Propofol Toxicity Research Articles

Dexmedetomidine alleviates propofol-induced pyroptosis of hippocampal neurons through NLRP3 inflammasome pathway.

Propofol is neurotoxic to trigger neuronal pyroptosis and dexmedetomidine possesses the ability to suppress proptosis. This study expounded on the protective functions of dexmedetomidine on propofol-induced pyroptosis of primary hippocampal neurons via NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome pathway. At first, primary hippocampal neurons underwent separation and identification and were treated with different concentrations of propofol (1, 10, and 100 μM). The toxicity of propofol in the neurons was evaluated. Prior to propofol treatment, the neurons were treated with different concentrations of dexmedetomidine (0.01, 0.1, 1, 5, and 10 μM). The viability of neurons with different treatments was detected. The mRNA expressions of homeobox A5 (HOXA5) and NLRP3 were identified. The protein levels of intracellular HOXA5, NLRP3, the N-terminal fragment of gasdermin D (GSDMD-N), and cleaved-caspase-1 and the concentrations of interleukin (IL)-1β and IL-18 were examined. Subsequently, the binding of HOXA5 to the NLRP3 promoter was detected. Joint experiments were conducted with pcDNA3.1-HOXA5 or pcDNA3.1-NLRP3 in dexmedetomidine-treated neurons. Dexmedetomidine pretreatment attenuated propofol-induced pyroptosis of hippocampal neurons, increased cell viability, and repressed NLRP3, GSDMD-N, and cleaved-caspase-1 protein levels and IL-1β and IL-18 concentrations. Dexmedetomidine pretreatment inhibited intracellular HOXA5 expression, and HOXA5 bound to the NLRP3 promoter region to promote NLRP3 expression. Overexpressing HOXA5 or NLRP3 reversed anti-pyroptosis role of dexmedetomidine pretreatment in hippocampal neurons. Dexmedetomidine pretreatment suppressed NLRP3 expression by downregulating HOXA5 expression, inhibiting propofol-induced pyroptosis in primary hippocampal neurons.

Environmental risk assessment of propofol in wastewater: a narrative review of regulatory guidelines.

Concerns relating to the negative environmental impacts of anaesthesia are increasing, and in recent years, there has been an environmentally motivated trend towards greater use of propofol-based total intravenous anaesthesia. Consequently, the environmental burden of propofol waste and disposal, particularly into wastewater, has gained attention. Current literature reporting levels of propofol in wastewater are scarce and the threat this presents to the environment is unclear. We review the regulatory requirements for conducting an environmental risk assessment, with a focus on the process for analysing whether drugs or drug metabolites cause harm to aquatic species. Furthermore, we present a profile for the aquatic toxicity of propofol based on available data and discuss the implications of this for future practice.

Propofol toxicity in the developing mouse heart mitochondria

BackgroundPropofol infusion syndrome (PRIS) is a potentially lethal consequence of long-term propofol administration. Children are vulnerable and cardiac involvement is often prominent and associated with mortality. We aimed to determine the mechanism of propofol toxicity in newborn mice, hypothesizing that propofol would induce discrete defects within immature cardiac mitochondria.MethodsNewborn murine cardiac mitochondria were exposed to propofol or intralipid in vitro. Non-exposed mitochondria served as controls. Mitochondrial respiration and membrane potential (ΔΨ) were measured and respiratory chain complex kinetics were determined.ResultsPropofol and intralipid exerted biological activity in isolated mitochondria. Although intralipid effects were a potential confounder, we found that propofol induced a dose-dependent increase in proton leak and caused a defect in substrate oxidation at coenzyme Q (CoQ). These impairments prevented propofol-exposed cardiomyocyte mitochondria from generating an adequate ΔΨ. The addition of the quinone analog, CoQ0, blocked propofol-induced leak and increased Complex II+III activity.ConclusionsPropofol uncoupled immature cardiomyocyte mitochondria by inducing excessive CoQ-sensitive leak and interfered with electron transport at CoQ. The findings provide new insight into the mechanisms of propofol toxicity in the developing heart and may help explain why children are vulnerable to developing PRIS.ImpactPropofol uncouples immature cardiomyocyte mitochondria by inducing excessive coenzyme Q (CoQ)-sensitive proton leak.Propofol also interferes with electron transport at the level of CoQ.These defects provide new insight into propofol toxicity in the developing heart.

Fluoride-assisted liquid chromatography-tandem mass spectrometry method for simultaneous analysis of propofol and its metabolites without derivatization in urine

The misuse of propofol for recreational purposes has become a serious social issue. Accordingly, practical and sensitive analytical methods to investigate the chronic abuse and toxicity of propofol are required. However, current propofol determination methods using liquid chromatography-mass spectrometry (LC-MS/MS) suffer from problems associated with loss in sample preparation due to its volatility and its poor ionization efficiency and collision-induced dissociation in mass spectrometry. Herein, we have developed a sensitive and accurate fluoride-assisted LC-MS/MS method combined with direct-injection for propofol determination. Ionization via fluoride-ion attachment/induced deprotonation, effected by ammonium fluoride in the mobile phase, was found to dramatically improve the sensitivity of propofol without derivatization. Furthermore, direct injection without derivatization enables the simultaneous analysis of propofol and its phase II metabolites without analyte loss. The optimal concentration of ammonium fluoride in the mobile phase was found to be 1 mM under methanol conditions. The linearity is good (R2 ≥ 0.999) and the intra- and inter-day precisions for propofol determination are between 1.9 and 8.7%. The accuracies range from 87.5% to 105.4% and the limits of detection and quantitation for propofol in urine are 0.15 and 0.44 ng mL−1, respectively. The present method was successfully applied to human urine and showed a sufficient sensitivity to determine propofol and five phase II metabolites over 48 h in human urine after administration. Consequently, the fluoride-assisted LC-MS/MS method was demonstrated to be sensitive, accurate, and practical for the determination of propofol and its metabolites.

MicroRNA-582-5p Reduces Propofol-induced Apoptosis in Developing Neurons by Targeting ROCK1

Propofol is an intravenous drug commonly used in anesthesia procedures and intensive care in children. However, it also has neurotoxic effects on children. MicroRNA plays an important role in neurological diseases and neurotoxicity. In this study, primary rat hippocampal neurons were used to investigate the role of miR- 582-5p in propofol-induced neurotoxicity. Cell viability was monitored by 3-(4,5-dimethylthiazolyl)- 2,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while the expression of proteins was monitored by real-time quantitation polymerase chain reaction (RT-qPCR) and western blot. TargetScan and double luciferase report assay were used to predict the targeting relationship between miR-582-5p and Rho-associated serine-threonine protein kinase 1 (ROCK1). In the present study, the viability of neurons and the expression of miR-582-5p were decreased in a time-dependent manner after propofol treatment. Besides, miR-582-5p overexpression significantly reduced the toxicity of propofol on neuron cells but had no significant effect on normal nerve cells. In addition, miR-582-5p overexpression significantly reversed the expression of apoptosis-related proteins (cleaved caspase 3 and cleaved caspase 9) induced by propofol but had no significant effect in normal nerve cells. TargetScan and Dual-luciferase report assay revealed that ROCK1 was a targeted regulatory gene for miR-582-5p, and propofol treatment up-regulated ROCK1 expression by inhibiting miR-582-5p expression. Notably, miR-582-5p overexpression significantly increased cell viability, while ROCK1 overexpression reversed the effect of miR-582- 5p. Taken together, these findings suggest that miR-582-5p alleviated propofol-induced apoptosis of newborn rat neurons by inhibiting ROCK1.

Suppression of mitochondrial oxygen metabolism mediated by the transcription factor HIF-1 alleviates propofol-induced cell toxicity

A line of studies strongly suggest that the intravenous anesthetic, propofol, suppresses mitochondrial oxygen metabolism. It is also indicated that propofol induces the cell death in a reactive oxygen species (ROS)-dependent manner. Because hypoxia-inducible factor 1 (HIF-1) is a transcription factor which is involved in cellular metabolic reprogramming by modulating gene expressions of enzymes including glycolysis pathway and oxygen utilization of mitochondria, we examined the functional role of HIF-1 activity in propofol-induced cell death. The role of HIF-1 activity on oxygen and energy metabolisms and propofol-induced cell death and caspase activity was examined in renal cell-derived RCC4 cells: RCC4-EV cells which lack von Hippel-Lindau protein (VHL) protein expression and RCC4-VHL cells, which express exogenous VHL, and in neuronal SH-SY5Y cells. It was demonstrated that HIF-1 is involved in suppressing oxygen consumption and facilitating glycolysis in cells and that the resistance to propofol-induced cell death was established in a HIF-1 activation-dependent manner. It was also demonstrated that HIF-1 activation by treatment with HIFα-hydroxylase inhibitors such as n-propyl gallate and dimethyloxaloylglycine, alleviated the toxic effects of propofol. Thus, the resistance to propofol toxicity was conferred by HIF-1 activation by not only genetic deletion of VHL but also exposure to HIFα-hydroxylase inhibitors.

Propofol induces a metabolic switch to glycolysis and cell death in a mitochondrial electron transport chain-dependent manner.

The intravenous anesthetic propofol (2,6-diisopropylphenol) has been used for the induction and maintenance of anesthesia and sedation in critical patient care. However, the rare but severe complication propofol infusion syndrome (PRIS) can occur, especially in patients receiving high doses of propofol for prolonged periods. In vivo and in vitro evidence suggests that the propofol toxicity is related to the impaired mitochondrial function. However, underlying molecular mechanisms remain unknown. Therefore, we investigated effects of propofol on cell metabolism and death using a series of established cell lines of various origins, including neurons, myocytes, and trans-mitochondrial cybrids, with defined mitochondrial DNA deficits. We demonstrated that supraclinical concentrations of propofol in not less than 50 μM disturbed the mitochondrial function and induced a metabolic switch, from oxidative phosphorylation to glycolysis, by targeting mitochondrial complexes I, II and III. This disturbance in mitochondrial electron transport caused the generation of reactive oxygen species, resulting in apoptosis. We also found that a predisposition to mitochondrial dysfunction, caused by a genetic mutation or pharmacological suppression of the electron transport chain by biguanides such as metformin and phenformin, promoted propofol-induced caspase activation and cell death induced by clinical relevant concentrations of propofol in not more than 25 μM. With further experiments with appropriate in vivo model, it is possible that the processes to constitute the molecular basis of PRIS are identified.

Role of mitochondrial complex I and protective effect of CoQ10 supplementation in propofol induced cytotoxicity.

Propofol (2,6-diisopropylphenol) is an anaesthetic widely used for human sedation. Due to its intrinsic antioxidant properties, rapid induction of anaesthesia and fast recovery, it is employed in paediatric anaesthesia and in the intensive care of premature infants. Recent studies have pointed out that exposure to anaesthesia in the early stage of life might be responsible of long-lasting cognitive impairment. The apoptotic neurodegeneration induced by general anaesthetics (GA) involves mitochondrial impairment due to the inhibition of the OXPHOS machinery. In the present work, we aim to identify the main mitochondrial respiratory chain target of propofol toxicity and to evaluate the possible protective effect of CoQ10 supplementation. The propofol effect on the mitochondrial functionality was assayed in isolated mitochondria and in two cell lines (HeLa and T67) by measuring oxygen consumption rate. The protective effect of CoQ10 was assessed by measuring cells viability, NADH-oxidase activity and ATP/ADP ratio in cells treated with propofol. Our results show that propofol reduces cellular oxygen consumption rate acting mainly on mitochondrial Complex I. The kinetic analysis of Complex I inhibition indicates that propofol interferes with the Q module acting as a non-competitive inhibitor with higher affinity for the free form of the enzyme. Cells supplemented with CoQ10 are more resistant to propofol toxicity. Propofol exposure induces cellular damages due to mitochondrial impairment. The site of propofol inhibition on Complex I is the Q module. CoQ10 supplementation protects cells against the loss of energy suggesting its possible therapeutic role to minimizing the detrimental effects of general anaesthesia.

The Fas Ligand/Fas Death Receptor Pathways Contribute to Propofol-Induced Apoptosis and Neuroinflammation in the Brain of Neonatal Rats.

A number of experimental studies have reported that exposure to common, clinically used anesthetics induce extensive neuroapoptosis and cognitive impairment when applied to young rodents, up to 2weeks old, in phase of rapid synaptogenesis. Propofol is the most used general anesthetic in clinical practice whose mechanisms of neurotoxicity on the developing brain remains to be examined in depth. This study investigated effects of different exposures to propofol anesthesia on Fas receptor and Fas ligand expressions, which mediate proapoptotic and proinflammation signaling in the brain. Propofol (20mg/kg) was administered to 7-day-old rats in multiple doses sufficient to maintain 2-, 4- and 6-h duration of anesthesia. Animals were sacrificed at 0, 4, 16 and 24h after termination of anesthesia. It was found that propofol anesthesia induced Fas/FasL and downstream caspase-8 expression more prominently in the thalamus than in the cortex. Opposite, Bcl-2 and caspase-9, markers of intrinsic pathway activation, were shown to be more influenced by propofol treatment in the cortex. Further, we have established upregulation of caspase-1 and IL-1β cytokine transcription as well as subsequent activation of microglia that is potentially associated with brain inflammation. Behavioral analyses revealed that P35 and P60 animals, neonatally exposed to propofol, had significantly higher motor activity during three consecutive days of testing in the open field, though formation of the intersession habituation was not prevented. This data, together with our previous results, contributes to elucidation of complex mechanisms of propofol toxicity in developing brain.

Posttraumatic Propofol Neurotoxicity Is Mediated via the Pro-Brain-Derived Neurotrophic Factor-p75 Neurotrophin Receptor Pathway in Adult Mice.

The gamma-aminobutyric acid modulator propofol induces neuronal cell death in healthy immature brains by unbalancing neurotrophin homeostasis via p75 neurotrophin receptor signaling. In adulthood, p75 neurotrophin receptor becomes down-regulated and propofol loses its neurotoxic effect. However, acute brain lesions, such as traumatic brain injury, reactivate developmental-like programs and increase p75 neurotrophin receptor expression, probably to foster reparative processes, which in turn could render the brain sensitive to propofol-mediated neurotoxicity. This study investigates the influence of delayed single-bolus propofol applications at the peak of p75 neurotrophin receptor expression after experimental traumatic brain injury in adult mice. Randomized laboratory animal study. University research laboratory. Adult C57BL/6N and nerve growth factor receptor-deficient mice. Sedation by IV propofol bolus application delayed after controlled cortical impact injury. Propofol sedation at 24 hours after traumatic brain injury increased lesion volume, enhanced calpain-induced αII-spectrin cleavage, and increased cell death in perilesional tissue. Thirty-day postinjury motor function determined by CatWalk (Noldus Information Technology, Wageningen, The Netherlands) gait analysis was significantly impaired in propofol-sedated animals. Propofol enhanced pro-brain-derived neurotrophic factor/brain-derived neurotrophic factor ratio, which aggravates p75 neurotrophin receptor-mediated cell death. Propofol toxicity was abolished both by pharmacologic inhibition of the cell death domain of the p75 neurotrophin receptor (TAT-Pep5) and in mice lacking the extracellular neurotrophin binding site of p75 neurotrophin receptor. This study provides first evidence that propofol sedation after acute brain lesions can have a deleterious impact and implicates a role for the pro-brain-derived neurotrophic factor-p75 neurotrophin receptor pathway. This observation is important as sedation with propofol and other compounds with GABA receptor activity are frequently used in patients with acute brain pathologies to facilitate sedation or surgical and interventional procedures.

Is acute severe asthma a risk factor for the propofol infusion syndrome?

Propofol infusion syndrome (PRIS) is a rare but potentially fatal syndrome observed more commonly in young obese men receiving high dose (usually >4mg/kg/hr) or long term (>48 hrs) propofol. It can cause metabolic acidosis, renal failure, rhabdomyolysis, hyperkalemia, and cardiac failure. We report a case of possible PRIS in a 24-year-old obese Hispanic man admitted for acute severe asthma who developed PRIS in less than 12 hours on lower doses of propofol (3 mg/kg/hr tapered within 3 hrs) while on concurrent corticosteroids. Patients with acute asthma and subclinical myopathy may be at increased risk for propofol toxicity and need careful monitoring if this drug is used for sedation.

Protective effect of acetyl-l-carnitine on propofol-induced toxicity in embryonic neural stem cells

Propofol is a widely used general anesthetic. A growing body of data suggests that perinatal exposure to general anesthetics can result in long-term deleterious effects on brain function. In the developing brain there is evidence that general anesthetics can cause cell death, synaptic remodeling, and altered brain cell morphology. Acetyl-l-carnitine (l-Ca), an anti-oxidant dietary supplement, has been reported to prevent neuronal damage from a variety of causes. To evaluate the ability of l-Ca to protect against propofol-induced neuronal toxicity, neural stem cells were isolated from gestational day 14 rat fetuses and on the eighth day in culture were exposed for 24h to propofol at 10, 50, 100, 300 and 600μM, with or without l-Ca (10μM). Markers of cellular proliferation, mitochondrial health, cell death/damage and oxidative damage were monitored to determine: (1) the effects of propofol on neural stem cell proliferation; (2) the nature of propofol-induced neurotoxicity; (3) the degree of protection afforded by l-Ca; and (4) to provide information regarding possible mechanisms underlying protection. After propofol exposure at a clinically relevant concentration (50μM), the number of dividing cells was significantly decreased, oxidative DNA damage was increased and a significant dose-dependent reduction in mitochondrial function/health was observed. No significant effect on lactase dehydrogenase (LDH) release was observed at propofol concentrations up to 100μM. The oxidative damage at 50μM propofol was blocked by l-Ca. Thus, clinically relevant concentrations of propofol induce dose-dependent adverse effects on rat embryonic neural stem cells by slowing or stopping cell division/proliferation and causing cellular damage. Elevated levels of 8-oxoguanine suggest enhanced oxidative damage [reactive oxygen species (ROS) generation] and l-Ca effectively blocks at least some of the toxicity of propofol, presumably by scavenging oxidative species and/or reducing their production.

Central depressant effects and toxicity of propofol in chicks

Propofol is an ultra-short acting anesthetic agent. The information on the pharmacological and toxicological effects of propofol in the chicken is rather limited. This study examines the toxicity and pharmaco-behavioral effects of propofol given intraperitoneally in 7–10 day-old chicks. The median effective doses of propofol for the induction of sedation, analgesia to electric stimulation and sleep in the chicks were 1.82, 2.21 and 5.71 mg/kg, respectively. The 24-h median lethal dose of propofol in chicks was 57.22 mg/kg. The therapeutic indices of propofol for sedation, analgesia and sleep were 31.4, 25.9 and 10, respectively. Propofol at 0.5 and 1 mg/kg reduced the locomotor activity and increased the duration of tonic immobility in chicks. Propofol at 2 and 4 mg/kg caused analgesia to electric stimulation as well as analgesia and anti-inflammatory responses against formalin test in chicks. Propofol at 5, 10 and 20 mg/kg induced sleep in chicks for 8.4 to 25 min. Physostigmine shortened the sleep duration of propofol. Data suggest that propofol induces anti-inflammatory action and central nervous system depression in chicks resulting in sedation, analgesia and anesthesia with wide safety margin. These effects could form the basis of further pharmacological and toxicological studies on propofol in the young chick model, and the drug could be safely applied clinically in the chicken.

Propofol-related infusion syndrome heralding a mitochondrial disease: Case report

Propofol-related infusion syndrome (PRIS) is a rare but catastrophic complication of propofol use. It is clinically characterized by metabolic acidosis, rhabdomyolysis, arrhythmias, myocardial failure, renal failure, and hepatomegaly, and may lead to death.1 Some risk factors are associated with PRIS, namely young age, critical illness, high fat intake, catecholamine or steroid use, inborn error of fatty acid oxidation, propofol doses exceeding 4–5 mg/kg/hour, and duration of use exceeding 48 hours.1 Some evidence also suggests that PRIS is related to a mitochondrial toxicity of propofol.2,3 The authors thank Éric Laflamme for his help revising this manuscript.

A review onthe reproductive toxicity of propofol

Backgroud Propofol is a clinic frequently used intravenous anesthetic.Anesthesiologists highly concerned about its safety and the possibility of propofol anesthesia-induced damage to patients.Objective This paper reviews the studies about the reproductive toxicity of propofol in recent years and summaries all the related experimental methods.Content Animal experiments revealed that propofol could cause neuron damage to the developing brain.In-vitro fertilization,as analgesic or sedative,propofol accumulation could be detected in the follicular fluid.Controversy still exists whether propofol is harmful to the offspring in cesarean section or non-obstetric surgery during pregnancy.Trend Further clinical studies of reproduction toxicity of propofol are urgently needed,as well as proper approaches assessing the toxicity of anesthetics on future generation. Key words: Propofol; Reproductive toxicity

A PROLONGED INTRODUCTION PROPOFOL AS A PREDICTOR OF THE ONSET OF TOXIC HEPATITIS

It has been established that an 18-hour introduction of propofol to rats leads to the onset of essential changes in the liver structure, mainly in the centrolobular regions of the lobes. A marked character of pathomorphologic changes in the liver intensified in a combination of propofol with tramadol and butorfanol. A simultaneous introduction of propopofol with ketorolac, on the contrary, diminishes morphological manifestations of propofol toxicity.

Attenuation of Propofol Tolerance Conferred by Remifentanil Co-Administration Does Not Reduce Propofol Toxicity in Rabbits Under Prolonged Mechanical Ventilation

Prolonged sedation with propofol at high doses may lead to fatal multi-organ dysfunction, know as propofol infusion syndrome. We tested the hypothesis that propofol plus remifentanil co-administration attenuates propofol tolerance to its sedative effect and assessed if such an effect has an impact on propofol toxicity in rabbits under prolonged mechanical ventilation. Eighteen healthy male rabbits were mechanically ventilated and received propofol (group P, n = 6), propofol plus remifentanil (group PR, n = 6), or remifentanil plus sevoflurane (group RS, n = 6) in order to be kept under sedation (group P) or sedation/analgesia (groups PR and RS) for up to 48 h. Initial propofol and remifentanil infusion rates (IRs) were adjusted, if needed, to maintain the desired level of sedation and analgesia, respectively (groups P and PR). In group RS, remifentanil was infused at IRs equivalent to those of group PR. Propofol IRs were recorded, propofol concentrations were measured in the arterial plasma, and blood biochemical parameters and organ histopathology were assessed. Animals survived for 29-36 h in group P and 22-38 h in group PR (100% mortality rate). Tolerance was developed to propofol's sedative effect. The onset of tolerance was delayed and its magnitude was decreased in group PR compared with group P. Propofol was accumulated in the systemic circulation. Propofol clearance rate was gradually decreased. Arterial lactate, and serum aspartate aminotransferase (AST), lactate dehydrogenase (LDH), bilirubin, cholesterol, triglycerides, and creatine kinase (CK) levels were increased. The heart, lungs, liver, gallbladder, kidneys, urinary bladder, and skeletal muscles were seriously injured in groups P and PR. In group RS, mortality was 0%, while there was only mild injury of the lungs, liver, gallbladder, kidneys, and urinary bladder. Although propofol tolerance is attenuated in propofol plus remifentanil receiving rabbits under prolonged mechanical ventilation, fatal multi-organ injury occurs resembling human propofol infusion syndrome.

Cardiac Conduction Disturbances and Ventricular Tachycardia after Prolonged Propofol Infusion in an Infant

We report an infant who, after prolonged intravenous propofol infusion for treatment of status epilepticus, developed dramatic cardiac conduction disturbances and tachyarrhythmias in the setting of only mild metabolic acidosis and good ventricular function. Certain electrocardiographic findings were similar to those observed in the Brugada syndrome as well as in adult patients with propofol toxicity who suffered fatal ventricular arrhythmias. This case illustrates that serious arrhythmias can occur during prolonged high-dose propofol infusion in young patients, probably through a direct electrophysiologic membrane effect.

GABAergic mechanism of propofol toxicity in immature neurons

GABAergic mechanism of propofol toxicity in immature neurons

Short-Term Low-Dose Propofol Anaesthesia Associated with Severe Metabolic Acidosis

Propofol-induced metabolic acidosis is well recognised in the paediatric literature, but the existence of such a syndrome in adults remains contentious. In most reported cases, metabolic acidosis complicated prolonged administration of propofol in critically ill patients. We present a case of severe non-fatal reversible metabolic acidosis, without ventilatory depression or hypoxia, related to short-term propofol infusion in an adult during and after coronary artery bypass grafting. We suggest that lactic acidosis occurred in a genetically susceptible patient with an abnormality of mitochondrial function. This report discusses an unusual adverse effect of propofol anaesthesia and sedation and highlights the need for further investigation to define propofol toxicity.