Objective To evaluate the relationship between hippocampal cyclic adenosine monophosphate response element-binding protein(CREB)/brain-derived neurotrophic factor(BDNF)signaling pathway and cognitive dysfunction in rats with chronic pathological pain.Methods Thirty-two healthy adult male Sprague-Dawley rats,weighing 220-250 g,were divided into 3 groups using a random number table:control group(group C,n=8),sham operation group(group S,n=8)and chronic pathological pain group(group CP,n=16).Chronic pathological pain model was established by injecting cobra venom 0.4 mg(4 μl)into the sheath of the infraorbital nerve.The mechanical pain threshold was measured at 3 days before establishment of the model(baseline)and 4 days and 1,2,3,4 and 8 weeks after establishment of the model.Morris water maze test was performed to evaluate the spatial learning and memory abilities at 5 and 9 weeks after establishment of the model.Eight rats were sacrificed at 5 and 9 weeks after establishment of the model in CP group,and rats were sacrificed after the end of Morris water maze test at 9 weeks after establishment of the model in C and S groups.The hippocampi were isolated for determination of the expression of phosphorylated CREB and BDNF in the hippocampal tissues using Western blot.Results Compared with group C,the mechanical pain threshold was significantly decreased at each time point after establishment of the model,the escape latency was prolonged at 5 and 9 weeks after establishment of the model,the rate of time of staying at the target quadrant was decreased,the frequency of crossing the original platform was decreased,and the expression of phosphorylated CREB and BDNF was down-regulated at 9 weeks after establishment of the model in group CP(P<0.05),and no significant change was found in the parameters mentioned above in group S(P>0.05).Conclusion The mechanism underlying cognitive dysfunction may be related to inhibited activation of CREB/BDNF signaling pathway in the hippocampus of rats with chronic pathological pain.

Objective To evaluate the effect of dexmedetomidine on the mammalian target of rapamycin(mTOR)/tau protein signaling pathway in the hippocampus of aged rats after splenectomy.Methods One hundred and fifty pathogen-free healthy male Sprague-Dawley rats,aged 18 months,weighing 400-540 g,were divided into 5 groups(n=30 each)using a random number table:control group(group C),sham operation group(group S),operation group(group O),normal saline group(group NS)and dexmedetomidine group(group D).Group C received no treatment.Ten percent chloral hydrate 0.3 ml/100 g was injected intraperitoneally in group S.Group O underwent splenectomy.Dexmedetomidine 50 μg/kg was injected intraperitoneally at 5 min before splenectomy in group D.The equal volume of normal saline was injected intraperitoneally at 5 min before splenectomy in group NS.Morris water maze test was performed at day 7 after surgery.At days 1,3 and 7 after surgery,the rats were sacrificed,and the hippocampi were removed for examination of the pathological changes in the hippocampal CA3 region and for determination of the expression of mTOR protein and mRNA,tau protein mRNA and phosphor-tau protein(pS396 tau protein)(by real-time polymerase chain reaction or Western blot).Results Compared with group C,the escape latency and swimming distance were significantly prolonged,and the expression of mTOR protein and mRNA,tau protein mRNA and pS396 tau protein was up-regulated in O,D and NS groups(P<0.05),and no significant change was found in the parameters mentioned above in group S(P>0.05).Compared with group O,the escape latency and swimming distance were significantly shortened,and the expression of mTOR protein and mRNA,tau protein mRNA and pS396 tau protein was down-regulated in group D(P<0.05),and no significant change was found in the parameters mentioned above in group NS(P>0.05).The pathological changes in the hippocampal CA3 region were significantly attenuated in group D as compared with group O.Conclusion The mechanism by which dexmedetomidine improves postoperative cognitive function may be associated with inhibited activation of mTOR/tau protein signaling pathway in the hippocampus of aged rats.

Objective To evaluate the effect of sevoflurane postconditioning on the expression of CCAAT/enhancer-binding protein homologous protein (CHOP) in a rat model of hemorrhagic shock and resuscitation.Methods Thirty-six healthy adult male Sprague-Dawley rats,weighing 300-350 g,were divided into 3 groups (n=12 each) using a random number table:sham operation group (group S),hemorrhagic shock and resuscitation group (group HSR) and sevoflurane postconditioning group (group SP).Hemorrhagic shock was induced by withdrawing 40% of the total blood volume from the right carotid artery over an interval of 30 min,and 1 h later the removed blood was reinfused via the left jugular vein for resuscitation.Group SP inhaled 2.4% sevoflurane for 30 min starting from the onset of reinfusion.Mean arterial pressure was monitored and recorded at a 10 min interval.Before withdrawing blood (T0),immediately after the end of withdrawing blood(T1), at 1 h after the end of withdrawing blood(T2) and immediately after the end of reinfusion (T3),blood samples were collected from the common carotid artery for blood gas analysis.At 4 days after reinfusion,6 rats of each group were selected to detect spatial learning and memory ability by using Morris water maze test.The animals were then sacrificed,brains were removed for determination of neuronal apoptosis in hippocampal CA1 area using TUNEL.The rest 6 rats in each group were sacrificed at 72 h after reinfusion,and the hippocampus was isolated to detect the expression of CHOP by Western blot.Results Compared with group S,mean arterial pressure was significantly decreased,and lactic acid concentrations were increased at T1,2 in HSR and SP groups,and the escape latency was significantly prolonged,the percentage of time staying at the target quadrant was decreased,the number of apoptotic neurons in hippocampal CA1 area was increased,and the expression of CHOP was up-regulated in group HSR (P<0.05).Compared with group HSR,the escape latency was significantly shortened,the percentage of time staying at the target quadrant was increased,the number of apoptotic neurons in hippocampal CA1 area was decreased,and the expression of CHOP was down-regulated in group SP (P<0.05).Conclusion The mechanism by which sevoflurane postconditioning improves cognitive function is related to down-regulation of CHOP expression and inhibition of apoptosis in hippocampal neurons in a rat model of hemorrhagic shock and resuscitation.

Objective To evaluate the effect of dexmedetomidine on the expression of gamma-aminobutyric acid(GABAA)receptors during ventilator-induced lung injury(VILI)in rats. Methods Thirty pathogen-free adult male Sprague-Dawley rats,weighing 280-320 g,were divided into 3 groups(n=10 each)using a random number table:control group(group C),group VILI and dexmedetomidine group(group Dex).The rats were mechanically ventilated for 4 h with the tidal volume of 40 ml/kg to establish VILI model. Dexmedetomidine 50 μg/kg was injected intraperitoneally after the rats were anesthetized in group Dex,while the equal volume of normal saline was given instead in C and VILI groups. The animals were sacrificed at 4 h of mechanical ventilation,the lungs were removed for examination of pathological changes which were scored,bronchoalveolar lavage fluid(BALF)was collected for determination of concentrations of total protein,interleukin-1 beta(IL-1β),IL-6 and tumor necrosis factor-alpha(TNF-α),and the lung specimens were obtained for determination of the wet/dry weight ratio(W/D ratio),alveolar fluid clearance(AFC)and expression of GABAA receptors,IL-1β,IL-6 and TNF-α mRNA in lung tissues. Results Compared with group C,the W/D ratio,pathological scores,expression of total protein,IL-1β,IL-6 and TNF-α in BALF and expression of IL-1β,IL-6 and TNF-α mRNA in lung tissues were significantly increased,and the GABAA receptor expression and AFC were decreased in VILI and Dex groups(P<0.05).Compared with group VILI,the W/D ratio,pathological scores,expression of total protein,IL-1β,IL-6 and TNF-α in BALF and expression of IL-1β,IL-6 and TNF-α mRNA in lung tissues were significantly decreased,and the GABAA receptor expression and AFC were increased in group Dex(P<0.05).Conclusion The mechanism by which dexmedetomidine reduces VILI is related to up-regulation of GABAA receptor expression in rats.

Objective To evaluate the effect of hypoxemia factor on hippocampal long-term potentiation(LTP)in newborn rats undergoing propofol anesthesia. Methods Forty-two pathogen-free healthy Sprague-Dawley rats(21 males,21 females),aged 7 days,weighing 14-18 g,were divided into 3 groups(n=14 each)using a random number table:propofol plus air group(group PA),propofol plus pure oxygen group(group PO)and intralipid plus pure oxygen group(group IO).Propofol 50 mg/kg was injected intraperitoneally once a day for 7 consecutive days in PA and PO groups. Intralipid 5.0 ml/kg was injected intraperitoneally once a day for 7 consecutive days in IO group. The rats were exposed to air or pure oxygen for 6 h after the end of each injection. The arterial oxygen saturation and respiratory rate were determined after administration. The rats were returned to the cage after recovery of righting reflex. Six rats in each group were selected for preparation of hippocampal slices at 24 h after the last injection on 7th day,and the electric stimulation-induced field excitatory post synaptic potential(fEPSP)and success rate of LTP induction were recorded. Morris water maze test was performed in the other rats at 2 weeks after administration to assess the cognitive function. Results Compared with group IO,the respiratory rate,amplitude of fEPSP and success rate of LTP induction were significantly decreased,and the escape latency was prolonged in group PO(P<0.05).Compared with group PO,the arterial oxygen saturation,amplitude of fEPSP and success rate of LTP induction were significantly decreased,the escape latency was prolonged,and the number of crossing the original platform was decreased in group PA(P<0.05).Conclusion Hypoxemia factor increases propofol-induced neurotoxicity in the central nervous system of newborn rats.

Objective To evaluate the efficacy of superficial temporal artery(STA)pressure-guided selective cerebral perfusion(SCP)during deep hypothermic circulatory arrest(DHCA)in patients undergoing aortic arch surgery.Methods Ninety-six patients of both sexes,aged 35-64 yr,with body mass index of 19-23kg/m2,of American Society of Anesthesiologists physical status Ⅲ or Ⅳ,undergoing aortic arch surgery,were divided into STA pressure group(group A)and clinical experience group(group B)using a random number table,with 48 patients in each group.In group A,STA catheterization was performed after tracheal intubation,and arterial pressure was monitored.SCP flow was adjusted to maintain the target value of STA pressure between 30 and 40mmHg during DHCA in group A.SCP flow rate was set at 5-10ml·kg-1·min-1 according to clinical experience in group B.The volume of fluid perfused during SCP,emergence time,extubation time and duration of intensive care unit stay were recorded.Neurological function was evaluated during length of hospitalization after surgery,and the development of permanent and transient neurological dysfunction and mortality in hospital were recorded.Results Compared with group B,the volume of fluid perfused during SCP was significantly decreased,the emergence time,extubation time and duration of intensive care unit stay were shortened,the incidence of permanent and transient neurological dysfunction(2% and 4%,respectively)was decreased(P < 0.05),and no significant change was found in the mortality rate in hospital in group A(P>0.05).Conclusion Maintaining STA pressure at 30-40mmHg is a reliable method for guiding SCP during DHCA in patients undergoing aortic arch surgery.

Objective To evaluate the effect of oxycodone pretreatment on autophagy during renal ischemia-reperfusion (I/R) in rats.Methods Thirty-six SPF healthy adult male Wistar rats,aged 6-9 weeks,weighing 180-220 g,were divided into 3 groups (n=12 each) using a random number table:sham operation group (Sham group),I/R group and oxycodone pretreatment group (Oxy group).The left renal pedicles were clamped with atraumatic microclips for 45 min followed by reperfusion to establish the model of renal I/R injury in I/R and Oxy groups.Oxycodone 0.5 mg/kg was injected via the caudal vein at 15 min before ischemia in group Oxy,and the equal volume of normal saline was given instead in I/R and Sham groups.At 24 h of reperfusion,blood samples were collected from hearts for measurement of serum creatinine (Cr) and blood urea nitrogen (BUN) concentrations.The animals were then sacrificed and left renal tissues were obtained for examination of pathological changes (with a light microscope) and for determination of Bcl-2 and Beclin-1 expression (by immunohistochemistry).Results Compared with Sham group,the concentrations of serum Cr and BUN were significantly increased,and the expression of Bcl-2 and Beclin-1 in renal tissues was up-regulated at 24 h of reperfusion in I/R and Oxy groups (P<0.05).Compared with I/R group,the concentrations of serum Cr and BUN were significantly decreased,the expression of Bcl-2 in renal tissues was up-regulated,and the expression of Beclin-1 in renal tissues was down-regulated at 24 h of reperfusion (P<0.05),and the pathological changes were significantly attenuated in Oxy group.Conclusion Oxycodone pretreatment inhibits autophagy through up-regulating the expression of Bcl-2 and down-regulating the expression of Beclin-1,thus attenuating renal I/R injury in rats.

Objective To evaluate the effect of high-level spinal cord injury(SCI)on the expression of mitochondrial voltage-dependent anion channel 2(VDAC2)in rat cardiomyocytes.Methods Forty-eight pathogen-free healthy adult male Sprague-Dawley rats,weighing 200-250 g,were divided into 2 groups(n=24 each)using a random number table:sham operation group(group S)and high-level SCI group(group H).The animals were anesthetized with intraperitoneal chloral hydrate and subjected to SCI using the modified Allen weight-drop method in group H.The spinal cord was only exposed in group S.At 6,12,24 and 48 h after SCI(T1-4),6 rats in each group were randomly selected and sacrificed,and myocardial specimens were collected from the cardiac apex for microscopic examination of the cell morphology(with a transmission electron microscope) and for determination of cell apoptosis(by TUNEL assay),expression of Bax,Bcl-2 and VDAC2 protein and mRNA in cardiomyocytes(by Western blot and real-time polymerase chain reaction,respectively).The apoptosis rate and ratios of Bax/Bcl-2 protein and mRNA were calculated.Results Compared with group S,the apoptosis rate and ratios of Bax/Bcl-2 protein and mRNA were significantly increased at T1-4,the expression of VDAC2 protein and mRNA was significantly down-regulated at T2-4(P<0.05 or 0.01),and the pathologic changes of cardiomyocytes were aggravated in group H.Conclusion The mechanism of myocardial damage is related to down-regulation of mitochondrial VDAC2 expression in cardiomyocytes and promotion of cell apoptosis in rats with high-level SCI.

Objective To evaluate the role of nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) singling pathway in reduction of myocardial ischemia-reperfusion (I/R) injury by zinc sulfate preconditioning in rats.Methods SPF healthy male Sprague-Dawley rats,weighing 250-280 g,aged 16-20 weeks,were used in this study.After the animals were anesthetized,their hearts were immediately removed and retrogradely perfused with an oxygenated K-H solution at 37 ℃ in a Langendorff apparatus.Forty isolated rat hearts were randomly divided into 4 groups (n=10 each):control group (group C),I/R group,zinc sulfate preconditioning group (group Zn) and zinc sulfate preconditioning plus Nrf2/ARE singling pathway blocker luteolin group (group Zn+Lut).After 20 min of equilibration,the hearts were continuously perfused for 100 min in group C,the hearts were perfused with 4 ℃ St.Thomas′ cardioplegic solution before ischemia and then subjected to 40 min global ischemia followed by 60 min reperfusion to establish the model of I/R in group I/R,200 μmol/L zinc sulfate 1.5 ml/kg was injected intraperitoneally,and 24 h later the model of I/R was established in group Zn,and in group Zn+Lut,the hearts were perfused for 3 min with K-H solution containing luteolin 50 μmol/L starting from the time point immediately before ischemia,and the other treatments were similar to those previously described in group Zn.Heart rate (HR),left ventricular end diabetic pressure (LVEDP),left ventricular developed pressure (LVDP) and the maximum rate of increase of left ventricular pressure (+dp/dtmax) were recorded at the end of equilibration and reperfusion.Coronary effluent was collected at the end of reperfusion to measure the levels of lactate dehydrogenase (LDH) and malondialdehyde (MDA).The expression of heme oxygenase-1 (HO-1),quinone oxidoreductase (NQO1),superoxide dismutase 1 (SOD1) and Nrf2 in myocardial tissues was detected by Western blot.Results Compared with group C,HR,+dp/dtmax and LVDP were significantly decreased,LVEDP was increased,and the levels of LDH and MDA in coronary effluent were increased at the end of reperfusion in I/R and Zn+Lut groups,and the expression of NQO1,HO-1,Nrf2 and SOD1 was up-regulated in I/R,Zn and Zn+Lut groups (P<0.05).Compared with group I/R,the HR,+dp/dtmax and LVDP were significantly increased,LVEDP was decreased,and the levels of LDH and MDA in coronary effluent were decreased at the end of reperfusion,and the expression of NQO1,HO-1,Nrf2 and SOD1 was up-regulated in group Zn (P<0.05).Compared with group Zn,HR,+dp/dtmax and LVDP were significantly decreased,LVEDP was increased,and the levels of LDH and MDA in coronary effluent were increased at the end of reperfusion,and the expression of NQO1,HO-1 and SOD1 was down-regulated(P<0.05),and no significant change was found in Nrf2 expression in group Zn+Lut (P>0.05).Conclusion The mechanism by which zinc sulfate preconditioning reduces myocardial I/R injury is related to activation of Nrf2/ARE singling pathway in rats.