The primary intravenous anesthetics employed in clinical practice encompass dexmedetomidine (Dex), propofol, ketamine, etomidate, midazolam, and remimazolam. Apart from their established sedative, analgesic, and anxiolytic properties, an increasing body of research has uncovered neuroprotective effects of intravenous anesthetics in various animal and cellular models, as well as in clinical studies. However, there also exists conflicting evidence pointing to the potential neurotoxic effects of these intravenous anesthetics. The role of intravenous anesthetics for neuro on both sides of protection or toxicity has been rarely summarized. Considering the mentioned above, this work aims to offer a comprehensive understanding of the underlying mechanisms involved both in the central nerve system (CNS) and the peripheral nerve system (PNS) and provide valuable insights into the potential safety and risk associated with the clinical use of intravenous anesthetics.
Animals ; Humans ; Anesthetics, Intravenous/adverse effects* ; Neuroprotective Agents/pharmacology* ; Propofol ; Neurotoxicity Syndromes/prevention & control* ; Central Nervous System/drug effects* ; Dexmedetomidine

OBJECTIVE: To determine whether the glutamatergic neurons in the paraventricular nucleus of the thalamus (PVT) is involved in the change of consciousness induced by propofol through a combination of behavioral and electroencephalography (EEG) recordings. METHODS: Healthy male VGluT2-IRES-Cre mice aged 8-12 weeks were used in this experiment. (1) The glutamatergic neurons in the PVT was selectively damaged, and its effect on propofol anesthesia induction and recovery times as well as the energy of EEG in different frequency bands were observed. (2) Optogenetics was utilized to selectively activate or inhibit glutamatergic neurons in the PVT to assess their influence on anesthesia induction and recovery times under propofol as well as the energy of EEG in different frequency bands. RESULTS: (1) Selective ablation of glutamatergic neurons in the PVT significantly delayed recovery from propofol anesthesia with statistical difference as compared with the control group (s: 409.43±117.49 vs. 273.71±51.52, P < 0.05), but had no significant effect on anesthesia induction time. During the recovery phase of propofol, selective ablation of glutamatergic neurons in the PVT exhibited higher α-wave (1-4 Hz) power and reduced β-wave (12-15 Hz) power as compared with the control group. (2) Optogenetic activation of glutamatergic neurons in the PVT significantly prolonged anesthesia induction time under propofol (s: 161.67±29.09 vs. 119.33±18.98, P < 0.05) while significantly shortening the recovery time from propofol anesthesia (s: 208.67±57.19 vs. 288.83±34.52, P < 0.05). During the induction phase of propofol, activation of glutamatergic neurons in PVT reduced α-wave and α-wave (8-12 Hz) power, while during the recovery phase, α-wave power significantly increased as compared with the control group. (3) Optogenetic inhibition of glutamatergic neurons in the PVT delayed recovery from propofol anesthesia (s: 403.50±129.06 vs. 252.83±45.31, P < 0.05), but had no significant effect on induction time. During both the induction phase and recovery phase of propofol, the optogenetic inhibition of glutamatergic neurons in the PVT exhibited increased α-wave power. CONCLUSION Glutamatergic neurons in the PVT are involved in the regulation of propofol anesthesia recovery process.
Animals ; Propofol/pharmacology* ; Mice ; Neurons/physiology* ; Male ; Electroencephalography ; Wakefulness ; Midline Thalamic Nuclei ; Optogenetics

OBJECTIVE: To explore the regulatory effects of GABAergic neurons in the zona incerta (ZI) on sevoflurane and propofol anesthesia. METHODS: Forty-eight male C57BL/6J mice divided into 8 groups (n=6) were used in this study. In the study of sevoflurane anesthesia, chemogenetic experiment was performed in 2 groups of mice with injection of either adeno-associated virus carrying hM3Dq (hM3Dq group) or a virus carrying only mCherry (mCherry group). The optogenetic experiment was performed in another two groups of mice injected with an adeno-associated virus carrying ChR2 (ChR2 group) or GFP only (GFP group). The same experiments were also performed in mice for studying propofol anesthesia. Chemogenetics or optogenetics were used to induce the activation of GABAergic neurons in the ZI, and their regulatory effects on anesthesia induction and arousal with sevoflurane and propofol were observed; EEG monitoring was used to observe the changes in sevoflurane anesthesia maintenance after activation of the GABAergic neurons. RESULTS: In sevoflurane anesthesia, the induction time of anesthesia was significantly shorter in hM3Dq group than in mCherry group (P < 0.05), and also shorter in ChR2 group than in GFP group (P < 0.01), but no significant difference was found in the awakening time between the two groups in either chemogenetic or optogenetic tests. Similar results were observed in chemogenetic and optogenetic experiments with propofol (P < 0.05 or 0.01). Photogenetic activation of the GABAergic neurons in the ZI did not cause significant changes in EEG spectrum during sevoflurane anesthesia maintenance. CONCLUSION Activation of the GABAergic neurons in the ZI promotes anesthesia induction of sevoflurane and propofol but does not affect anesthesia maintenance or awakening.
Male ; Animals ; Mice ; Mice, Inbred C57BL ; Propofol/pharmacology* ; Sevoflurane/pharmacology* ; Zona Incerta ; Anesthesia, General ; GABAergic Neurons

OBJECTIVES: To investigate the effects of propofol on the proliferation and invasion of glioma U87 cells and to explore the possible anti-tumor mechanisms. METHODS: The glioma U87 cells was divided into a blank group, a positive control group, and the propofol groups (1.00, 2.00 or 5.00 mmol/L). Cell counting kit-8 (CCK-8) was used to detect cell proliferation; Transwell method was used to detect the effect of propofol on invasion and migration of U87 cells; real-time PCR was used to detect the expression of microRNA-134 (miR-134); Western blotting was used to detect the expression levels of reproduction-related protein Ki-67, invasion-related protein metalloproteinase-2 (MMP-2), metalloproteinase-9 (MMP-9) and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway-related protein. RESULTS: Compared with the blank group, the proliferation, invasion and migration capacity of U87 cells were reduced in the positive control group and the propofol groups after 48 hours (all CONCLUSIONS Propofol can decrease the proliferation rate, and the invasion and migration abilities of U87 cells, which may be achieved by up-regulation of miR-134 and suppression of PI3K/Akt signaling pathway.
Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Glioma/genetics* ; Humans ; Matrix Metalloproteinase 2/genetics* ; MicroRNAs/genetics* ; Phosphatidylinositol 3-Kinases/genetics* ; Propofol/pharmacology* ; Proto-Oncogene Proteins c-akt/genetics*

The aim of the present study was to investigate the protective effect of propofol on the experimental myocardial infarction in rats. The myocardial infarction model was established by ligating the anterior descending branch of left coronary artery in rats. Model rats were treated with propofol. Cardiac function was evaluated by echocardiography. Cardiac hemodynamic changes were detected by multiconductor biorecorder. Pathological changes in the infarcted myocardia were detected by HE staining. The expression levels of cardiac hypertrophy marker genes and fibrosis marker proteins were analyzed by real-time quantitative PCR and Western blot. The results showed that, compared with the sham surgery group, the model group exhibited larger infarct size (> 40%), impaired heart function, and significantly increased left ventricular end-diastolic pressure (LVEDP). Propofol reduced cardiac function impairment and decreased LVEDP in the model group. Propofol significantly reduced lung weight/body weight ratio, heart weight/body weight ratio, left ventricular weight/body weight ratio and left atrial weight/body weight ratio in the model group. Furthermore, after myocardial infarction, the administration of propofol significantly improved the diastolic strain rate, down-regulated the mRNA expression levels of myocardial hypertrophy markers, atrial natriuretic peptide and β-myosin heavy chain, and reversed the up-regulation of matrix metalloproteinase 2 (MMP2), MMP9 and tissue inhibitor of metalloproteinase-2 (TIMP-2) induced by myocardial infarction. These results suggest propofol can reduce adverse ventricular remodeling, cardiac dysfunction, myocardial hypertrophy and fibrosis after myocardial infarction, and has protective effect against the experimental myocardial infarction induced by coronary artery ligation in rats.
Animals ; Cardiotonic Agents/pharmacology* ; Matrix Metalloproteinase 2 ; Matrix Metalloproteinase 9 ; Myocardial Infarction/drug therapy* ; Myocardium ; Propofol/pharmacology* ; Rats ; Tissue Inhibitor of Metalloproteinase-2/genetics* ; Ventricular Remodeling

To explore the effect of propofol on human cardiac AC16 cells under CoCl2-induced hypoxic injury and the possible mechanisms.
 Methods: Human AC16 cardiomyocytes were treated with cobalt chloride (CoCl2) to mimic hypoxic condition in cultured cardiomyocytes. The AC16 cells were divided into 3 groups: a control group, a CoCl2 hypoxia group (CoCl2 group), and a propofol+CoCl2 group (propofol+ CoCl2 group). The cell viability was assessed by cell counting kit-8 (CCK-8). Cell apoptosis ratio (AR) and the mitochondrial membrane potential (Δψm) were detected by flow cytometry. The reactive oxygen species (ROS) production in AC16 cells were determined with the ROS-sensitive fluorescent probe. Meanwhile, total intracellular levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in AC16 cells were detected with commercially available kits. Western blot was used to evaluate the activation of c-Jun N-terminal kinase (JNK) and p38 signaling pathways.
 Results: 1) Compared with the control group, AC16 cell viability was decreased significantly in the CoCl2 group following the treatment with 500 μmol/L CoCl2 (P<0.01); 2) Compared with the control group, AR value in AC16 cells was increased significantly in the CoCl2 group, while Δψm was decreased significantly (all P<0.01). Compared with the CoCl2 group, AR value in AC16 cells was decreased significantly in the propofol+CoCl2 group, while Δψm was increased significantly (both P<0.05); 3) Compared with the control group, the levels of ROS and MDA were increased significantly, and the level of SOD was significantly decreased in the CoCl2 group (all P<0.01). Compared with the CoCl2 group, the ROS and MDA levels in the propofol+CoCl2 group were increased significantly and the SOD levels were decreased significantly (all P<0.05); 4) Compared with the control group, the phosphorylation levels of JNK and p38 were increased significantly (both P<0.05) in the CoCl2 group. Compared with the CoCl2 group, the phosphorylation levels of JNK and p38 were decreased significantly in the propofol+CoCl2 group (both P<0.05).
 Conclusion: The pretreatment with propofol may protect human cardiac AC16 cells from the chemical hypoxia-induced injury through regulation of JNK and p38 signaling pathways.
Apoptosis ; Cell Hypoxia ; Cell Line ; Cell Survival ; Cobalt ; pharmacology ; Humans ; Hypoxia ; JNK Mitogen-Activated Protein Kinases ; Propofol ; Reactive Oxygen Species

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a serious complication after surgery, especially in elderly patients. The anesthesia technique is a potentially modifiable risk factor for POCD. This study assessed the effects of dexmedetomidine, propofol or midazolam sedation on POCD in elderly patients who underwent hip or knee replacement under spinal anesthesia. METHODS: The present study was a prospective randomized controlled preliminary trial. From July 2013 and December 2014, a total of 164 patients aged 65 years or older who underwent hip or knee arthroplasty at China-Japan Friendship Hospital and 41 non-surgical controls were included in this study. Patients were randomized in a 1:1:1 ratio to 3 sedative groups. All the patients received combined spinal-epidural anesthesia (CSEA) with midazolam, dexmedetomidine or propofol sedation. The sedative dose was adjusted to achieve light sedation (bispectral index[BIS] score between 70 and 85). All study participants and controls completed a battery of 5 neuropsychological tests before and 7 days after surgery. One year postoperatively, the patients and controls were interviewed over the telephone using the Montreal cognitive assessment 5-minute protocol. RESULTS: In all, 60 of 164 patients (36.6%) were diagnosed with POCD 7 days postoperatively, POCD incidence in propofol group was significantly lower than that in dexmedetomidine and midazolam groups (18.2% vs. 40.0%, 51.9%, χ = 6.342 and 13.603, P = 0.012 and < 0.001). When the patients were re-tested 1 year postoperatively, the incidence of POCD was not significantly different among the 3 groups (14.0%, 10.6% vs. 14.9%, χ = 0.016 and 0.382, P = 0.899 and 0.536). CONCLUSION Among dexmedetomidine, propofol and midazolam sedation in elderly patients, propofol sedation shows a significant advantage in term of short-term POCD incidence.
Aged ; Cognitive Dysfunction ; epidemiology ; Dexmedetomidine ; pharmacology ; Female ; Humans ; Hypnotics and Sedatives ; pharmacology ; Male ; Midazolam ; pharmacology ; Middle Aged ; Neuropsychological Tests ; Postoperative Complications ; epidemiology ; Propofol ; pharmacology ; Prospective Studies

OBJECTIVE: To explore the effects of propofol sedation on psychological stress in patients undergoing surgery under epidural anesthesia. METHODS: Sixty patients scheduled to undergo elective ileostomy closure under epidural anesthesia were randomized into propofol sedation group and control group (=30). The patients in the sedation group received a loading dose of propofol of 0.6 mg·kg· h followed by a maintenance dose with continuous infusion of 3 mg·kg· h given after the Observer's Assessment of Alertness/Sedation (OAA/S) score reached 2-3. An equivalent volume of normal saline was administered in patients in the control group. The patients' preoperative and intraoperative anxiety scores were assessed with the State Anxiety Inventory (SAI) on the day before and on the first day after the surgery, respectively. The mean blood pressure (MBP), heart rate (HR), SpO, OAA/S, and the indicators of psychological stress of brain functional state of the patients (including the wavelet index [WLi], anxiety index [ANXi], comfortable index [CFi] and pain index [Pi]) were recorded at 5 min after entering the operating room (T), at the time of lumbar puncture (T) and change to supine position after the puncture (T), at 20 s (T), 40 s (T), and 60 s (T) after intravenous administration, and at 2 min (T), 4 min (T), 6 min (T), 8 min (T), 10 min (T) and 40 min (T) after skin incision. The patient's satisfaction with anesthesia was assessed with the Visual Analog Scale (VAS) score on the first day after the operation. Serum cortisol level was measured before anesthesia and at the end of operation to calculate the changes in cortisol level. RESULTS: The two groups of patients were comparable for preoperative SAI scores (>0.05); The patients in the sedation group appeared to have lower intraoprative SAI scores, but this difference was not statistically significant (=0.05). MBP, HR, and SpO at the time points from T to T and OAA/S, WLi, ANXi, CFi, and Pi at the time points from T to T were significantly lower in the sedation group (all < 0.05), and these parameters were not significantly different between the two groups at the other time points (all >0.05). The patient satisfaction scores were significantly higher in the sedation group (Z=2.07, < 0.05). Compared with the preoperative levels, serum cortisol level at the end of the operation was increased in the sedation group but lowered in the control group, and the variations of serum cortisol level differed significantly between the two groups (=4.75, < 0.01). CONCLUSIONS Intraoperative propofol sedation can alleviate the patients' anxiety, improve the comfort level, and lessen physiological stress during surgeries under epidural anesthesia.
Anesthesia, Epidural ; Blood Pressure ; drug effects ; Conscious Sedation ; Heart Rate ; drug effects ; Humans ; Hypnotics and Sedatives ; administration & dosage ; pharmacology ; Ileostomy ; Propofol ; administration & dosage ; pharmacology ; Stress, Psychological ; drug therapy ; Visual Analog Scale

OBJECTIVE: To investigate the effects of propofol combined with hypoxia on cognitive function of immature rats and the possible role of p38 pathway and tau protein in mediating such effects. METHODS: Ninety 7-day-old (P7) SD rats were randomized for daily intraperitoneal injection of propofol (50 mg/kg) or lipid emulsion (5.0 mL/kg) for 7 consecutive days. After each injection, the rats were placed in a warm box (38 ℃) with an oxygen concentration of 18% (hypoxia), 21% (normal air), or 50% (oxygen) until full recovery of the righting reflex. Another 90 P7 rats were similarly grouped and received intraperitoneal injections of p-p38 blocker (15 mg/kg) 30 min before the same treaments. The phosphorylated tau protein, total tau protein and p-p38 content in the hippocampus were detected using Western blotting. The spatial learning and memory abilities of the rats were evaluated with Morris water maze test. RESULTS: Compared with lipid emulsion, propofol injection resulted in significantly increased levels of p-p38, phosphorylated tau and total tau proteins in rats with subsequent hypoxic or normal air treatment ( < 0.05), but propofol with oxygen and injections of the blocker before propofol did not cause significant changes in the proteins. Without subsequent oxygenation, the rats receiving injections of propofol, with and without prior blocker injection, all showed significantly prolonged latency time and reduced platform-crossing times and third quadrant residence time compared with the corresponding lipid emulsion groups ( < 0.05). With oxygen treatment, the rats in propofoland blocker-treated groups showed no significant difference in the performance in Morris water maze test from the corresponding lipid emulsion group. The results of Morris water maze test differed significantly between blocker-propofol group and propofol groups irrespective of exposures to different oxygen levels ( < 0.05), but not between the lipid emulsion and blocker group pairs with exposures to different oxygen levels. CONCLUSIONS Propofol combined with hypoxia can affect the expression of tau protein through p38 pathway to impair the cognitive function of immature rats, in which oxygen plays a protective role.
Animals ; Cognitive Dysfunction ; etiology ; metabolism ; Hippocampus ; chemistry ; Hypnotics and Sedatives ; pharmacology ; Hypoxia, Brain ; complications ; metabolism ; MAP Kinase Signaling System ; Maze Learning ; drug effects ; physiology ; Memory ; drug effects ; physiology ; Propofol ; pharmacology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; tau Proteins ; analysis

BACKGROUNDPropofol and etomidate are the most important intravenous general anesthetics in the current clinical use and that mediate gamma-aminobutyric acid's (GABAergic) synaptic transmission. However, their long-term effects on GABAergic synaptic transmission induced by neonatal propofol or etomidate exposure remain unclear. We investigated the long-term GABAergic neurotransmission alterations, following neonatal propofol and etomidate administration.

METHODSSprague-Dawley rat pups at postnatal days 4-6 were underwent 6-h-long propofol-induced or 5-h-long etomidate-induced anesthesia. We performed whole-cell patch-clamp recording from pyramidal cells in the cornus ammonis 1 area of acute hippocampal slices of postnatal 80-90 days. Spontaneous and miniature inhibitory GABAergic currents (spontaneous inhibitory postsynaptic currents [sIPSCs] and miniature inhibitory postsynaptic currents [mIPSCs]) and their kinetic characters were measured. The glutamatergic tonic effect on inhibitory transmission and the effect of bumetanide on neonatal propofol exposure were also examined.

RESULTSNeonatal propofol exposure significantly increased the frequency of mIPSCs (from 1.87 ± 0.35 Hz to 3.43 ± 0.51 Hz, P< 0.05) and did not affect the amplitude of mIPSCs and sIPSCs. Both propofol and etomidate slowed the decay time of mIPSCs kinetics (168.39 ± 27.91 ms and 267.02 ± 100.08 ms vs. 68.18 ± 12.43 ms; P< 0.05). Bumetanide significantly blocked the frequency increase and reversed the kinetic alteration of mIPSCs induced by neonatal propofol exposure (3.01 ± 0.45 Hz and 94.30 ± 32.56 ms).

CONCLUSIONSNeonatal propofol and etomidate exposure has long-term effects on inhibitory GABAergic transmission. Propofol might act at pre- and post-synaptic GABA receptor A (GABAA) receptors within GABAergic synapses and impairs the glutamatergic tonic input to GABAergic synapses; etomidate might act at the postsynaptic site.

Animals ; CA1 Region, Hippocampal ; drug effects ; metabolism ; Electrophysiology ; Etomidate ; pharmacology ; Hippocampus ; drug effects ; metabolism ; Neurons ; drug effects ; metabolism ; Propofol ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, GABA-A ; metabolism ; Synaptic Transmission ; drug effects ; gamma-Aminobutyric Acid ; metabolism