Dopaminergic neurons in the ventral tegmental area (VTA) play an important role in cognition, emergence from anesthesia, reward, and aversion, and their projection to the cortex is a crucial part of the "bottom-up" ascending activating system. The prelimbic cortex (PrL) is one of the important projection regions of the VTA. However, the roles of dopaminergic neurons in the VTA and the VTA^DA-PrL pathway under sevoflurane anesthesia in rats remain unclear. In this study, we found that intraperitoneal injection and local microinjection of a dopamine D1 receptor agonist (Chloro-APB) into the PrL had an emergence-promoting effect on sevoflurane anesthesia in rats, while injection of a dopamine D1 receptor antagonist (SCH23390) deepened anesthesia. The results of chemogenetics combined with microinjection and optogenetics showed that activating the VTA^DA-PrL pathway prolonged the induction time and shortened the emergence time of anesthesia. These results demonstrate that the dopaminergic system in the VTA has an emergence-promoting effect and that the bottom-up VTA^DA-PrL pathway facilitates emergence from sevoflurane anesthesia.
Anesthesia ; Animals ; Dopaminergic Neurons/metabolism* ; Rats ; Receptors, Dopamine D1/metabolism* ; Sevoflurane/pharmacology* ; Ventral Tegmental Area/metabolism*

A growing number of studies have identified sex differences in response to general anesthesia; however, the underlying neural mechanisms are unclear. The medial preoptic area (MPA), an important sexually dimorphic structure and a critical hub for regulating consciousness transition, is enriched with estrogen receptor alpha (ERα), particularly in neuronal clusters that participate in regulating sleep. We found that male mice were more sensitive to sevoflurane. Pharmacological inhibition of ERα in the MPA abolished the sex differences in sevoflurane anesthesia, in particular by extending the induction time and facilitating emergence in males but not in females. Suppression of ERα in vitro inhibited GABAergic and glutamatergic neurons of the MPA in males but not in females. Furthermore, ERα knockdown in GABAergic neurons of the male MPA was sufficient to eliminate sex differences during sevoflurane anesthesia. Collectively, MPA ERα positively regulates the activity of MPA GABAergic neurons in males but not in females, which contributes to the sex difference of mice in sevoflurane anesthesia.
Anesthesia ; Animals ; Estrogen Receptor alpha/metabolism* ; Female ; Male ; Mice ; Preoptic Area ; Sevoflurane/pharmacology* ; Sex Characteristics

OBJECTIVES: Myocardial ischemia reperfusion injury (IRI) occurs occasionally in the process of ischemic heart disease. Sevoflurane preconditioning has an effect on attenuating IRI. Preserving the structural and functional integrity of mitochondria is the key to reduce myocardial IRI. Silent information regulator 3 (SIRT3), a class of nicotinamide adenine dinucleotide (NAD⁺) dependent deacetylases, is an important signal-regulating molecule in mitochondria. This study aims to explore the role of mitochondrial NAD⁺-SIRT3 pathway in attenuating myocardial IRI in rats by sevoflurane preconditioning. METHODS: A total of 60 male Sprague Dawley (SD) rats were randomly divided into 5 groups (n=12): A sham group (Sham group), an ischemia reperfusion group (IR group), a sevoflurane preconditioning group (Sev group, inhaled 2.5% sevoflurane for 30 min), a sevoflurane preconditioning+SIRT3 inhibitor 3-TYP group (Sev+3-TYP group, inhaled 2.5% sevoflurane for 30 min and received 5 mg/kg 3-TYP), and a 3-TYP group (5 mg/kg 3-TYP). Except for the Sham group, the IR model in the other 4 groups was established by ligating the left anterior descending coronary artery. The size of myocardial infarction was determined by double staining. Serum cardiac troponin I (cTnI) level was measured. The contents of NAD⁺ and ATP, the activities of mitochondrial complexes I, II, and IV, the content of MDA, the activity of SOD, and the changes of mitochondrial permeability were measured. The protein expression levels of SIRT3, SOD2, catalase (CAT), and voltage dependent anion channel 1 (VDAC1) were detected by Western blotting. The ultrastructure of myocardium was observed under transmission electron microscope. MAP and HR were recorded immediately before ischemia (T0), 30 min after ischemia (T1), 30 min after reperfusion (T2), 60 min after reperfusion (T3), and 120 min after reperfusion (T4). RESULTS: After ischemia reperfusion, the content of NAD⁺ in cardiac tissues and the expression level of SIRT3 protein were decreased (both P<0.01), and an obvious myocardial injury occurred, including the increase of myocardial infarction size and serum cTnI level (both P<0.01). Correspondingly, the mitochondria also showed obvious damage on energy metabolism, antioxidant function, and structural integrity, which was manifested as: the activities of mitochondrial complexes I, II, and IV, ATP content, protein expression levels of SOD2 and CAT were decreased, while MDA content, VDAC1 protein expression level and mitochondrial permeability were increased (all P<0.01). Compared with the IR group, the content of NAD⁺ in cardiac tissues and the expression level of SIRT3 protein were increased in the Sev group (both P<0.01); the size of myocardial infarction and the level of serum cTnI were decreased in the Sev group (both P<0.01); the activities of mitochondrial complexes I, II, and IV, ATP content, protein expression levels of SOD2 and CAT were increased, while MDA content, VDAC1 protein expression level, and mitochondrial permeability were decreased in the Sev group (all P<0.01). Compared with the Sev group, the content of NAD⁺ in cardiac tissues and the expression level of SIRT3 protein were decreased in the Sev+3-TYP group (both P<0.01); the size of myocardial infarction and the level of serum cTnI were increased in the Sev+3-TYP group (both P<0.01); the activities of mitochondrial complexes I, II, and IV, ATP content, protein expression levels of SOD2 and CAT were decreased, while MDA content, VDAC1 protein expression level, and mitochondrial permeability were increased in the Sev+3-TYP group (all P<0.01). CONCLUSIONS Sevoflurane preconditioning attenuates myocardial IRI through activating the mitochondrial NAD⁺-SIRT3 pathway to preserve the mitochondrial function.
Adenosine Triphosphate/metabolism* ; Animals ; Male ; Mitochondria/metabolism* ; Myocardial Infarction/metabolism* ; Myocardial Reperfusion Injury/metabolism* ; NAD/metabolism* ; Rats ; Rats, Sprague-Dawley ; Sevoflurane/metabolism* ; Sirtuin 3/metabolism* ; Voltage-Dependent Anion Channel 1/metabolism*

Objective To explore the effect of dexmedetomidine(Dex)on sevoflurane-induced cognitive impairment in neonatal rats through Wnt signaling pathway. Methods Sixty 7-day-old SD rats were assigned into five groups:control group(without any intervention),Dex group(intraperitoneal injection of 25 μg/kg Dex),sevoflurane group(3% sevoflurane treatment for 4 hours),sevoflurane+Dex group(inhalation of 3% sevoflurane after injection of 25 μg/kg Dex for 4 hours),and sevoflurane+Dex+Wnt inhibitor group(Wnt inhibitor XAV393 and 25 μg/kg Dex were injected and 3% sevoflurane was inhaled for 4 hours).Three weeks later,Morris water maze was used to detect the cognitive function;TdT-mediated dUTP nick end labeling(TUNEL)staining was performed to detect the apoptosis of hippocampal neurons;neuronal nuclei (NeuN) staining was conducted to detect the survival of hippocampal neurons;Western blot was carried out to detect the expression of apoptosis-related proteins.The expression of the factors involved in Wnt/GSK-3β/β-catenin signaling pathway was detected by fluorescence quantitative polymerase chain reaction,and Western blot. Results Compared with the control group,there was no significant difference in the escape latency of Dex group(t=0.304,P=0.768);the escape latency in sevoflurane group(t=5.823,P=0.002),sevoflurane+Dex group(t=3.188,P=0.010),and sevoflurane+Dex+Wnt inhibitor group(t=5.784,P=0.002)was significantly prolonged.Compared with that in the sevoflurane group,the escape latency in sevoflurane+Dex group(t=3.646,P=0.005)was significantly shortened.Compared with that in sevoflurane+Dex group,the escape latency in sevoflurane+Dex+Wnt inhibitor group(t=3.296,P=0.008)was prolonged.Compared with that in the control group,the times of crossing platform in sevoflurane group(t=5.179, P=0.004),sevoflurane+Dex group(t=2.309,P=0.043),and sevoflurane+Dex+Wnt inhibitor group(t=3.871, P=0.003)decreased.Compared with that in sevoflurane group,the times of crossing platform in sevoflurane+Dex group(t=3.296,P=0.008)significantly increased.Compared with that in sevoflurane+Dex group,the times of crossing platform in sevoflurane+Dex+Wnt inhibitor group(t=2.361, P=0.041)reduced.Compared with the control group,there was no significant difference in the number of apoptotic cells in Dex group(t=1.920,P=0.127),and the number of apoptotic cells in sevoflurane group,sevoflurane+Dex group,and sevoflurane+Dex+Wnt inhibitor group increased by 16%(t=13.436,P=0.002),5%(t=7.752, P=0.001),and 11.5%(t=12.612,P=0.002),respectively.Compared with that in the sevoflurane group,the number of apoptotic cells in sevoflurane+Dex group and sevoflurane+Dex+Wnt inhibitor group decreased by 11%(t=8.521,P=0.002)and 5.5%(t=3.123,P=0.036),respectively.Compared with that in the sevoflurane+Dex group,the number of apoptotic cells in sevoflurane+Dex+Wnt inhibitor group increased by 6.5%(t=6.250,P=0.003).Compared with that in the control group,the number of positive cells in 0.15 mm
Animals ; Animals, Newborn ; Cognitive Dysfunction/chemically induced* ; Dexmedetomidine/pharmacology* ; Glycogen Synthase Kinase 3 beta ; Rats ; Rats, Sprague-Dawley ; Sevoflurane/toxicity* ; Wnt Signaling Pathway ; beta Catenin/metabolism*

OBJECTIVE: To explore the delayed neuroprotective effect of sevoflurane on the expression of NF-kappaB in rat models of transient focal ischemia-reperfusion. METHODS: Adult male Sprague-Dawley rats (220 approximately 300 g) were randomly assigned into 3 groups:an ischemia-reperfusion (I/R) group, and a 2.5% Sevoflurane (Sevo1) group, and a 4.0% sevoflurane (Sevo2) group. All the rats were subjected to right middle cerebral artery occlusion (MCAO) for 2 hours. The rats in the I/R group were exposed to pure oxygen 60 min at 24 h before MCAO. Sevoflurane preconditioning was induced 24 h before brain ischemia by exposing the rats to 2.5% or 4.0% sevoflurane + oxygen for 60 min. The effects of sevoflurane on the brain was analyzed by evaluating the infarct volume and the expression of NF-kappaB protein through 2, 3, 5-triphenyltetrazolium chloride (TTC) staining and immunohistochemistry at 24 and 72 h after the reperfusion. RESULTS: The infarct volumes were significantly reduced in the Sevo1 and Sevo2 groups at 24 and 72 h after the reperfusion, compared with the I/R group. The expression of NF-kappaB in the ischemic territory increased after cerebral ischemia, sevoflurane could remarkably decrease the expression of NF-kappaB in 24 and 72 h after the reperfusion. CONCLUSION Sevoflurane inhibits the expression of NF-kappaB protein during focal ischemia the reperfusion,which may be part of the mechanism of its delayed neuroprotective function.
Animals ; Ischemic Attack, Transient ; drug therapy ; metabolism ; Male ; Methyl Ethers ; pharmacology ; therapeutic use ; NF-kappa B ; genetics ; metabolism ; Neuroprotective Agents ; pharmacology ; therapeutic use ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury ; metabolism ; prevention & control ; Sevoflurane

OBJECTIVE: To observe the effects of different maintain doses of Dexmedetomidine on plasma cortisol and glucose during anesthesia recovery period in patients undergoing uvulopalatopharyngoplasty under sevoflurane inhalation anesthesia. METHOD: In this prospective, randomized, double-blind study, 120 ASA I and II patients undergoing selective uvulopalatopharyngoplasty under general anesthesia were included. The patients were randomly allocated to three groups (n = 40): Dexmedetomidine low maintain dose group (D1), Dexmedetomidine high maintain dose group (group D2) and control group (group C). The Dexmedetomidine groups and control group were given Dexmedetomidine 1 microg/kg and normal saline in 20 ml within 15 min just before induction of anesthesia. Then Dexmedetomidine were maintained at 0.2 microg x kg(-1) x h(-1) and 0.7 microg x kg(-1) x h(-1) in group D1 and group D2 and were withdrawed 5 min before the end of operation, the same maintained speed of normal saline was given in group C. BIS value was maintained at 40-60 by adjusting the inhaled concentration of sevoflurane. Anesthetic was withdrawed 10 min before the end of operation. Thus, plasma cortisol concentration and blood glucose was needed to be detected just before anesthesia (T0), tracheal extubation (T1), 5 min after extubation (T2) and 15 min after extubation (T3). Duration of operation and anesthesia, consumption of sevoflurane, emergence time, extubation time, the occurrence of dysphoria, bucking and hypoxemia (SpO2 < 90%) during extubation were recorded. RESULT: Compared with group C, MAP and HR at T1, plasma cortisol concentration and blood glucose at T1 - T3 were all significantly lower in group D1 and group D2 (P < 0.05), and so were the consumption of sevoflurane and the occurrence of dysphoria (P < 0.05). The emergence time and extubation time were significantly prolonged in group D2 compared with group D1 and group C (P < 0.05). There was no significant difference in the occurrence of bucking and hypoxemia in three groups (P > 0.05). CONCLUSION In the patients undergoing UPPP under sevoflurane inhalation anesthesia, Dexmedetomidine infused at 0.2 microg x kg(-1) x h(-1) maintains a stable hemodynamics without respiratory depression, alleviates stress response during extubation and reduces both the consumption of sevoflurane and the occurrence of dysphoria without prolonging emergence time and extubation time.
Adult ; Anesthesia Recovery Period ; Anesthesia, Inhalation ; Blood Glucose ; metabolism ; Dexmedetomidine ; administration & dosage ; Double-Blind Method ; Female ; Humans ; Hydrocortisone ; blood ; Hypnotics and Sedatives ; administration & dosage ; Male ; Methyl Ethers ; Middle Aged ; Otorhinolaryngologic Surgical Procedures ; Palate, Soft ; surgery ; Pharynx ; surgery ; Sevoflurane ; Uvula ; surgery

OBJECTIVE: To investigate whether the reactive oxygen species (ROS) and mitochondrial ATP-sensitive potassium (mitoKATP) channels were involved in delayed neuroprotection induced by sevoflurane on tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels. METHODS: Eighty-four male SD rats weighing 250 approximately 280 g, undergoing thread embolism of the right middle cerebral artery occlusion (MCAO) to cause focal ischemia for 2 h and then undergoing 24 h reperfusion, were randomly divided into 7 groups (n=12, each): a sham group(S), an ischemia-reperfusion group (I/R), a sevoflurane preconditioning group (Sevo), a 2-mercaptopropionylglycine (ROS scavenger)+sevoflurane group (MPG+Sevo), a 5-hydroxydecanoate (a mitoK(ATP) blocker) + sevoflurane group (5-HD+Sevo), an MPG group, and a 5-HD group. The protein level of TNF-alpha and IL-1beta in the cerebral issue was detected by enzyme linked immunosorbent assay (ELISA) and the expression of mRNA was measured by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Apoptosis index (AI), the protein level and the mRNA expression of TNF-alpha and IL-1beta were significantly higher in the I/R group than those of Group S. Pre-administration of sevoflurane could inhibit the increase of the protein level and the expression of mRNA of TNF-alpha, and IL-1beta and attenuate the cerebral damage induced by ischemia-reperfusion. Neuroprotection of sevoflurane preconditioning was abolished by MPG and 5-HD. However, MPG and 5-HD alone had no effect. CONCLUSION Sevoflurane can produce delayed protection against cerebral ischemia-reperfusion injury by down-regulating TNF-alpha, IL-1beta protein, and mRNA expression.
Animals ; Hypoxia-Ischemia, Brain ; complications ; drug therapy ; Infarction, Middle Cerebral Artery ; complications ; drug therapy ; Interleukin-1beta ; genetics ; metabolism ; Ischemic Preconditioning ; methods ; KATP Channels ; metabolism ; Male ; Methyl Ethers ; pharmacology ; therapeutic use ; Neuroprotective Agents ; pharmacology ; therapeutic use ; RNA, Messenger ; genetics ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; metabolism ; Reperfusion Injury ; etiology ; prevention & control ; Sevoflurane ; Tumor Necrosis Factor-alpha ; genetics ; metabolism