in the ciprofol group and the propofol group were 64.7±44.1 and 53.4±35.4, respectively. Furthermore, the 95% confidence interval of the difference was -25.78 to 3.12, with the upper limit of the difference being lower than the non-inferiority boundary of 6.6. Ciprofol could achieve non-inferior effectiveness in comparison with propofol in IONM of MVD. The result during anesthesia induction showed that the magnitude of the blood pressure drop and the incidence of injection pain in the ciprofol group were significantly lower than those in the propofol group (P<0.05). The sedative drug and norepinephrine consumption in the ciprofol group was significantly lower than that in the propofol group (P<0.05)., Conclusion: Ciprofol is not inferior to propofol in the effectiveness and safety of IONM and the surgical outcome. Concurrently, ciprofol is more conducive to reducing injection pain and improving hemodynamic stability, which may be more suitable for IONM-related surgery, and has a broad application prospect., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Zhu et al.)

Methaqualone, a quinazolinone marketed commercially as Quaalude, is a central nervous system depressant that was used clinically as a sedative-hypnotic, then became a notorious recreational drug in the 1960s-80s. Due to its high abuse potential, medical use of methaqualone was eventually prohibited, yet it persists as a globally abused substance. Methaqualone principally targets GABA A receptors, which are the major inhibitory neurotransmitter-gated ion channels in the brain. The restricted status and limited accessibility of methaqualone have contributed to its pharmacology being understudied. Here, we use cryo-EM to localize the GABA A receptor binding sites of methaqualone and its more potent derivative, PPTQ, to the same intersubunit transmembrane sites targeted by the general anesthetics propofol and etomidate. Both methaqualone and PPTQ insert more deeply into subunit interfaces than the previously-characterized modulators. Binding of quinazolinones to this site results in widening of the extracellular half of the ion-conducting pore, following a trend among positive allosteric modulators in destabilizing the hydrophobic activation gate in the pore as a mechanism for receptor potentiation. These insights shed light on the underexplored pharmacology of quinazolinones and further elucidate the molecular mechanisms of allosteric GABA A receptor modulation through transmembrane binding sites., (© 2024. The Author(s).)

Background: Laparoscopic partial hepatectomy inevitably decrease patient immune function. Propofol has been shown to have immunomodulatory effects but is associated with hemodynamic side effects. Despite studies showing a negligible impact of remimazolam tosylate on hemodynamics, it has not been reported for partial hepatectomy patients. Its influence on immune function also remains unexplored. This study sought to investigate the differences in immune function and intraoperative hemodynamics between patients who underwent laparoscopic partial hepatectomy with remimazolam tosylate and those who underwent laparoscopic partial hepatectomy with propofol., Methods: This was a single-center, randomized controlled trial involving 70 patients, who underwent elective laparoscopic partial hepatectomy. The patients were randomly divided into two groups: the remimazolam group (group R) and the propofol group (group P). In this study, the primary outcomes assessed included the patient's immune function and hemodynamic parameters, and the secondary outcomes encompassed the patient's liver function and adverse events., Results: Data from 64 patients (group R, n = 31; group P, n = 33) were analyzed. The differences in the percentages of CD3 + , CD4 + , CD8 + , and NK cells and the CD4 + /CD8 + ratio between the two groups were not statistically significant at 1 day or 3 days after surgery. Compared with those in group P, the MAP and HR at T2 and the MAP at T1 in group R were significantly increased(P < 0.05). The differences in HR and MAP at T0, T3, T4, T5, T6, and T7 and HR at T1 between the two groups were not statistically significant. There were no differences in liver function or adverse effects between the two groups, suggesting that remimazolam tosylate is a safe sedative drug(P > 0.05)., Conclusion: The effects of remimazolam tosylate on the immune function of patients after partial hepatectomy are comparable to those of propofol. Additionally, its minimal effect on hemodynamics significantly decreases the incidence of hypotension during anesthesia induction, thereby enhancing overall perioperative safety., Trial Registration: The trial was registered on May 9, 2022 in the Chinese Clinical Trial Registry, registration number ChiCTR2200059715 (09/05/2022)., (© 2024. The Author(s).)

Background: When inhalant anesthetic equipment is not available or during upper airway surgery, intravenous infusion of one or more drugs are commonly used to induce and/or maintain general anesthesia. Total intravenous anesthesia (TIVA) does not require endotracheal intubation, which may be more difficult to achieve in rabbits. A range of different injectable drug combinations have been used as continuous infusion rate in animals. Recently, a combination of ketamine and propofol (ketofol) has been used for TIVA in both human patients and animals. The purpose of this prospective, blinded, randomized, crossover study was to evaluate anesthetic and cardiopulmonary effects of ketofol total intravenous anesthesia (TIVA) in combination with constant rate infusion (CRI) of midazolam, fentanyl or dexmedetomidine in eight New Zealand White rabbits. Following IV induction with ketofol and endotracheal intubation, anesthesia was maintained with ketofol infusion in combination with CRIs of midazolam (loading dose [LD]: 0.3 mg/kg; CRI: 0.3 mg/kg/hr; KPM), fentanyl (LD: 6 µg/kg; CRI: 6 µg/kg/hr; KPF) or dexmedetomidine (LD: 3 µg/kg; CRI: 3 µg/kg/hr; KPD). Rabbits in the control treatment (KPS) were administered the same volume of saline for LD and CRI. Ketofol infusion rate (initially 0.6 mg kg - 1 minute - 1 [0.3 mg kg - 1 minute - 1 of each drug]) was adjusted to suppress the pedal withdrawal reflex. Ketofol dose and physiologic variables were recorded every 5 min., Results: Ketofol induction doses were 14.9 ± 1.8 (KPM), 15.0 ± 1.9 (KPF), 15.5 ± 2.4 (KPD) and 14.7 ± 3.4 (KPS) mg kg - 1 and did not differ among treatments (p > 0.05). Ketofol infusion rate decreased significantly in rabbits in treatments KPM and KPD as compared with saline. Ketofol maintenance dose in rabbits in treatments KPM (1.0 ± 0.1 mg/kg/min) and KPD (1.0 ± 0.1 mg/kg/min) was significantly lower as compared to KPS (1.3 ± 0.1 mg/kg/min) treatment (p < 0.05). Ketofol maintenance dose did not differ significantly between treatments KPF (1.1 ± 0.3 mg/kg/min) and KPS (1.3 ± 0.1 mg/kg/min). Cardiovascular variables remained at clinically acceptable values but ketofol infusion in combination with fentanyl CRI was associated with severe respiratory depression., Conclusions: At the studied doses, CRIs of midazolam and dexmedetomidine, but not fentanyl, produced ketofol-sparing effect in rabbits. Mechanical ventilation should be considered during ketofol anesthesia, particularly when fentanyl CRI is used., (© 2024. The Author(s).)

Background: Anesthetic drugs may alter exosomal microRNA (miRNA) contents and mediate cancer progression and tumor microenvironment remodeling. Our study aims to explore how the anesthetics (sevoflurane and propofol) impact the miRNA makeup within exosomes in hepatocellular carcinoma (HCC), alongside the interconnected signaling pathways linked to the tumor immune microenvironment., Methods: In this prospective study, we collected plasma exosomes from two groups of HCC patients (n = 5 each) treated with either propofol or sevoflurane, both before anesthesia and after hepatectomy. Exosomal miRNA profiles were assessed using next-generation sequencing (NGS). Furthermore, the expression data from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) was used to pinpoint the differentially expressed exosomal miRNAs (DEmiRNAs) attributed to the influence of propofol or sevoflurane in the context of HCC. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were used to dissect the signaling pathways and biological activities associated with the identified DEmiRNAs and their corresponding target genes., Results: A total of 35 distinct DEmiRNAs were exclusively regulated by either propofol (n = 9) or sevoflurane (n = 26). Through TCGA-LIHC database analysis, 8 DEmiRNAs were associated with HCC. These included propofol-triggered miR-452-5p and let-7c-5p, as well as sevoflurane-induced miR-24-1-5p, miR-122-5p, miR-200a-3p, miR-4686, miR-214-3p, and miR-511-5p. Analyses revealed that among these 8 DEmiRNAs, the upregulation of miR-24-1-5p consistently demonstrated a significant association with lower histological grades (p < 0.0001), early-stage tumors (p < 0.05) and higher survival (p = 0.029). Further analyses using GSEA and GSVA indicated that miR-24-1-5p, along with its target genes, were involved in governing the tumor immune microenvironment and potentially inhibiting tumor progression in HCC., Conclusions: This study provided bioinformatics evidence suggesting that sevoflurane-induced plasma exosomal miRNAs may have a potential impact on the immune microenvironment of HCC. These findings established a foundation for future research into mechanistic outcomes in cancer patients., (© 2024. The Author(s).)

States of consciousness are likely mediated by multiple parallel yet interacting cortico-subcortical recurrent networks. Although the mesocircuit model has implicated the pallidocortical circuit as one such network, this circuit has not been extensively evaluated to identify network-level electrophysiological changes related to loss of consciousness (LOC). We characterize changes in the mesocircuit in awake versus propofol-induced LOC in humans by directly simultaneously recording from sensorimotor cortices (S1/M1) and globus pallidus interna and externa (GPi/GPe) in 12 patients with Parkinson disease undergoing deep brain stimulator implantation. Propofol-induced LOC is associated with increases in local power up to 20 Hz in GPi, 35 Hz in GPe, and 100 Hz in S1/M1. LOC is likewise marked by increased pallidocortical alpha synchrony across all nodes, with increased alpha/low beta Granger causal (GC) flow from GPe to all other nodes. In contrast, LOC is associated with decreased network-wide beta coupling and beta GC from M1 to the rest of the network. Results implicate an important and possibly central role of GPe in mediating LOC-related increases in alpha power, supporting a significant role of the GPe in modulating cortico-subcortical circuits for consciousness. Simultaneous LOC-related suppression of beta synchrony highlights that distinct oscillatory frequencies act independently, conveying unique network activity., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

It is crucial to understand how anesthetics disrupt information transmission within the whole-brain network and its hub structure to gain insight into the network-level mechanisms underlying propofol-induced sedation. However, the influence of propofol on functional integration, segregation, and community structure of whole-brain networks were still unclear. We recruited 12 healthy subjects and acquired resting-state functional magnetic resonance imaging data during 5 different propofol-induced effect-site concentrations (CEs): 0, 0.5, 1.0, 1.5, and 2.0 μg/ml. We constructed whole-brain functional networks for each subject under different conditions and identify community structures. Subsequently, we calculated the global and local topological properties of whole-brain network to investigate the alterations in functional integration and segregation with deepening propofol sedation. Additionally, we assessed the alteration of key nodes within the whole-brain community structure at each effect-site concentrations level. We found that global participation was significantly increased at high effect-site concentrations, which was mediated by bilateral postcentral gyrus. Meanwhile, connector hubs appeared and were located in posterior cingulate cortex and precentral gyrus at high effect-site concentrations. Finally, nodal participation coefficients of connector hubs were closely associated to the level of sedation. These findings provide valuable insights into the relationship between increasing propofol dosage and enhanced functional interaction within the whole-brain networks., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The marbled crayfish ( Procambarus virginalis ) is a parthenogenetic invasive species across much of the world, and when found, euthanasia is often recommended to reduce spread to naïve ecosystems. Euthanasia recommendations in crustaceans includes a two-step method: first to produce nonresponsiveness and then to destroy central nervous tissue. Minimal data exist on adequate anesthetic or immobilization methods for crayfish. A population of 90 marbled crayfish was scheduled for euthanasia due to invasive species concerns. The population was divided into six treatment groups to evaluate whether immersion in emulsified isoflurane or propofol solutions could produce nonresponsiveness. Each group was exposed to one of six treatments for 1 h: isoflurane emulsified at 0.1%, 0.5%, 2%, 5%, and 15% or propofol at 10 mg/L and then increased to 100 mg/L. Crayfish from all treatment groups were moved to nonmedicated water after completion of 1 h and observed for an additional 4 h. All crayfish treated with isoflurane showed lack of a righting reflex at 5 min and loss of movement after 30 min. By 240 min (4 h), none of the crayfish from the isoflurane treatment groups regained movement. None of the crayfish in the propofol treatment achieved loss of reflexes or responsiveness, and all remained normal upon return to nonmedicated water. Isoflurane emulsified in water produces nonresponsiveness that is appropriate for the first step of euthanasia, while propofol was insufficient at these treatment doses.

Electroconvulsive shock (ECS) is utilized to treat depression but may cause learning/memory impairments, which may be ameliorated by anesthetics through the modulation of hippocampal synaptic plasticity. Given that synaptic plasticity is governed by aerobic glycolysis, it remains unclear whether anesthetics modulate aerobic glycolysis to enhance learning and memory function. Depression-like behavior in rats was induced by chronic mild unpredictable stress (CUMS), with anhedonia assessed via sucrose preference test (SPT). Depressive-like behaviors and spatial learning/memory were assessed with forced swim test (FST), open field test (OFT), and Morris water maze (MWM) test. Changes in aerobic glycolysis and synaptic plasticity in the hippocampal region of depressive-like rats post-ECS were documented using immunofluorescence analysis, Western blot, Lactate Assay Kit and transmission electron microscopy. Both the OFT and FST indicated that ECS was effective in alleviating depressive-like behaviors. The MWM test demonstrated that anesthetics were capable of attenuating ECS-induced learning and memory deficits. Immunofluorescence analysis, Western blot, Lactate Assay Kit and transmission electron microscopy revealed that the decline in learning and memory abilities in ECS-induced depressive-like rats was correlated with decreased aerobic glycolysis, and that the additional use of ciprofol or propofol ameliorated these alterations. Adding the glycolysis inhibitor 2-DG diminished the ameliorative effects of the anesthetic. No significant difference was observed between ciprofol and propofol in enhancing aerobic glycolysis in astrocytes and synaptic plasticity after ECS. These findings may contribute to understanding the mechanisms by which anesthetic drugs modulate learning and memory impairment after ECS in depressive-like behavior rats., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: The effect-site concentration (Ce) at loss of response (Ce-LOR) to propofol closely correlates both with Ce as electroencephalographic alpha power becomes highest (Ce-alpha) and with Ce at onset of burst suppression (BS) (Ce-OBS), when no opioids are administered. Co-administration of opioids dose-dependently decreases Ce-LOR. We investigated the influence of remifentanil on the relationship between these three Ces., Methods: After receiving approval from our local ethical committee, with written informed consent, we enrolled 90 participants (ASA-PS I or II) who were scheduled for elective surgery. Participants were randomly assigned to three groups: constant remifentanil Ce 0 ng/ml (Remi&#95;0); 1 ng/mL (Remi&#95;1); and 2 ng/mL (Remi&#95;2). We recorded both raw EEG and EEG-derived parameters on a computer. After reaching remifentanil equilibrium, we administered propofol using a target-controlled infusion pump such that propofol Ce increased to about 0.3 μg/mL/min. After determining Ce-LOR, we administered 0.6 mg/kg of rocuronium and started mask ventilation. The study protocol ended after observation of BS., Results: Three participants were excluded. Ce-LOR in each group (Remi&#95;0, Remi&#95;1, Remi&#95;2) was 2.00 ± 0.58 μg/mL, 1.43 ± 0.49 μg/mL, and 1.37 ± 0.42 μg/mL. Ce-alpha was 2.91 ± 0.63 μg/mL, 2.30 ± 0.41 μg/mL, and 2.12 ± 0.39 μg/mL. Ce-OBS was 3.80 ± 0.69 μg/mL, 3.25 ± 0.68 μg/mL, and 2.90 ± 0.57 μg/mL. In three other instances, Ce was decreased by remifentanil. Generalized linear model analysis revealed that remifentanil had no influence on the relationship between the three Ces., Conclusion: During propofol anesthesia, even low concentrations of remifentanil shifted concentration-related electroencephalographic changes., (© 2024. The Author(s) under exclusive licence to Japanese Society of Anesthesiologists.)

Cigarette smoke extract (CSE) is known as a significant contributor to chronic obstructive pulmonary disease (COPD). Propofol, an anesthetic agent, has been studied for its potential protective effects against lung damage. This study aimed to elucidate the protective mechanisms of propofol against CSE-induced damage in human bronchial epithelial 16HBE cells. In CSE-induced 16HBE cells treated by propofol with or without transfection of nuclear factor erythroid 2-related factor 2 (Nrf2) interference plasmids, CCK-8 assay and lactate dehydrogenase (LDH) assay evaluated cytotoxicity. TUNEL assay and Western blot appraised cell apoptosis. ELISA and relevant assay kits severally measured inflammatory and oxidative stress levels. DCFH-DA fluorescent probe detected intracellular reactive oxygen species (ROS) activity. Immunofluorescence staining and Western blot estimated pyroptosis. Also, Western blot analyzed the expression of Nrf2/NLR family pyrin domain containing 3 (NLRP3) signaling-related proteins. Propofol was found to enhance the viability, reduce LDH release, and alleviate the apoptosis, inflammatory response, oxidative stress and pyroptosis in CSE-induced 16HBE cells in a concentration-dependent manner. Meanwhile, propofol decreased NLRP3 expression while raised Nrf2 expression. Further, after Nrf2 was silenced, the impacts of propofol on Nrf2/NLRP3 signaling, LDH release, apoptosis, inflammatory response, oxidative stress and pyroptosis in CSE-exposed 16HBE cells were eliminated. Conclusively, propofol may exert protective effects against CSE-induced damage in 16HBE cells, partly through the modulation of the Nrf2/NLRP3 signaling pathway, suggesting a potential therapeutic role for propofol in CSE-induced bronchial epithelial cell damage., Competing Interests: Declaration of Competing Interest The authors have declared no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The thalamus system plays critical roles in the regulation of reversible unconsciousness induced by general anesthetics, especially the arousal stage of general anesthesia (GA). But the function of thalamus in GA-induced loss of consciousness (LOC) is little known. The thalamic reticular nucleus (TRN) is the only GABAergic neurons-composed nucleus in the thalamus, which is composed of parvalbumin (PV) and somatostatin (SST)-expressing GABAergic neurons. The anterior sector of TRN (aTRN) is indicated to participate in the induction of anesthesia, but the roles remain unclear. This study aimed to reveal the role of the aTRN in propofol and isoflurane anesthesia., Methods: We first set up c-Fos straining to monitor the activity variation of aTRN PV and aTRN SST neurons during propofol and isoflurane anesthesia. Subsequently, optogenetic tools were utilized to activate aTRN PV and aTRN SST neurons to elucidate the roles of aTRN PV and aTRN SST neurons in propofol and isoflurane anesthesia. Electroencephalogram (EEG) recordings and behavioral tests were recorded and analyzed. Lastly, chemogenetic activation of the aTRN PV neurons was applied to confirm the function of the aTRN neurons in propofol and isoflurane anesthesia., Results: c-Fos straining showed that both aTRN PV and aTRN SST neurons are activated during the LOC period of propofol and isoflurane anesthesia. Optogenetic activation of aTRN PV and aTRN SST neurons promoted isoflurane induction and delayed the recovery of consciousness (ROC) after propofol and isoflurane anesthesia, meanwhile chemogenetic activation of the aTRN PV neurons displayed the similar effects. Moreover, optogenetic and chemogenetic activation of the aTRN neurons resulted in the accumulated burst suppression ratio (BSR) during propofol and isoflurane GA, although they represented different effects on the power distribution of EEG frequency., Conclusion: Our findings reveal that the aTRN GABAergic neurons play a critical role in promoting the induction of propofol- and isoflurane-mediated GA., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Icaritin is a prenylflavonoid derivative of the genus Epimedium (Berberidaceae) and has a variety of pharmacological actions. Icaritin is approved by the National Medical Products Administration as an anticancer drug that exhibits efficacy and safety advantages in patients with hepatocellular carcinoma cells. This study aimed to evaluate the inhibitory effects of icaritin on UDP-glucuronosyltransferase (UGT) isoforms. 4-Methylumbelliferone (4-MU) was employed as a probe drug for all the tested UGT isoforms using in vitro human liver microsomes (HLM). The inhibition potentials of UGT1A1 and 1A9 in HLM were further tested by employing 17β-estradiol (E2) and propofol (PRO) as probe substrates, respectively. The results showed that icaritin inhibits UGT1A1, 1A3, 1A4, 1A7, 1A8, 1A10, 2B7, and 2B15. Furthermore, icaritin exhibited a mixed inhibition of UGT1A1, 1A3, and 1A9, and the inhibition kinetic parameters (K i ) were calculated to be 3.538, 2.117, and 0.306 (μM), respectively. The inhibition of human liver microsomal UGT1A1 and 1A9 both followed mixed mechanism, with K i values of 2.694 and 1.431 (μM). This study provides supporting information for understanding the drug-drug interaction (DDI) potential of the flavonoid icaritin and other UGT-metabolized drugs in clinical settings. In addition, the findings provide safety evidence for DDI when liver cancer patients receive a combination therapy including icaritin., (© 2024 John Wiley & Sons Ltd.)

Background: The use of anesthetics may result in depression of the hypoxic ventilatory response. Since there are no receptor-specific antagonists for most anesthetics, there is the need for agnostic respiratory stimulants that increase respiratory drive irrespective of its cause. The authors tested whether ENA-001, an agnostic respiratory stimulant that blocks carotid body BK-channels, could restore the hypoxic ventilatory response during propofol infusion. They hypothesize that ENA-001 is able to fully restore the hypoxic ventilatory response., Methods: In this randomized, double-blind crossover trial, 14 male and female healthy volunteers were randomized to receive placebo and low- and high-dose ENA-001 on three separate occasions. On each occasion, isohypercapnic hypoxic ventilatory responses were measured during a fixed sequence of placebo, followed by low- and high-dose propofol infusion. The authors conducted a population pharmacokinetic/pharmacodynamic analysis that included oxygen and carbon dioxide kinetics., Results: Twelve subjects completed the three sessions; no serious adverse events occurred. The propofol concentrations were 0.6 and 2.0 µg/ml at low and high dose, respectively. The ENA-001 concentrations were 0.6 and 1.0 µg/ml at low and high dose, respectively. The propofol concentration that reduced the hypoxic ventilatory response by 50% was 1.47 ± 0.20 µg/ml. The steady state ENA-001 concentration to increase the depressed ventilatory response by 50% was 0.51 ± 0.04 µg/ml. A concentration of 1 µg/ml ENA-001 was required for full reversal of the propofol effect at the propofol concentration that reduced the hypoxic ventilatory response by 50%., Conclusions: In this pilot study, the authors demonstrated that ENA-001 restored the hypoxic ventilatory response impaired by propofol. This finding is not only of clinical importance but also provides mechanistic insights into the peripheral stimulation of breathing with ENA-001 overcoming central depression by propofol., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Anesthesiologists.)

Background: Sleep disruption is a common occurrence during medical care and is detrimental to patient recovery. Long-term sedation in the critical care setting is a modifiable factor that affects sleep, but the impact of different sedative-hypnotics on sleep homeostasis is not clear., Methods: We conducted a systematic comparison of the effects of prolonged sedation (8 h) with i.v. and inhalational agents on sleep homeostasis. Adult Sprague-Dawley rats (n=10) received dexmedetomidine or midazolam on separate days. Another group (n=9) received propofol or sevoflurane on separate days. A third group (n=12) received coadministration of dexmedetomidine and sevoflurane. Wakefulness (wake), slow-wave sleep (SWS), and rapid eye movement (REM) sleep were quantified during the 48-h post-sedation period, during which we also assessed wake-associated neural dynamics using two electroencephalographic measures: theta-high gamma phase-amplitude coupling and high gamma weighted phase-lag index., Results: Dexmedetomidine-, midazolam-, or propofol-induced sedation increased wake and decreased SWS and REM sleep (P<0.0001) during the 48-h post-sedation period. Sevoflurane produced no change in SWS, decreased wake for 3 h, and increased REM sleep for 6 h (P<0.02) post-sedation. Coadministration of dexmedetomidine and sevoflurane induced no change in wake (P>0.05), increased SWS for 3 h, and decreased REM sleep for 9 h (P<0.02) post-sedation. Dexmedetomidine, midazolam, and coadministration of dexmedetomidine with sevoflurane reduced wake-associated phase-amplitude coupling (P≤0.01). All sedatives except sevoflurane decreased wake-associated high gamma weighted phase-lag index (P<0.01)., Conclusions: In contrast to i.v. drugs, prolonged sevoflurane sedation produced minimal changes in sleep homeostasis and neural dynamics. Further studies are warranted to assess inhalational agents for long-term sedation and sleep homeostasis., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Propofol is effective and used as a kind of routine anesthetics in procedure sedative anesthesia (PSA) for ureteroscopy. However, respiratory depression and unconscious physical activity always occur during propofol-based PSA, especially in elderly patients. Esketamine has sedative and analgesic effects but without risk of cardiorespiratory depression. The purpose of this study is to investigate whether esketamine can reduce the propofol median effective dose (ED 50 ) for successful ureteroscope insertion in elderly male patients., Materials and Methods: 49 elderly male patients undergoing elective rigid ureteroscopy were randomly divided into two groups: SK Group (0.25 mg/kg esketamine+propofol) and SF Group (0.1 µg/kg sufentanil+propofol). Patients in both two groups received propofol with initial bolus dose of 1.5 mg/kg after sufentanil or esketamine was administered intravenously. The effective dose of propofol was assessed by a modified Dixon's up-and-down method and then was adjusted with 0.1 mg/kg according to the previous patient response. Patients' response to ureteroscope insertion was classified as "movement" or "no movement". The primary outcome was the ED 50 of propofol for successful ureteroscope insertion with esketamine or sufentanil. The secondary outcomes were the induction time, adverse events such as hemodynamic changes, hypoxemia and body movement were also measured., Result: 49 patients were enrolled and completed this study. The ED 50 of propofol for successful ureteroscope insertion in SK Group was 1.356 ± 0.11 mg/kg, which was decreased compared with that in SF Group, 1.442 ± 0.08 mg/kg (P = 0.003). The induction time in SK Group was significantly shorter than in SF Group (P = 0.001). In SK Group, more stable hemodynamic variables were observed than in SF Group. The incidence of AEs between the two groups was not significantly different., Conclusion: The ED 50 of propofol with esketamine administration for ureteroscope insertion in elderly male patients is 1.356 ± 0.11 mg/kg, significantly decreased in comparsion with sufentanil., Trial Registration: Chinese Clinical Trial Registry, No: ChiCTR2300077170. Registered on 1 November 2023. Prospective registration. http://www.chictr.org.cn ., (© 2024. The Author(s).)

General anesthesia is widely applied in clinical practice. However, the precise mechanism of loss of consciousness induced by general anesthetics remains unknown. Here, we measured the dynamics of five neurotransmitters, including γ-aminobutyric acid, glutamate, norepinephrine, acetylcholine, and dopamine, in the medial prefrontal cortex and primary visual cortex of C57BL/6 mice through in vivo fiber photometry and genetically encoded neurotransmitter sensors under anesthesia to reveal the mechanism of general anesthesia from a neurotransmitter perspective. Results revealed that the concentrations of γ-aminobutyric acid, glutamate, norepinephrine, and acetylcholine increased in the cortex during propofol-induced loss of consciousness. Dopamine levels did not change following the hypnotic dose of propofol but increased significantly following surgical doses of propofol anesthesia. Notably, the concentrations of the five neurotransmitters generally decreased during sevoflurane-induced loss of consciousness. Furthermore, the neurotransmitter dynamic networks were not synchronized in the non-anesthesia groups but were highly synchronized in the anesthetic groups. These findings suggest that neurotransmitter dynamic network synchronization may cause anesthetic-induced loss of consciousness.

Introduction: When assessing the spatio-temporal distribution of electroencephalographic (EEG) activity, characteristic patterns have been identified for several anesthetic drugs in humans. A shift in EEG power from the occipital to the prefrontal regions has been widely observed during anesthesia induction. This has been called "anteriorization" and has been correlated with loss of consciousness in humans. The spatio-temporal distribution of EEG spectral power in pigs and its modulation by anesthetics have not been described previously. The aim of the present study was to analyze EEG power across an anterior-posterior axis in pigs receiving increasing doses of propofol to 1) characterize the region of highest EEG power during wakefulness, 2) depict its spatio-temporal modification during propofol infusion, and 3) determine the region demonstrating the most significant modulations across different doses administered., Materials and Methods: Six pigs with a body weight of 33.3 ± 3.6 kg and aged 11.3 ± 0.5 weeks were included in a prospective experimental study. Electroencephalographic activity was collected at the occipital, parietal and prefrontal regions at increasing doses of propofol (starting at 10 mg kg-1 h-1 and increasing it by 10 mg kg-1 h-1 every 15 minutes). The EEG power was assessed using a generalized linear mixed model in which propofol doses and regions were treated as fixed effects, whereas pig was used as a random effect. Pairwise comparisons of marginal linear predictions were used to assess the change in power when the specific propofol dose (or region) was considered., Results: During both wakefulness and propofol infusion, the highest EEG power was located in the prefrontal region (p<0.001). The EEG power, both total and for each frequency band, mostly followed the same pattern, increasing from awake until propofol 20 mg kg-1 h-1 and then decreasing at propofol 30 mg kg-1 h-1. The region showing the strongest differences in EEG power across propofol doses was the prefrontal., Conclusion: In juvenile pigs receiving increasing doses of propofol, the prefrontal region showed the highest EEG power both during wakefulness and propofol administration and was the area in which the largest frequency-band specific variations were observed across different anesthetic doses. The assessment of the spectral EEG activity at this region could be favorable to distinguish DoA levels in pigs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Mirra et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The exact mechanisms and the neural circuits involved in anesthesia induced unconsciousness are still not fully understood. To elucidate them valid animal models are necessary. Since the most commonly used species in neuroscience are mice, we established a murine model for commonly used anesthetics/sedatives and evaluated the epidural electroencephalographic (EEG) patterns during slow anesthesia induction and emergence. Forty-four mice underwent surgery in which we inserted a central venous catheter and implanted nine intracranial electrodes above the prefrontal, motor, sensory, and visual cortex. After at least one week of recovery, mice were anesthetized either by inhalational sevoflurane or intravenous propofol, ketamine, or dexmedetomidine. We evaluated the loss and return of righting reflex (LORR/RORR) and recorded the electrocorticogram. For spectral analysis we focused on the prefrontal and visual cortex. In addition to analyzing the power spectral density at specific time points we evaluated the changes in the spectral power distribution longitudinally. The median time to LORR after start anesthesia ranged from 1080 [1st quartile: 960; 3rd quartile: 1080]s under sevoflurane anesthesia to 1541 [1455; 1890]s with ketamine. Around LORR sevoflurane as well as propofol induced a decrease in the theta/alpha band and an increase in the beta/gamma band. Dexmedetomidine infusion resulted in a shift towards lower frequencies with an increase in the delta range. Ketamine induced stronger activity in the higher frequencies. Our results showed substance-specific changes in EEG patterns during slow anesthesia induction. These patterns were partially identical to previous observations in humans, but also included significant differences, especially in the low frequencies. Our study emphasizes strengths and limitations of murine models in neuroscience and provides an important basis for future studies investigating complex neurophysiological mechanisms., (© 2024. The Author(s).)

Objective: We compared the effective networks derived from Single Pulse Electrical Stimulation (SPES) in intracranial electrocorticography (ECoG) of awake epilepsy patients and while under general propofol-anesthesia to investigate the effect of propofol on these brain networks., Methods: We included nine patients who underwent ECoG for epilepsy surgery evaluation. We performed SPES when the patient was awake (SPES-clinical) and repeated this under propofol-anesthesia during the surgery in which the ECoG grids were removed (SPES-propofol). We detected the cortico-cortical evoked potentials (CCEPs) with an automatic detector. We constructed two effective networks derived from SPES-clinical and SPES-propofol. We compared three network measures (indegree, outdegree and betweenness centrality), the N1-peak-latency and amplitude of CCEPs between the two effective networks., Results: Fewer CCEPs were observed during SPES-propofol (median: 6.0, range: 0-29) compared to SPES-clinical (median: 10.0, range: 0-36). We found a significant correlation for the indegree, outdegree and betweenness centrality between SPES-clinical and SPES-propofol (respectively r s  = 0.77, r s  = 0.70, r s  = 0.55, p < 0.001). The median N1-peak-latency increased from 22.0 ms during SPES-clinical to 26.4 ms during SPES-propofol., Conclusions: Our findings suggest that the number of effective network connections decreases, but network measures are only marginally affected., Significance: The primary network topology is preserved under propofol., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate cardiovascular effects of oral tasipimidine on propofol-isoflurane anaesthesia with or without methadone and dexmedetomidine at equianaesthetic levels., Study Design: Prospective, placebo-controlled, blinded, experimental trial., Animals: A group of seven adult Beagle dogs weighing (mean ± standard deviation) 12.4 ± 2.6 kg and a mean age of 20.6 ± 1 months., Methods: The dogs underwent four treatments 60 minutes before induction of anaesthesia with propofol. PP: placebo orally and placebo (NaCl 0.9%) intravenously (IV); TP: tasipimidine 30 μg kg -1 orally and placebo IV; TMP: tasipimidine 30 μg kg -1 orally and methadone 0.2 mg kg -1 IV; and TMPD: tasipimidine 30 μg kg -1 orally with methadone 0.2 mg kg -1 and dexmedetomidine 1 μg kg -1 IV followed by 1 μg kg -1 hour -1 . Isoflurane in oxygen was maintained for 120 minutes at 1.2 individual minimum alveolar concentration preventing motor movement. Cardiac output (CO), tissue blood flow (tbf), tissue oxygen saturation (stO 2 ) and relative haemoglobin content were determined. Arterial and mixed venous blood gases, arterial and pulmonary artery pressures and heart rate (HR) were measured at baseline; 60 minutes after oral premedication; 5 minutes after IV premedication; 15, 30, 60, 90 and 120 minutes after propofol injection; and 30 minutes after switching the vaporiser off. Data were analysed by two-way anova for repeated measures; p < 0.05., Results: Tasipimidine induced a significant 20-30% reduction in HR and CO with decreases in MAP (10-15%), tbf (40%) and stO 2 (43%). Blood pressure and oxygenation variables were mainly influenced by propofol-isoflurane-oxygen anaesthesia, preceded by short-lived alterations related to IV methadone and dexmedetomidine., Conclusions and Clinical Relevance: Tasipimidine induced mild to moderate cardiovascular depression. It can be incorporated into a common anaesthetic protocol without detrimental effects in healthy dogs, when anaesthetics are administered to effect and cardiorespiratory function is monitored., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Remifentanil may have a dose-dependent haemodynamic effect during the induction of general anaesthesia combined with propofol. Our objective was to investigate whether systolic arterial blood pressure (SAP) was reduced to a greater extent when the remifentanil dose was increased., Methods: This randomised, double-blind, dose-controlled study was conducted at the Day Surgery Unit of Haugesund Hospital, Norway. Ninety-nine healthy women scheduled for gynaecological surgery were randomly allocated in a 1:1:1 ratio to receive remifentanil induction with a low, medium or high dose corresponding to maximum effect-site concentrations (Ce) of 2, 4 and 8 ng/mL. The induction dose of propofol was 1.8 mg/kg, with a Ce of 2.9 μg/mL. Anaesthesia was induced using target-controlled infusion. After 150 s of sedation, a bolus of remifentanil and propofol was administered. Baseline was defined as 55-5 s before the bolus dose, and the total observation time was 450 s. We used beat-to-beat haemodynamic monitoring with LiDCOplus. The primary outcome variable was the maximum decrease in SAP within 5 min after bolus administration of remifentanil and propofol. Absolute and relative changes from baseline to minimal values and the area under the curve (AUC) were used as effect measures. Comparisons of groups were performed using analysis of variance (ANOVA)., Results: Median remifentanil doses were 0.75, 1.5 and 3.0 μg/kg in the low-, medium- and high-dose groups, respectively. The absolute changes (mean ± standard deviation) in SAP in the low-, medium- and high-dose groups of remifentanil were -39 ± 9.6 versus -43 ± 9.1, and -41 ± 10 mmHg, respectively. No difference (95% confidence interval) in the absolute change in SAP was observed between the groups (ANOVA, p = .29); medium versus low dose 3.7 (-2.0, 9.4) mmHg, and high versus medium dose -2.2 (-8.0; 3.5) mmHg. The relative changes from baseline to minimum SAP values were -30% versus -32% versus -32% (p = .52). The between-group differences in the AUC were not statistically significant. Relative changes in heart rate (-20% vs. -21% vs. -21%), stroke volume (-19% vs. -16% vs. -16%), cardiac output (-32% vs. -32% vs. -32%), systemic vascular resistance (-24% vs. -27% vs. -28%), and AUC were not statistically significant., Conclusion: This trial demonstrated major haemodynamic changes during the induction of anaesthesia with remifentanil and propofol. However, we did not observe any statistically significant differences between low, medium or high doses of remifentanil when using continuous invasive high-accuracy beat-to-beat monitoring., (© 2024 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Objective: This study aimed to explore the effects of sedative doses of propofol and isoflurane on microcirculation in septic mice compared to controls. Isoflurane, known for its potential as a sedation drug in bedside applications, lacks clarity regarding its impact on the microcirculation system. The hypothesis was that propofol would exert a more pronounced influence on the microvascular flow index, particularly amplified in septic conditions., Material and Methods: Randomized study was conducted from December 2020 to October 2021 involved 60 BALB/c mice, with 52 mice analyzed. Dorsal skinfold chambers were implanted, followed by intraperitoneal injections of either sterile 0.9 % saline or lipopolysaccharide for the control and sepsis groups, respectively. Both groups received propofol or isoflurane treatment for 120 min. Microcirculatory parameters were obtained via incident dark-field microscopy videos, along with the mean blood pressure and heart rate at three time points: before sedation (T0), 30 min after sedation (T30), and 120 min after sedation (T120). Endothelial glycocalyx thickness and syndecan-1 concentration were also analyzed., Results: In healthy controls, both anesthetics reduced blood pressure. However, propofol maintained microvascular flow, differing significantly from isoflurane at T120 (propofol, 2.8 ± 0.3 vs. isoflurane, 1.6 ± 0.9; P < 0.001). In the sepsis group, a similar pattern occurred at T120 without statistical significance (propofol, 1.8 ± 1.1 vs. isoflurane, 1.2 ± 0.7; P = 0.023). Syndecan-1 levels did not differ between agents, but glycocalyx thickness index was significantly lower in the isoflurane-sepsis group than propofol (P = 0.001)., Conclusions: Propofol potentially offers protective action against microvascular flow deterioration compared to isoflurane, observed in control mice. Furthermore, a lower degree of sepsis-induced glycocalyx degradation was evident with propofol compared to isoflurane., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Addictive properties of propofol have been demonstrated in both humans and animals. The nucleus accumbens (NAc) shell (NAsh) in the brain, along with the interactions between N-methyl-D-aspartate receptor (NMDAR) and the dopamine D1 receptor (D1R), as well as their downstream ERK/CREB signalling pathway in the NAc, are integral in regulating reward-seeking behaviour. Nevertheless, it remains unclear whether NMDARs and the NMDAR-D1R/ERK/CREB signalling pathway in the NAsh are involved in mediating propofol addiction. To investigate it, we conducted experiments with adult male Sprague-Dawley rats to establish a model of propofol self-administration behaviour. Subsequently, we microinjected D-AP5 (a competitive antagonist of NMDARs, 1.0-4.0 μg/0.3 μL/site) or vehicle into bilateral NAsh in rats that had previously self-administered propofol to examine the impact of NMDARs within the NAsh on propofol self-administration behaviour. Additionally, we examined the protein expressions of NR2A and NR2B subunits, and the D1R/ERK/CREB signalling pathways within the NAc. The results revealed that propofol administration behaviour was enhanced by D-AP5 pretreatment in NAsh, accompanied by elevated expressions of phosphorylation of NR2A (Tyr1246) and NR2B (Tyr1472) subunits. There were statistically significant increases in the expressions of D1Rs, as well as in the phosphorylated ERK1/2 (p-ERK1/2) and CREB (p-CREB). This evidence substantiates a pivotal role of NMDARs in the NAsh, with a particular emphasis on the NR2A and NR2B subunits, in mediating propofol self-administration behaviour. Furthermore, it suggests that this central reward processing mechanism may operate through the NMDAR-D1R/ERK/CREB signal transduction pathway., (© 2024 The Author(s). Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Objective: To evaluate the effect of oral tasipimidine on dog handling, ease of catheter placement and propofol and isoflurane requirements for anaesthesia., Study Design: Placebo-controlled, randomized, blinded, experimental trial., Animals: A group of seven adult Beagle dogs weighing (mean ± standard deviation) 13.1 ± 2.7 kg with a mean age of 18.6 ± 1 months., Methods: The dogs underwent four treatments before induction of anaesthesia with propofol. PP: placebo orally (PO) 60 minutes before induction of anaesthesia followed by placebo (NaCl 0.9%) intravenously (IV). TP: tasipimidine 30 μg kg -1 (PO) 60 minutes before induction of anaesthesia followed by placebo (NaCl 0.9%) IV. TMP: tasipimidine 30 μg kg -1 PO 60 minutes before induction of anaesthesia followed by methadone 0.2 mg kg -1 IV. TMPD: tasipimidine 30 μg kg -1 PO 60 minutes before induction of anaesthesia followed by methadone 0.2 mg kg -1 and dexmedetomidine 1 μg kg -1 IV followed by a dexmedetomidine constant rate infusion of 1 μg kg -1 hour -1 . Sedation, response to catheter placement, intubation quality, time to loss of consciousness, time to intubation, required dose of propofol and minimum alveolar isoflurane concentration preventing motor movement (MAC NM ) were determined. A mixed-model analysis or the Friedman and Mann-Whitney test were used; p-value < 0.05., Results: Response to catheter placement did not differ between treatments. Tasipimidine alone reduced the propofol dose by 30%. Addition of methadone or methadone and dexmedetomidine reduced the propofol dose by 48% and 50%, respectively. Isoflurane MAC NM was reduced by 19% in tasipimidine-medicated dogs, whereas in combination with methadone or methadone and dexmedetomidine, isoflurane MAC NM was reduced by 35%., Conclusions and Clinical Relevance: An anxiolytic dose of tasipimidine induced mild signs of sedation in dogs and reduced propofol and isoflurane requirements to induce and maintain anaesthesia, which needs to be considered in an anaesthetic plan., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Propofol, a commonly used intravenous anesthetic, has demonstrated potential in protecting against myocardial ischemia/reperfusion injury (MIRI) based on preclinical animal studies. However, the clinical benefits of propofol in this context are subject to debate. We conducted a systematic search across eight databases to identify all relevant animal studies investigating the preventive effects of propofol on MIRI until October 30, 2023. We assessed the methodological quality of the included studies using SYRCLE's bias risk tool. Statistical analysis was performed using STATA 15.1. The primary outcome measures analyzed in this study were myocardial infarct size (IS) and myocardial injury biomarkers. This study presents a comprehensive analysis of 48 relevant animal studies investigating propofol's preventive effects on MIRI. Propofol administration demonstrated a reduction in myocardial IS and decreased levels of myocardial injury biomarkers (CK-MB, LDH, cTnI). Moreover, propofol improved myocardial function parameters (+dp/dtmax, -dP/dtmax, LVEF, LVFS), exhibited favorable effects on inflammatory markers (IL-6, TNF-α) and oxidative stress markers (SOD, MDA), and reduced myocardial cell apoptotic index (AI). These findings suggest propofol exerts cardioprotective effects by reducing myocardial injury, decreasing infarct size, and improving heart function. However, the absence of animal models that accurately represent comorbidities such as aging and hypertension, as well as inconsistent administration methods that align with clinical practice, may hinder its clinical translation. Further robust investigations are required to validate these findings, elucidate the underlying mechanisms of propofol, and facilitate its potential translation into clinical practice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: Cardiac surgery with cardiopulmonary bypass and cardioplegic arrest is known to be responsible for ischaemia and reperfusion organ injury. In a previous study, ProMPT, in patients undergoing coronary artery bypass or aortic valve surgery we demonstrated improved cardiac protection when supplementing the cardioplegia solution with propofol (6 mcg/ml). The aim of the ProMPT2 study is to determine whether higher levels of propofol added to the cardioplegia could result in increased cardiac protection., Methods and Analysis: The ProMPT2 study is a multi-centre, parallel, three-group, randomised controlled trial in adults undergoing non-emergency isolated coronary artery bypass graft surgery with cardiopulmonary bypass. A total of 240 patients will be randomised in a 1:1:1 ratio to receive either cardioplegia supplementation with high dose of propofol (12 mcg/ml), low dose of propofol (6 mcg/ml) or placebo (saline). The primary outcome is myocardial injury, assessed by serial measurements of myocardial troponin T up to 48 hours after surgery. Secondary outcomes include biomarkers of renal function (creatinine) and metabolism (lactate)., Ethics and Dissemination: The trial received research ethics approval from South Central - Berkshire B Research Ethics Committee and Medicines and Healthcare products Regulatory Agency in September 2018. Any findings will be shared though peer-reviewed publications and presented at international and national meetings. Participants will be informed of results through patient organisations and newsletters., Trial Registration: ISRCTN15255199. Registered in March 2019., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CE declares; grants or contracts from British Heart Foundation chair, programme grant and PhD scholarship, Rosetrees Trust, MEDIRAD & Covirna (EU grants); participation on a Data Safety Monitoring Board or advisory board for Diabetes UK and Scientific Research Advisory Group (SRAG).

Background/aim: Chronic cerebral hypoxia often leads to brain damage and inflammation. Propofol is suggested to have neuroprotective effects under anaesthesia., Materials and Methods: This study used rat models with carotid artery coarctation or closure. Four groups of rats were compared: a control group, a propofol-treated group, a group with bilateral common carotid artery blockage (BCAO), and a BCAO group treated with propofol post-surgery., Results: The Morris water maze test indicated cognitive impairment in BCAO rats, which also showed hippocampal structure changes, oxidative stress markers alteration, and reduced Klotho expression. Propofol treatment post-BCAO surgery improved these outcomes, suggesting its potential in mitigating chronic cerebral hypoxia effects., Conclusion: Propofol may increase klotho levels and reduce apoptosis and inflammation linked to oxidative stress in cognitively impaired mice., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Anesthesia techniques and drug selection may influence tumor recurrence and metastasis. Neutrophil extracellular trapping (NETosis), an immunological process, has been linked to an increased susceptibility to metastasis in individuals with tumors. Furthermore, recurrence may be associated with vascular endothelial growth factor A (VEGF-A), a mediator of angiogenesis. This study investigates the impact of lidocaine (combined with sevoflurane or propofol anesthesia ) during breast cancer surgery inhibits the expression of biomarkers associated with metastasis and recurrence (specifically H3Cit, NE, MPO, MMP-9 and VEGF-A)., Methods: We randomly assigned 120 women undergoing primary or invasive breast tumor resection to receive one of four anesthetics: sevoflurane (S), sevoflurane plus i.v. lidocaine (SL), propofol (P), and propofol plus i.v. lidocaine (PL). Blood samples were collected before induction and 3 h after the operation. Biomarkers associated with NETosis (citrullinated histone H3 [H3Cit], myeloperoxidase [MPO], and neutrophil elastase [NE]) and angiogenesis were quantified using enzyme-linked immunosorbent assays., Results: Patient and breast tumor characteristics, along with perioperative management, did not differ between study groups. In intra-group comparisons, S and P groups demonstrated a statistically significant increase in post-operative MPO (S group: 10.39[6.89-17.22] vs. 14.31[8.55-20.87] ng ml-1, P = 0.032; P group: 9.45[6.73-17.37] vs. 14.34[9.87-19.75] ng ml-1, P = 0.035)and NE(S group: 182.70[85.66-285.85] vs. 226.20[91.85-391.65] ng ml-1, P = 0.045; P group: 154.22[97.31-325.30] vs. 308.66[132.36-483.57] ng ml-1, P = 0.037) concentrations compared to pre-operative measurements, whereas SL and PL groups did not display a similar increase. H3Cit, MMP-9, and VEGF-A concentrations were not significantly influenced by the anesthesia techniques and drugs., Conclusions: Regardless of the specific technique employed for general anesthesia, there was no increase in the postoperative serum concentrations of MPO and NE after perioperative lidocaine infusion compared to preoperative serum concentrations. This supports the hypothesis that intravenous lidocaine during cancer surgery aimed at achieving a cure may potentially decrease the likelihood of recurrence. Further interpretation and discussion of clinical implications are warranted, emphasizing the significance of these findings in the context of cancer surgery and recurrence prevention., Clinical Trial Registration: ChiCTR2300068563., (© 2024. The Author(s).)