Propofol Exposure Research Articles

Propofol-induced transient arginine vasopressin deficiency.

We describe and characterise the case of a 26-year-old female undergoing surgery for a right-sided sinonasal alveolar rhabdomyosarcoma who developed profound, transient arginine vasopressin deficiency (AVP-D, formerly central diabetes insipidus (DI)) associated with anaesthesia. In this case report, we characterise the development of AVP-D with serial copeptin and paired urine and serum osmolality measurements. Based on the anaesthetic agent's profile and the literature, we attribute this presentation to propofol exposure. We present a description of the literature on anaesthesia-associated DI as well as poignant learning points. Exposure to anaesthetic agents is a rare cause of self-limited but sudden and profound arginine vasopressin deficiency (AVP-D) or arginine vasopressin resistance (AVP-R). Sevoflurane has been associated with AVP-R and propofol with AVP-D, although the responsible agent may be difficult to identify. Differentiation of AVP-R and AVP-D can be made based on copeptin concentration, where available, or clinical response to desmopressin. Whilst the patient is anaesthetised, intravenous fluid replacement should be targeted to match urine output until the patient is able to drink to thirst. This should be clearly communicated to staff and the patient. Rapid resolution of AVP-R/AVP-D when the causative agent is discontinued has been reported with both propofol and sevoflurane. As such, switching the agent used to maintain anaesthesia may terminate increased urine output in a clinically meaningful timeframe.

The lateral septum partakes the regulation of propofol-induced anxiety-like behavior

Repeated exposure to propofol during early brain development is associated with anxiety disorders in adulthood, yet the mechanisms underlying propofol-induced susceptibility to anxiety disorders remain elusive. The lateral septum (LS), primarily composed of γ-aminobutyric acidergic (GABAergic) neurons, serves as a key brain region in the regulation of anxiety. However, it remains unclear whether LS GABAergic neurons are implicated in propofol-induced anxiety. Therefore, we conducted c-Fos immunostaining of whole-brain slices from mice exposed to propofol during early life. Our findings indicate that propofol exposure activates GABAergic neurons in the LS. Selective activation of LS GABAergic neurons resulted in increased anxiety-like behavior, while selective inhibition of these neurons reduced such behaviors. These results suggest that the LS is a critical brain region involved in propofol-induced anxiety. Furthermore, we investigated the molecular mechanism of propofol-induced anxiety in the LS. Microglia activation underlies the development of anxiety. Immunofluorescence staining and Western blot analysis of LS revealed activated microglia and significantly elevated levels of phospho–NF–κB p65 protein. Additionally, a decrease in the number of neuronal spines was observed. Our study highlights the crucial role of the LS in the development of anxiety-like behavior in adulthood following childhood propofol exposure, accompanied by the activation of inflammatory pathways.

Impact of Propofol Exposure on Neurocognitive Outcomes in Children With High-Risk B ALL: A Children's Oncology Group Study.

Many children treated for ALL develop long-term neurocognitive impairments. Increased risk of these impairments is associated with treatment and demographic factors. Exposure to anesthesia is an additional possible risk factor. This study evaluated the impact of cumulative exposure to anesthesia on neurocognitive outcomes among a multicenter cohort of children with ALL. This study was embedded in AALL1131, a Children's Oncology Group phase III trial for patients with high-risk B-ALL. In consenting patients age 6-12 years, prospective uniform assessments of neurocognitive function were performed during and at 1 year after completion of therapy. Exposure to all episodes of anesthetic agents was abstracted. Multivariable linear regression models determined associations of cumulative anesthetic agents with the primary neurocognitive outcome reaction time/processing speed (age-normed) at 1 year off therapy, adjusting for baseline neurocognitive score, age, sex, race/ethnicity, insurance status (as a proxy for socioeconomic status), and leukemia risk group. One hundred and forty-four children, 76 (52.8%) males, mean age of 9.1 (min-max, 6.0-12.0) years at diagnosis, underwent a median of 27 anesthetic episodes (min-max, 1-37). Almost all patients were exposed to propofol (140/144, 97.2%), with a mean cumulative dose of 112.3 mg/kg. One year after therapy, the proportion of children with impairment (Z-score ≤-1.5) was significantly higher compared with a normative sample. In covariate-adjusted multivariable analysis, cumulative exposure to propofol was associated with a 0.05 Z-score decrease in reaction time/processing speed per each 10 mg/kg propofol exposure (P = .03). In a multicenter and uniformly treated cohort of children with B-ALL, cumulative exposure to propofol was an independent risk factor for impairment in reaction time/processing speed 1 year after therapy. Anesthesia exposure is a modifiable risk, and opportunities to minimize propofol use should be considered.

Restrictive use of Restraints and Delirium Duration in the Intensive Care Unit (R2D2-ICU): protocol for a French multicentre parallel-group open-label randomised controlled trial

IntroductionPhysical restraint (PR) is prescribed in patients receiving invasive mechanical ventilation in the intensive care unit (ICU) to avoid unplanned removal of medical devices. However, it is associated with an...

Effects of propofol on myelin basic protein expression in zebrafish at different developmental stages

To observe the effect of propofol on the expression of myelin basic protein (MBP) in developing zebrafish and explore the possible mechanisms. A total of 180 zebrafish embryos at 6-48 h post-fertilization were randomly allocated into 3 equal groups and raised in fresh water (control group), water containing dimethyl sulfoxide (DMSO group) and water containing 30 μg/mL propofol (propofol group). On 3, 4, 5, 6, 7, 10 d post-fertilization, the juvenile fish were collected for detection of mRNA and protein expressions of MBP using RT-qPCR and Western blotting. TUNEL assay and immunofluorescence assay were used to detect apoptosis of the oligodendrocytes of the fish at 3 d post-fertilization; RT-qPCR and Western blotting were performed to detect the expressions of apoptosis-related factors caspase-8, caspase-9 and caspase-3. Compared with the control group, the fish with propofol exposure showed significantly decreased mRNA and protein expression of MBP at 3-7 d post-fertilization (P<0.05) with increased apoptosis of the oligodendrocytes and upregulated expressions of caspase-8, caspase-9 and caspase-3 at both the mRNA and protein levels. Propofol persistently inhibits MBP expression in developing zebrafish within a short term possibly by mediating apoptosis of the oligodendrocytes.

Electroacupuncture Pretreatment Attenuates Learning Memory Impairment Induced by Repeated Propofol Exposure and Modulates Hippocampal Synaptic Plasticity in Rats.

Recurrent propofol anesthesia in the peak of neurodevelopment may lead to learning-memory decline. This study aimed to examine the efficacy of electroacupuncture pretreatment in ameliorating the aforementioned learning memory deficits and to explore its underlying mechanisms in a rat model of repeated propofol exposure. 10-day-old Sprague Dawley rats were randomly assigned to five groups: the control, fat emulsion, propofol, electroacupuncture pretreatment and electroacupuncture pretreatment combined with propofol groups. The electroacupuncture pretreatment involved three consecutive daily sessions, while propofol was received intraperitoneally once daily for five days. Following the modeling period, the rats' learning-memory performance was assessed using the New Novel Arm Y-maze, New Object Recognition, and Morris Water Maze. The Nissl staining method was used to observe the development of hippocampal neurons, while Golgi staining was employed to observe hippocampal synaptic development. The electroacupuncture pretreatment significantly attenuated the learning and memory impairment induced by recurring propofol exposure in rats. Additionally, it facilitated the development of hippocampal neurons and synaptic plasticity in the hippocampus. Immunofluorescence and Western Blot analyses were conducted to detect the expression of proteins related to apoptosis, learning memory, and synaptic plasticity. In the propofol group, the pro-apoptotic factors Caspase-3 and Bax was up-regulated, while the anti-apoptotic factor Bcl-2 was down-regulated, as compared to the blank group. Additionally, the phosphorylated cAMP-response element binding protein (pCREB), brain-derived neurotrophic factor (BDNF), synaptophysin, and growth associated protein-43 (GAP-43) was significantly decreased. In contrast, the electroacupuncture pretreatment combined with propofol group exhibited decreased the Caspase-3 and Bax and increased the Bcl-2, as compared to the propofol group, meanwhile, the pCREB, BDNF, Synaptophysin and GAP-43 was increased. Our findings indicate that electroacupuncture pretreatment can alleviate the learning and memory impairment induced by recurring propofol exposure in rats. This is achieved by enhancing hippocampal synaptic plasticity, activating the pCREB/BDNF pathway and inhibiting neuronal apoptosis.

Toll-Like Receptor 4 Deficiency Ameliorates Propofol-Induced Impairments of Cognitive Function and Synaptic Plasticity in Young Mice.

Propofol is one of the most used intravenous anesthetic agents, which is widely used in clinical anesthesia induction and maintenance of pediatric patients. Exposure of the developing brain to propofol has been reported to lead to adverse brain changes, which in turn can induce persistent behavioral abnormalities in adulthood. However, the mechanisms by which propofol exposure in the developing brain induces cognitive impairment remain unclear. Here we report that repeated propofol exposure during the second postnatal week impairs spatial learning and memory in young mice. The reduced excitatory synaptic function and synaptogenesis in hippocampal CA1 neurons underlie this cognitive impairment. Propofol exposure specifically activates Toll-like receptor 4 (TLR4)-myeloid differentiation primary response protein 88 (MyD88)-NF-κB signaling pathway. TLR4 deficiency recues propofol exposure-induced synaptic function and cognitive deficits in young mice. Thus, we provide evidence that the activation of the TLR4-mediated pathway by propofol exposure may serve as a crucial trigger for the cognitive impairment in young adulthood caused by repeated exposure to propofol in the developing brain.

Propofol elicits apoptosis and attenuates cell growth in esophageal cancer cell lines.

Propofol is a pharmaceutical agent commonly used as an intravenous anesthetic in surgical treatments and a sedative in intensive care. However, it is largely unknown how exposure to propofol affects the proliferation, invasion, and apoptosis of neoplastic cells in esophageal cancer. In this study, we sought to elucidate the impact of propofol exposure on the growth properties of human esophageal cancer cell lines in vitro. We treated two human esophageal cancer cell lines, KYSE30 and KYSE960, with up to 10 µg/mL of propofol for 12-36 h. The treated cells were then analyzed by cell proliferation assay, Matrigel invasion assay, quantification of caspase-3/7 and -9 activities, and cell staining with Annexin V and 7-aminoactinomycin D to detect early apoptosis and cell death, respectively, via flow cytometry. We found that 3-5 µg/mL propofol reduced the growth and Matrigel invasion of both cell lines in a dose-dependent manner. Executioner caspase-3/7, but not caspase-9 involved in intrinsic apoptosis pathway, was activated by cell exposure to 3-5 µg/mL propofol. In addition, 3-5 µg/mL propofol augmented early apoptosis in both cell lines and increased cell death in the KYSE30 cell line. In summary, exposure to propofol, at concentrations up to 5 µg/mL, led to the reduction of cell growth and Matrigel invasion, as well as the augmentation of apoptosis in esophageal cancer cell lines. These data will help define a methodology to safely utilize propofol, a common general anesthetic and sedative, with esophageal cancer patients.

Multidisciplinary Approach to Sedation and Early Mobility of Intubated Critically Ill Neurologic Patients Improves Mobility at Discharge.

Over-sedation may confound neurologic assessment in critically ill neurologic patients and prolong duration of mechanical ventilation (MV). Decreased sedative use may facilitate early functional independence when combined with early mobility. The objective of this study was to evaluate the impact of a stepwise, multidisciplinary analgesia-first sedation pathway and early mobility protocol on medication use and mobility in the neuroscience intensive care unit (ICU). We performed a single-center prospective cohort study with adult patients admitted to a neuroscience ICU between March and June 2016-2018 who required MV for greater than 48 hours. Patients were included from three separate phases of the study: Phase I - historical controls (2016); Phase II - analgesia-first pathway (2017); Phase III - early mobility protocol (2018). Primary outcomes included propofol requirements during MV, total rehabilitation therapy provided, and functional mobility during ICU admission. 156 patients were included in the analysis. Decreasing propofol exposure was observed during Phase I, II, and III (median 2243.7 mg/day vs 2065.6 mg/day vs 1360.8 mg/day, respectively; P = .04 between Phase I and III). Early mobility was provided in 59.7%, 40%, and 81.6% of patients while admitted to the ICU in Phase I, II, and III, respectively (P < .01). An increased proportion of patients in Phase III were walking or ambulating at ICU discharge (26.7%; 8/30) compared to Phase I (7.9%, 3/38, P = .05). An interdisciplinary approach with an analgesia-first sedation pathway with early mobility protocol was associated with less sedative use, increased rehabilitation therapy, and improved functional mobility status at ICU discharge.

Early-life propofol exposure does not affect later-life GABAergic inhibition, seizure induction, or social behavior.

The early developing brain is especially vulnerable to anesthesia, which can result in long lasting functional changes. We examined the effects of early-life propofol on adult excitatory-inhibitory balance and behavior. Postnatal day 7 male mice were exposed to propofol (250mg/kg i.p.) and anesthesia was maintained for 2h; control mice were given the same volume of isotonic saline and treated identically. The behavior and electrophysiology experiments were conducted when the mice were adults. We found that a 2-h neonatal propofol exposure did not significantly reduce paired pulse inhibition, alter the effect of muscimol (3µM) to inhibit field excitatory postsynaptic potentials or alter the effect of bicuculline (100µM) to increase the population spike in the CA1 region of hippocampal slices from adult mice. Neonatal propofol did not alter the evoked seizure response to pentylenetetrazol in adult mice. Neonatal propofol did not affect anxiety, as measured in the open field apparatus, depression-like behavior, as measured by the forced swim test, or social interactions with novel mice, in either the three-chamber or reciprocal social tests. These results were different from those with neonatal sevoflurane which demonstrated reduced adult GABAergic inhibition, increased seizure susceptibility and reduced social interaction. Even though sevoflurane and propofol both prominently enhance GABA inhibition, they have unique properties that alter the long-term effects of early-life exposure. These results indicate that clinical studies grouping several general anesthetic agents in a single group should be interpreted with great caution when examining long-term effects.

The Effects of Propofol on Efflux Activity in Alzheimer’s Disease Human Stem Cell-Derived Blood-Brain Barrier Models

Propofol is a common induction anesthetic that recently has been shown to diminish the integrity of the blood brain barrier (BBB) while maintaining efflux protein expression and activity. Furthermore, Alzheimer’s disease (AD), a neurodegenerative condition, compromises the integrity of the BBB including suppressed efflux activity. Efflux transporters, notably MRP-1, BCRP, and P-gp, play a role in clearing cytotoxic metabolites. The role of propofol on the activity of efflux proteins in AD patients is unknown. The goal of this study was to utilize human induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial cells (BMECs) differentiated from familial AD iPSCS (APP, PSEN1, and PSEN2) and healthy iPSCs to determine the effects of propofol on efflux activity and expression.To measure the effect of propofol on efflux activity, treated cells were exposed to 50μM propofol for three hours and then specific efflux fluorescent substrates and inhibitors were utilized to determine efflux activity ( P-gp: Rhodamine 123/CsA; MRP-1: DCFDA/MK571; BCRP: Hoechst/KO143). Cells were lysed and the fluorescent substrate was quantified by a plate reader and normalized to the uninhibited group. The difference between the inhibited and uninhibited groups were used to determine the efflux activity. Efflux protein expression was also qualitatively assessed using immunostaining.Our preliminary results demonstrated that propofol did not affect efflux activity similar to previous literature. Interestingly, PSEN 1 and PSEN2 had suppressed baseline efflux transporter activity and did not show any change following propofol exposure. APP-derived BMECs displayed suppressed P-GP activity and similarly to PSEN 1/2-derived BMECs were not altered by propofol. Our preliminary results implicate that AD-derived BMECs have suppressed baseline efflux activity; however propofol exposure did not further alter activity level. Additional studies are needed to determine the role of anesthesia-induced injury on efflux activity and expression.

Ketamine Infusion for Sedation and Analgesia during Mechanical Ventilation in the ICU: A Multicenter Evaluation.

We reviewed the electronic medical record of critically ill adults who received a continuous infusion of ketamine for ≥24 hours during invasive mechanical ventilation in three hospitals over a two-year period. We captured data including ketamine indication, dose, unintended effects, and adjustments to coadministered sedatives or opioids. We analyzed these data to determine the incidence of reported unintended effects of ketamine infusion (primary outcome) and changes in exposure to coadministered sedatives or opioids during ketamine use (secondary outcome). 95 mechanically ventilated adults received a ketamine infusion for a median duration of 75 hours (interquartile range [IQR] 44-115) at a mean ± standard deviation (SD) infusion rate of 1.3 ± 0.5 mg/kg/hour for the first 24 hours. At least one unintended effect attributed to ketamine was documented in 24% of cases, most frequently tachycardia (6%) and sialorrhea (6%). Other sedative or opioid infusions were administered with ketamine in 76% and 92% of cases, respectively. Comparing the total amount of sedative or opioid administered in the 24 hours prior to ketamine infusion with the total amount administered during the first 24 hours on ketamine, there were no significant differences in propofol, midazolam, or dexmedetomidine exposure, but the average fentanyl exposure was higher after ketamine (2740 ± 1812 mcg) than before (1975 ± 1860 mcg) (absolute difference 766 mcg, 95% confidence interval [CI] 442 to 1089 mcg). In this multicenter cohort of critically ill, mechanically ventilated adults, ketamine infusion was primarily used as an adjunct to conventional sedative and opioid infusions, with noticeable but unintended effects potentially related to ketamine in nearly one-quarter of cases.

Evaluation of the biological response of propofol in zebrafish (Danio rerio): Focusing on biochemical, transcriptional, and molecular level

Propofol, one of the most widely used intravenous anesthetic in clinical practice, has been reported to impair cognitive and memory function. However, the toxicological effects of propofol on aquatic organisms are still poorly understood. This study explored the toxic effects of chronic propofol exposure (0.008, 0.04, and 0.2 mg L−1) on adult zebrafish from biochemical, transcriptional, and molecular level after 7, 14, 21 and 28 days of exposure. Results indicated that the reactive oxygen species (ROS) levels were significantly upregulated during the 28 days exposure period, and excessive ROS caused lipid peroxidation, resulting in increased malondialdehyde (MDA) contents in the zebrafish brain. In order to relieve the oxidative damage induced by the excessive ROS, the activities of antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT)) were significantly activated, and detoxification enzyme (glutathione S-transferase, GST) activities showed an “activation-inhibition” trend. However, the antioxidant enzymes and detoxification enzyme system could not eliminate the excessive ROS in time and thus caused DNA damage in zebrafish brain. The olive tail moment (OTM) values displayed a “dose-response” relationship with propofol concentrations. Meanwhile, the transcription of related genes of Nrf2-Keap1 pathway was activated. Further molecular simulation experiments suggested that propofol could directly combine with SOD/CAT to change the activity of its biological enzyme. These findings indicated that zebrafish could regulate antioxidant capacity to combat oxidative stress at the early exposure stage, but the activity of antioxidant enzymes were significantly inhibited with the increase of propofol exposure time. Our results are of great importance for understanding toxicological effects of propofol on aquatic organisms.

The Impact of Cumulative Anesthesia Exposure on Neurocognitive Outcomes in Children with High-Risk Precursor B Acute Lymphoblastic Leukemia: A Multicenter Children's Oncology Group Study

Background: Following contemporary therapy, a substantial proportion of children with acute lymphoblastic leukemia (ALL) have long-term neurocognitive impairments of executive function, attention, and memory. Known risk factors for these impairments include treatment with cranial radiation, exposure to intrathecal and systemic methotrexate, acute toxicities during active treatment, as well as younger age, lower socioeconomic status, and female sex. Anesthesia exposure may be an additional risk factor and importantly, one that is potentially modifiable risk factor. We evaluated the impact of cumulative anesthesia exposure on neurocognitive outcomes one-year post treatment in a multicenter cohort of children with ALL. Methods: This study an embedded aim in the Children's Oncology Group AALL1131 trial for patients ages >1 to <31 years of age with high-risk B ALL. In a subgroup of consenting patients aged 6-12 years, receiving care at 73 centers in America, Canada, New Zealand and Australia, prospective uniform assessments of neurocognitive function were performed using a validated computerized battery (Cogstate) and parent-reported executive functioning using the Behavior Rating Inventory of Executive Functioning at baseline (3 months post diagnosis), during treatment, and one year post therapy completion. All neurocognitive scores were converted to age-adjusted z-scores (expected mean=0, standard deviation =1.0), with lower scores reflecting worse performance. Exposure to all anesthetic agents was abstracted retrospectively from medical records from time of study enrollment to one year post therapy for all patients who completed treatment and the neurocognitive assessments at baseline and post therapy. For each anesthetic, data collected included the medications, dose, and route of anesthetic agents, duration of anesthesia, and the indication for anesthesia. Results: 155 children met eligibility and were included in this analysis (n=82 [59%] males, mean age 9.10 years [range 6.0-12.8]). Three patients (1.9%) received cranial radiation. The median number of anesthetic episodes per patient was 27 (range 1-37); the most common indication was lumbar puncture with or without the administration of intrathecal therapy (median 24, range 0-32). Though multiple anesthetic agents were utilized, almost all patients were exposed to propofol (151/155, 97%). The mean cumulative dose of propofol for exposed patients was 109.6 mg/kg. At one year post therapy, the proportion of children with impairment (age-adjusted scores ≥ 1.5 standard deviations below the mean) was significantly higher compared to a standardized population in multiple domains including reaction time, sustained attention, working memory and executive function. In multivariable analysis accounting for baseline neurocognitive score, age, sex, race/ethnicity, socioeconomic status and leukemia risk group, cumulative exposure to propofol was associated with poorer reaction time/processing speed (decrease of 0.05 Z-score per 10 mg/kg propofol exposure, 95th CI 0.003, 0.09; p=0.035) and impaired executive function (decrease of 0.23 Z-score per 10 mg/kg propofol exposure, 95th CI 0.003-0.46; p=0.048). Conclusion: In a multicenter cohort of children treated for high-risk ALL and with variable anesthesia exposure, cumulative anesthesia exposure, as reflected by propofol total dosing (mg/kg) was an independent risk factor for impairments in neurocognitive function measured by both performance based and parent report one year post therapy. Anesthesia exposure is a modifiable risk and opportunities to minimize use, when feasible, in this group of patients should be systematically pursued.

Inhibition of the expression of rgs-3 alleviates propofol-induced decline in learning and memory in Caenorhabditis elegans.

Exposure to anesthesia leads to extensive neurodegeneration and long-term cognitive deficits in the developing brain. Caenorhabditis elegans also shows persistent behavioral changes during development after exposure to anesthetics. Clinical and rodent studies have confirmed that altered expression of the regulators of G protein signaling (RGS) in the nervous system is a factor contributing to neurodegenerative and psychological diseases. Evidence from preclinical studies has suggested that RGS controls drug-induced plasticity, including morphine tolerance and addiction. This study aimed to observe the effect of propofol exposure in the neurodevelopmental stage on learning and memory in the L4 stage and to study whether this effect is related to changes in rgs-3 expression. Caenorhabditis elegans were exposed to propofol at the L1 stage, and learning and memory abilities were observed at the L4 stage. The expression of rgs-3 and the nuclear distribution of EGL-4 were determined to study the relevant mechanisms. Finally, RNA interference was performed on rgs-3-expressing cells after propofol exposure. Then, we observed their learning and memory abilities. Propofol time- and dose-dependently impaired the learning capacity. Propofol induced a decline in non-associative and associative long-term memory, rgs-3 upregulation, and a failure of nuclear accumulation of EGL-4/PKG in AWC neurons. Inhibition of rgs-3 could alleviate the propofol-induced changes. Inhibition of the expression of rgs-3 alleviated propofol-induced learning and memory deficits in Caenorhabditis elegans.

Integrated Excitatory/Inhibitory Imbalance and Transcriptomic Analysis Reveals the Association between Dysregulated Synaptic Genes and Anesthetic-Induced Cognitive Dysfunction.

Emerging evidence from human epidemiologic and animal studies has demonstrated that developmental anesthesia neurotoxicity could cause long-term cognitive deficits and behavioral problems. However, the underlying mechanisms remain largely unknown. We conducted an electrophysiological analysis of synapse activity and a transcriptomic assay of 24,881 mRNA expression on hippocampal tissues from postnatal day 60 (P60) mice receiving propofol exposure at postnatal day 7 (P7). We found that developmentally propofol-exposed P60 mouse hippocampal neurons displayed an E/I imbalance, compared with control mice as evidenced by the decreased excitation and increased inhibition. We found that propofol exposure at P7 led to the abnormal expression of 317 mRNAs in the hippocampus of P60 mice, including 23 synapse-related genes. Various bioinformatic analyses revealed that these abnormally expressed synaptic genes were associated with the function and development of synapse activity and plasticity, E/I balance, behavior, and cognitive impairment. Our findings suggest that the altered E/I balance may constitute a mechanism for propofol-induced long-term impaired learning and memory in mice. The transcriptomic and bioinformatic analysis of these dysregulated genes related to synaptic function paves the way for development of therapeutic strategies against anesthetic neurodegeneration through the restoration of E/I balance and the modification of synaptic gene expression.

The Mechanism of Propofol on Non-Small Cell Lung Cancer (NSCLC) through Modulating Mesenchymal Transition (EMT)

Background: Intensive investigations have focused on the effect of propofol on the malignant behaviours of cancer cells. However, much is still unknown about the effect of propofol on non-small cell lung cancer (NSCLC). Here we aimed to investigate the effect of propofol on NSCLC with cancer stem-like cells (CSCs) A549. Methods: CCK-8 assays, flow cytometry, and transwell assay were used to assess the changes in the proliferation, migration, and invasion in A549 treated with propofol. By detecting hallmarks of mesenchymal transition (EMT), the mechanism of the effect of propofol on A549 was assessed. Results: In A549, propofol exposure promoted cell proliferation, while inhibiting migration and invasion. By activating EMT using TGF-β pretreatment, propofol treatment downregulated hallmarks of EMT and led to inactivation of EMT. Conclusion: Modulation of self-renewal capacity of CSCs by anesthetics may affect cancer malignant behaviors following surgery. The employment of propofol not only exerts inhibitory effects on cancer cells but also on CSCs in non-small cell lung cancer.

Enhanced hippocampal neurogenesis mediated by PGC-1α-activated OXPHOS after neonatal low-dose Propofol exposure.

BackgroundDeveloping brain is highly plastic and can be easily affected. Growing pediatric usage of anesthetics during painless procedures has raised concerns about the effect of low-dose anesthetics on neurodevelopment. It is urgent to ascertain the neuronal effect of low-dose Propofol, a widely used anesthetic in pediatrics, on developing brains.MethodsThe behavioral tests after neonatal exposure to low-dose/high-dose Propofol in mice were conducted to clarify the cognitive effect. The nascent cells undergoing proliferation and differentiation stage in the hippocampus and cultured neural stem cells (NSCs) were further identified. In addition, single-nuclei RNA sequencing (snRNA-seq), NSCs bulk RNA-seq, and metabolism trials were performed for pathway investigation. Furthermore, small interfering RNA and stereotactic adenovirus injection were, respectively, used in NSCs and hippocampal to confirm the underlying mechanism.ResultsBehavioral tests in mice showed enhanced spatial cognitive ability after being exposed to low-dose Propofol. Activated neurogenesis was observed both in hippocampal and cultured NSCs. Moreover, transcriptome analysis of snRNA-seq, bulk RNA-seq, and metabolism trials revealed a significantly enhanced oxidative phosphorylation (OXPHOS) level in NSCs. Furthermore, PGC-1α, a master regulator in mitochondria metabolism, was found upregulated after Propofol exposure both in vivo and in vitro. Importantly, downregulation of PGC-1α remarkably prevented the effects of low-dose Propofol in activating OXPHOS and neurogenesis.ConclusionsTaken together, this study demonstrates a novel alteration of mitochondrial function in hippocampal neurogenesis after low-dose Propofol exposure, suggesting the safety, even potentially beneficial effect, of low-dose Propofol in pediatric use.

The Effects of Propofol on a Human in vitro Blood-Brain Barrier Model.

BackgroundRecently, the safety of repeated and lengthy anesthesia administration has been called into question, a subset of these animal studies demonstrated that anesthetics induced blood-brain barrier (BBB) dysfunction. The BBB is critical in protecting the brain parenchyma from the surrounding micro-vasculature. BBB breakdown and dysfunction has been observed in several neurodegenerative diseases and may contribute to both the initiation and the progression of the disease. In this study we utilize a human induced pluripotent stem cell (iPSC) derived-BBB model, exhibiting near in vivo properties, to evaluate the effects of anesthetics on critical barrier properties.MethodsiPSC-derived brain microvascular endothelial cells (BMECs) expressed near in vivo barrier tightness assessed by trans-endothelial electrical resistance and para-cellular permeability. Efflux transporter activity was determined by substrate transport in the presence of specific inhibitors. Trans-cellular transport was measured utilizing large fluorescently tagged dextran. Tight junction localization in BMECs was evaluated with fluorescent microscopy. The anesthetic, propofol was exposed to BMECs at varying durations and concentrations and BBB properties were monitored post-exposure.ResultsFollowing propofol exposure, BMECs displayed reduced resistance and increased permeability indicative of a leaky barrier. Reduced barrier tightness and the dysregulation of occludin, a tight junction protein, were partly the result of an elevation in matrix metalloproteinase (MMP) levels. Efflux transporter activity and trans-cellular transport were unaffected by propofol exposure. Propofol induced barrier dysfunction was partially restored following matrix metalloproteinase inhibition.ConclusionFor the first time, we have demonstrated that propofol alters BBB integrity utilizing a human in vitro BBB model that displays key in vivo characteristics. A leaky BBB enables otherwise impermeable molecules such as pathogens and toxins the ability to reach vulnerable cell types of the brain parenchyma. A robust human in vitro BBB model will allow for the evaluation of several anesthetics at fluctuating clinical scenarios and to elucidate mechanisms with the goal of ultimately improving anesthesia safety.

Neonatal Exposure to Propofol Interferes with the Proliferation and Differentiation of Hippocampal Neural Stem Cells and the Neurocognitive Function of Rats in Adulthood via the Akt/p27 Signaling Pathway

ObjectiveNeonatal exposure to propofol has been reported to cause neurotoxicity and neurocognitive decline in adulthood; however, the underlying mechanism has not been established. MethodsSD rats were exposed to propofol on postnatal day 7 (PND-7). Double-immunofluorescence staining was used to assess neurogenesis in the hippocampal dentate gyrus (DG). The expression of p-Akt and p27 were measured by western blotting. The Morris water maze, novel object recognition test, and object location test were used to evaluate neurocognitive function 2-month-old rats. ResultsPhosphorylation of Akt was inhibited, while p27 expression was enhanced after neonatal exposure to propofol. Propofol also inhibited proliferation of neural stem cells (NSCs) and decreased differentiation to neurons and astroglia. Moreover, the neurocognitive function in 2-month-old rats was weakened. Of significance, intra-hippocampal injection of the Akt activator, SC79, attenuated the inhibition of p-AKT and increase of p27 expression. SC79 also rescued the propofol-induced inhibition of NSC proliferation and differentiation. The propofol-induced neurocognition deficit was also partially reversed by SC79. ConclusionTaken together, these results suggest that neurogenesis is hindered by neonatal propofol exposure. Specifically, neonatal propofol exposure was shown to suppress the proliferation and differentiation of NSCs by inhibiting Akt/p27 signaling pathway.