Effect Of Dexmedetomidine Pretreatment Research Articles

Dexmedetomidine Pretreatment of Neuronal Cells Has Protective Effect Against Cell Death During Oxygen-glucose Deprivation/Reoxygenation, Based on IGF-1 Production.

Insulin-like growth factor 1 (IGF-1) protects neuronal-cell damage by ischemia. Although neuronal cells have been reported to produce IGF-1, the molecular mechanisms remains obscure. Dexmedetomidine (DEX) protects neuronal cells from ischemic damage. We investigated the involvement of IGF-1 in the effect of DEX pretreatment on neuronal ischemic damage using an in vitro mouse hippocampal neuron model. We used Dexmedetomidine and cryopreserved passaged mouse hippocampal neuronal HT22. Other reagents in this study were analytical grade. Ischemia-reperfusion was modeled using the in vitro oxygen-glucose deprivation/reoxygenation (OGD/R). The effect of DEX was examined by incubating cells in DEX-containing medium for 1 hour prior to OGD/R. The cell damages were evaluated by lactate dehydrogenase (LDH) release. The amount of released IGF-1 were evaluated quantitatively by ELISA. The degree of Akt phosphorylation was evaluated by western blotting. OGD/R loading promoted LDH release from neuronal cells, while DEX pretreatment suppressed the LDH release. IGF-1 release from them was primed by DEX pretreatment under OGD/R condition, but not under normal conditions. Akt was activated in DEX-pretreated cells following OGD/R loading. IGF-1 neutralizing antibody (αIGF-1) eliminated the above effects of DEX pretreatment. However, IGF-1 receptor expression in neuronal cells was not affected by DEX pretreatment prior to OGD/R loading. Our results demonstrate that neuronal cells primed with DEX under OGD/R conditions could release IGF-1 and potentially protect themselves via the IGF-1/Akt pathway. Consequently, it appears that neuronal cells activated by DEX have the capacity to self-protect from ischemic damage.

Protective effect of dexmedetomidine pre treatment against myocardial ischemia reperfusion injury in rats

Purpose: To determine the protective effect of dexmedetomidine pre-treatment against myocardial ischemia-reperfusion injury (MRI), and the involvement of ER stress and protein kinase R-like ER enzyme (PERK) signaling pathway in the process.
 Methods: Sixty male Sprague-Dawley (SD) rats were assigned to three groups: sham, model (ischemia-reperfusion), and dexmedetomidine pre-treatment groups. Myocardial infarction area was measured using 2,3,5-triphenyl tetrazolium chloride (TTC) method. Changes in heart structure were examined using H & E, while myocardial cell apoptosis was determined with TUNEL assay. The protein expression levels of CHOP, glucose regulatory protein 78, ATF4, eukaryotic translation initiation factor 2-α (elf2-α), and PERK were assayed with Western blotting.
 Results: RPP, myocardial infarction area, myocardial cell apoptosis rate, and the expression levels of CHOP, GRP78, ATF4, elf2-α, and PERK were significantly raised, relative to sham. The structure of myocardial cells in sham-operated rats was intact and orderly. In contrast, the arrangement of myocardial cells in the model group was disordered, and the myofibrils were broken or wavy. However, the arrangement of myocardial cells in the dexmedetomidine group was significantly improved, when compared with the model group.
 Conclusion: Pretreatment with dexmedetomidine may exert a protective effect against MRI through suppression of ER stress and PERK signaling pathway. Further preclinical studies would be required to validate these findings.

Effects of Dexmedetomidine Pretreatment, Posttreatment, and Whole-Course Pumping on Myocardial Damage during Cardiac Valve Replacement.

To compare the effects of dexmedetomidine (DEX) pretreatment, posttreatment, and whole-course pumping on myocardial protection during cardiac valve replacement.One hundred and twenty patients undergoing cardiac valve replacement were randomly divided into the follow groups: DEX pretreatment (D1 group), DEX posttreatment (D2 group), DEX whole-course pumping (D3 group), and Control (C group). The concentrations of cardiac troponin I (cTnI), malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), rate of spontaneous heart rebound after aortic opening, time to heart rebound, incidence of arrhythmia, and use of sufentanil and vasoactive drugs were recorded.Compared with group C, the concentrations of cTnI, MDA, and TNF-α in the D1, D2, and D3 groups were lower, especially in the latter. The time to heart rebound was prolonged in all three groups (P < 0.05). The rate of automatic rebound was increased (P < 0.05) while the incidence of arrhythmia was decreased (P < 0.05) in all groups compared with group C. Group D3 had the highest rate of automatic rebound and the lowest incidence of arrhythmia. Compared with groups C and D2, the use of sufentanil and dopamine was lower in groups D1 and D3 (P < 0.05), especially in the latter.During cardiac valve replacement, DEX pretreatment, posttreatment, and whole-course pumping could have myocardial protective effects. The latter showed better effects.

Effect of dexmedetomidine pretreatment on a rat model of myocardial ischemia-reperfusion injury

&#x0D; &#x0D; &#x0D; &#x0D; Purpose: To study the effect of dexmedetomidine pretreatment on a rat model of myocardial ischemia-reperfusion injury (IRI)&#x0D; Methods: Three groups of SD rats (n = 48; mean body weight = 275 ± 25 g) were used (16 rats each): sham, IRI, and dexmedetomidine groups. Ischemia-reperfusion injury (IRI) was established via ligation of left anterior coronary artery. Rats in dexmedetomidine group were treated with single i.p. injection of dexmedetomidine (100 μg/kg) 30 min before induction of IRI. Serum levels of IL-1β, IL-6 and TNF-α were determined by enzyme-linked immunosorbent assay (ELISA). Western blotting was used to determine the protein expressions of bcl-2 and bax, while histopathological changes in rat myocardial tissue were determined with H&amp;E staining.&#x0D; Results: Serum TNF-α, IL-1β and IL-6 levels were significantly up-regulated in IRI rats, relative to sham rats, but were decreased by dexmedetomidine (p &lt; 0.05). Dexmedetomidine significantly reduced the level of malondialdehyde (MDA) in myocardial tissues of IRI rats, but it increased superoxide dismutase (SOD) activity (p &lt; 0.05). It also markedly increased bcl-2 protein level, while the protein expression of bax was decreased (p &lt; 0.05). Results of H &amp; E staining showed that dexmedetomidine significantly mitigated IRI-induced damage.&#x0D; Conclusion: Dexmedetomidine mitigates myocardial IRI in rats through suppression of inflammatory and apoptotic changes, and enhancement of physiological antioxidant potential. This finding may be useful for the management of myocardial ischemia-reperfusion injury.&#x0D; &#x0D; &#x0D; &#x0D;

Analysis of the Effect of Dexmedetomidine Pretreatment Combined with Post-treatment on Myocardial Ischemia-reperfusion Injury

Analysis of the Effect of Dexmedetomidine Pretreatment Combined with Post-treatment on Myocardial Ischemia-reperfusion Injury

Effects of dexmedetomidine pretreatment on rats with sepsis-induced acute kidney injury and miR-146a expression

The current research aimed to study the effects of dexmedetomidine (DEX) pretreatment on rats with sepsis-induced acute kidney injury (SAKI) and miR-146a expression. The model of SAKI was established through the tail vein injection of lipopolysaccharide (LSP). We used an automatic biochemical analyzer to detect serum urea nitrogen (BUN) and creatinine (Cre) levels. The expression levels of urine KIM-1 and NGAL and serum IL-1β and IL-6 were analyzed by enzyme-linked immunosorbent assay (ELISA). The content and activity of superoxide dismutase (SOD) were detected by the xanthine oxidase method. The content of malondialdehyde (MDA) was determined by the thiobarbituric acid (TBA) method. Reactive oxygen species (ROS) was detected by fluorescent probe DCFH-DA. Catalase (CAT) was detected by potassium permanganate titration. The expression level of miR-146a in the renal tissue and serum was detected by RT-PCR. The expression levels of Nrf2 and HO-1 proteins were detected by Western blot. Compared with those in the model group, rats in the DEX group had significantly lower expression levels of serum BUN, Cre, IL-1β, and IL-6, and oxidant markers MDA and ROS, but significantly higher expression levels of miR-146a and antioxidant markers SOD and CAT. DEX pretreatment could improve the kidney morphology, injury severity, and Nrf2 and HO-1 proteins of rats with SAKI. In conclusion, DEX can improve oxidative stress and inflammatory responses in rats with SAKI, reduce the severity of the renal injury, and up-regulate the expression level of miR-146a.

Effects of dexmedetomidine pretreatment on expression of TFAM and SDHA during lung ischemia-reperfusion in mice

Objective To evaluate the effect of dexmedetomidine pretreatment on the expression of mitochondrial transcription factor A (TFAM) and succinate dehydrogenase (SDHA) during lung ischemia-reperfusion (I/R) in mice. Methods Twenty-four clean-grade healthy male C57BL/6J mice, aged 8-10 weeks, weighing 18-22 g, were divided into 3 groups (n=8 each) using a random number table method: sham operation group (group S), lung I/R group (group I/R) and dexmedetomidine pretreatment group (group D). In I/R and D groups, lung I/R was induced by clamping the left pulmonary hilum for 60 min followed by 120-min reperfusion in anesthetized mice.The chest was only opened, but the left pulmonary hilum was not occluded in group S. Dexmedetomidine 25 μg/kg was intraperitoneally injected at 30 min before ischemia in group D, while the equal volume of normal saline was given instead of dexmedetomidine in I/R and S groups.The mice were sacrificed at 120 min of reperfusion, and lungs were removed for determination of wet/dry weight ratio (W/D ratio), cell apoptosis (by TUNEL) and expression of TFAM and SDHA mRNA in lung tissues (by real-time polymerase chain reaction) and for examination of the pathological changes of lung tissues.The apoptosis index was calculated. Results Compared with group S, the W/D ratio, apoptosis index and lung injury scores were significantly increased, and the expression of TFAM and SDHA mRNA was down-regulated in I/R and D groups (P<0.05). Compared with group I/R, the W/D ratio, apoptosis index and lung injury scores were significantly decreased, and the expression of TFAM and SDHA mRNA was up-regulated in group D (P<0.05). Conclusion The mechanism by which dexmedetomidine pretreatment attenuates lung I/R injury is related to up-regulating the expression of TFAM and SDHA in mice. Key words: Dexmedetomidine; Lung; Reperfusion injury; Mitochondria; Transcription factors; Succinate dehydrogenase

Effect of dexmedetomidine pretreatment on JAK/STAT signaling pathway during myocardial injury induced by liver ischemia-reperfusion in rats

Objective To investigate the effect of dexmedetomidine pretreatment on Janus kinase/signal transducer and activator of transcription(JAK/STAT)signaling pathway during myocardial injury induced by liver ischemia-reperfusion(I/R)in rats. Methods Twenty-four healthy adult male Sprague-Dawley rats, aged 8-10 weeks, weighing 220-250 g, were divided into 3 groups(n=8 each)using a random number table method: sham operation group(group S), liver I/R group(group I/R), and dexmedetomidine pretreatment group(group D). The portal vein, superior and inferior vena cava, subhepatic inferior vena cava and hepatic artery were clamped, and the liver was perfused with 4 ℃ lactated Ringer′s solution for 60 min through the portal vein to establish the model of liver cold I/R in anesthetized rats.Dexmedetomidine 100 μg/kg was intraperitoneally injected at 30 min before ischemia in group D. Blood samples were collected at 8 h of reperfusion from the inferior vena cava for determination of serum cardiac troponin Ⅰ (cTnI) and heart-type fatty acid binding protein(H-FABP)concentrations(using the automatic biochemistry analyzer), tumor necrosis factor-alpha(TNF-α)and high-mobility group box 1 protein(HMGB1)concentrations(by enzyme-linked immunosorbent assay). The rats were then sacrificed, and hearts were harvested for examination of histopathological changes(with a light microscope)and for determination of the malondialdehyde(MDA)content(using thiobarbituric acid method)and superoxide dismutase(SOD)activity(by xanthine oxidase method), and expression of phosphorylated STAT1 and STAT3(p-STAT1, p-STAT3)and phosphorylated JAK2(p-JAK2)in myocardial tissues(by Western blot). Results Compared with group S, the serum concentrations of cTnI, H-FABP, TNF-α and HMGB1 were significantly increased, the MDA content was increased, the SOD activity was decreased, and the expression of p-JAK2, p-STAT1 and p-STAT3 was up-regulated in I/R and D groups(P<0.05). Compared with group I/R, the serum concentrations of cTnI, H-FABP, TNF-α and HMGB1 were significantly decreased, the MDA content was decreased, the SOD activity was increased, the expression of p-JAK2, p-STAT1 and p-STAT3 was down-regulated(P<0.05), and pathological changes of myocardium were significantly attenuated in group D. Conclusion The mechanism by which dexmedetomidine pretreatment mitigates myocardial injury induced by liver cold I/R may be related to inhibiting activation of JAK/STAT signaling pathway in rats. Key words: Dexmedetomidine; Reperfusion injury; Liver; Myocardium; Janus kinase; Activating transcription factor

Effect of dexmedetomidine pretreatment on inflammatory visceral pain in rats

Objective To investigate the effect of dexmedetomidine pretreatment on inflammatory visceral pain in rats. Methods Forty healthy male Wistar rats, weighing 200-300 g, aged 6-8 weeks, were divided into 5 groups (n=8 each) using a random number table method: control group (group C), visceral pain group (group VP), dexmedetomidine 1 μg/kg group (group Dex1), dexmedetomidine 5 μg/kg group (group Dex2) and dexmedetomidine 10 μg/kg group (group Dex3). The model of inflammatory visceral pain was established by intraperitoneally injecting 0.9% acetic acid 10 ml/kg in VP, Dex1, Dex2 and Dex3 groups, and the equal volume of normal saline was given instead in group C. At 15 min before intraperitoneal injection, dexmedetomidine 1, 5 and 10 μg/kg were injected via the tail vein in Dex1, Dex2 and Dex3 groups, respectively, and the equal volume of normal saline was given instead in C and VP groups.Behavioral changes of rats were observed within 60 min after the model was established, and visceral pain index (VPI) was calculated.Blood samples were collected from the hearts at 180 min after establishing the model for determination of tumor necrosis factor-alpha (TNF-α) concentrations in serum.The animals were then sacrificed, and colons were obtained for examination of pathological changes with a light microscope. Results Compared with group C, the VPI and serum TNF-α concentrations were significantly increased in VP and Dex1-2 groups, and the serum TNF-α concentrations were significantly increased (P 0.05). Compared with group VP, the VPI and serum TNF-α concentrations were significantly decreased (P<0.05), and the pathological changes of colon tissues were significantly attenuated in group Dex1-3.Compared with group Dex1, the VPI and serum TNF-α concentrations were significantly decreased (P<0.01), and the pathological changes of colon tissues were significantly attenuated in Dex2-3 groups.Compared with group Dex2, the VPI and serum TNF-α concentrations were significantly decreased (P<0.01), and the pathological changes of colon tissues were significantly attenuated in group Dex3. Conclusion Dexmedetomidine pretreatment can mitigate inflammatory visceral pain in rats. Key words: Dexmedetomidine; Visceral pain; Inflammation

Effect of dexmedetomidine pretreatment on contents of glutamic acid and γ-aminobutyric acid dur-ing focal cerebral ischemia-reperfusion in rats

Objective To evaluate the effect of dexmedetomidine pretreatment on contents of glutamic acid and γ-aminobutyric acid during focal cerebral ischemia-reperfusion (I/R) in rats. Methods Thirty-six clean-grade healthy male Wistar rats, aged 10 months, weighing 250-300 g, were divided into 3 groups using a random number table method: sham operation group (group S), I/R group, and dexmedetomidine group (group D). Focal cerebral I/R was induced by occlusion of the left middle cerebral artery for 30 min followed by reperfusion in anesthetized rats.The left middle cerebral artery was only isolated but not occluded in group S. Sterile normal saline 1 ml was intraperitoneally injected, and 30 min later the model of focal cerebral I/R was established in group I/R.Rats were sacrificed at the end of reperfusion, and brains were removed for determination of contents of glutamic acid and γ-aminobutyric acid in brain tissues and for examination of ultrastructure (with an electron microscope). Results Compared with group S, the content of glutamic acid was significantly increased, and the content of γ-aminobutyric acid was decreased in I/R and D groups (P<0.05). Compared with group I/R, the content of glutamic acid was significantly decreased, and the content of γ-aminobutyric acid was increased in group D (P<0.05). The damage to the ultrastructure of brain tissues was significantly attenuated in group D when compared with group I/R. Conclusion Dexmedetomidine pretreatment can reduce focal cerebral I/R injury through decreasing the content of glutamic acid and increasing the content of γ-aminobutyric acid in rats. Key words: Dexmedetomidine; Brain; Reperfusion injury; Glutamic acid; gamma-Aminobutyric acid

Effects of dexmedetomidine pretreatment on hepatic ischemia/reperfusion injury in rats

Objective To investigate the role of extracellular signal-regulated kinase 1/2(ERK1/2) in attenuation of hepatic ischemia/reperfusion injury by dexmedetomidine (Dex) preconditioning in rats. Methods Adult male SD rats were randomly allocated into four groups (n=6): Sham group (group S), hepatic ischemia/reperfusion injury(HI/RI) group (group HI/RI), Dex pretreatment in HI/RI group (group D), U0126 (MEK inhibitor) pretreatment followed by same treatments as D group (group U). The results were observed at 6 h of reperfusion. The effects of Dex on phosphorylate(p)-ERK1/2 expression in the ischemic liver were measured by immunohistochemistry. Hepatic injuries were evaluated with the activity of ALT and AST, levels of Cleaved caspase-3, TUNEL assay, and H-E staining. Results Compared with group HI/RI, group D exhibited reduce activity of ALT and AST, lower levels of Cleaved casepase-3, and attenuated apoptosis index(P<0.05), but elevated levels of p-ERK1/2 (P<0.05). Compared with group D, group U showed enhanced activity in ALT and AST, raised expression of Cleaved casepase-3, increased apoptosis index (P<0.05), but reduced, expression of p-ERK1/2(P<0.05). Conclusions Dex treatment reduced expression of casepase-3 and inflammation in HI/RI rats, probably through activationg the ERK1/2 pathway. Key words: Dexmedetomidine; Ischemia/reperfusion injury; Liver; Extracellular signal-regulated kinase 1/2; Apoptosis

Effect of dexmedetomidine pretreatment on hippocampal endoplasmic reticulum stress-induced cell apoptosis after asphyxial cardiac arrest-resuscitation in rats

Objective To investigate the effect of dexmedetomidine pretreatment on hippocampal endoplasmic reticulum stress-induced cell apoptosis after asphyxial cardiac arrest-resuscitation in rats. Methods A total of 60 pathogen-free male Sprague-Dawley rats, aged 6-8 weeks, weighing 200-300 g, were divided into 3 groups (n=20 each) by using a random number table: control group (C group), asphyxial cardiac arrest-resuscitation group (CA group) and dexmedetomidine pretreatment group (Dex group). The anaesthetized rats were intubated with a 16G tracheal catheter which was connected to a rodent ventilator for mechanical ventilation.Cardiac arrest was induced by clamping the tracheal tube at the end of the exhalation until systolic blood pressure decreased to 25 mmHg lasting for 5 min, and then resuscitation was started.At 5 min before cardiac arrest, dexmedetomidine 4.0 μg/kg was intravenously injected in group Dex, and the equal volume of normal saline was given instead in C and CA groups.Rats were sacrificed at 6 h after successful resuscitation, brain tissues were removed for determination of wet to dry weight ratio (W/D ratio), and hippocampal tissues were obtained for examination of the pathological changes (with a light microscope) and ultrastructure (with an electron microscope) and for determination of cell apoptosis (by TUNEL), expression of CCAAT/enhancer-binding protein homologous protein (CHOP) and activated transcription factors (ATF4) and X-4 box binding protein 1 (XBP1) mRNA (by real-time polymerase chain reaction) and expression of CHOP, Bcl-2, Bax and caspase-3 (by Western blot). The apoptosis rate was calculated. Results Compared with group C, W/D ratio of brain tissues was significantly increased, the apoptosis rate of hippocampal tissues was decreased, the expression of XBP-1, ATF4 and CHOP mRNA was up-regulated, the expression of CHOP, Bax and caspase-3 was up-regulated, and the expression of Bcl-2 was down-regulated in CA and Dex groups (P<0.05). Compared with group CA, W/D ratio of brain tissues was significantly decreased, the apoptosis rate of hippocampal tissues was decreased, the expression of XBP-1, ATF4 and CHOP mRNA was down-regulated, the expression of CHOP, Bax and caspase-3 was down-regulated, the expression of Bcl-2 was up-regulated (P<0.05), and the pathological changes were significantly attenuated in group Dex. Conclusion The mechanism by which dexmedetomidine pretreatment mitigates brain injury after asphyxial cardiac arrest-resuscitation may be related to inhibiting cell apoptosis induced by endoplasmic reticulum stress in rats. Key words: Dexmedetomidine; Asphyxia; Heart arrest; Resuscitation; Brain injuries; Apoptosis; Endoplasmic reticulum; Stress

Reduced mitochondrial response sensitivity is involved in the anti‑apoptotic effect of dexmedetomidine pretreatment in cardiomyocytes.

Dexmedetomidine is a commonly used α2-adreno-ceptor agonist, which affects various organs, including providing beneficial effects on the heart. However, the mechanism underlying the cardiac benefit remains to be fully elucidated. In the present study, it was demonstrated that dexmedetomidine pretreatment on primary cultured rat cardiomyocytes protected against reactive oxygen species (ROS)‑induced apoptosis. In terms of the potential mechanism, it was demonstrated that dexmedetomidine inhibited mitochondrial biogenesis and mitochondrial respiratory complexes, but with increased coupling efficiency. However, dexmedetomidine upregulated mitochondrial membrane potential (Δψm) and resisted against the loss of Δψm induced by carbonilcyanide p‑triflouromethoxyphenylhydrazone. Due to the importance of mitochondria affecting ROS, the present study investigated the dexmedetomidine‑suppressed mitochondrial response to H2O2 stimulation, which was explained by suppressed ROS levels and the suppression of the increased oxygen consumption rate. Results demonstrated for the first time, to the best of our knowledge, a novel protective mechanism for dexmedetomidine on cardiomyocytes through the attenuated response of mitochondria towards H2O2, which had a protective effect against ROS‑induced apoptosis.

Effect of dexmedetomidine pretreatment on expression of Clara cell secretory protein during endotoxin-induced acute lung injury in rats

Objective To evaluate the effect of dexmedetomidine pretreatment on expression of secretion protein of Clara cell secretory protein(CC16)during endotoxin-induced acute lung injury(ALI)in rats. Methods One hundred and twelve healthy Wistar rats of both sexes, aged 8-12 weeks, weighing 250-350 g, were divided into ALI group(n=56)and dexmedetomidine pretreatment group(group DEX, n=56)using a random number table.ALI was induced by intravenously injecting lipopolysaccharide(LPS)5 mg/kg over 1 min.Dexmedetomidine 10 μg/kg was intravenously infused over 10 min starting from 10 min before LPS in group DEX.At 10 min before LPS injection and 0.5, 1, 2, 4, 6 and 24 h after LPS injection, 8 rats were sacrificed and lungs were removed for examination of the pathological changes(with a light microscope)and ultrastructure of Clara cells(with a transmission electron microscope)and for determination of CC16 expression in bronchioles(by immunohistochemistry). Results Compared with the baseline at 10 min before LPS injection, the expression of CC16 in bronchioles was significantly down-regulated at 1, 2, 4, 6 and 24 h after LPS injection in group ALI and at 1, 2, 4 and 6 h after LPS injection in group DEX(P<0.01), the pulmonary small arterial hyperemia, alveolar septa edema, red blood cell exudation and inflammatory cell infiltration were found, the Clara cells in bronchioles were reduced, the secretory granules in the cytoplasm were reduced, and the mitochondria were swollen and deformed after injection of LPS.Compared with group ALI, the expression of CC16 in bronchioles was significantly up-regulated at 1, 2, 4, 6 and 24 h after LPS injection(P<0.01), the pathologic changes of lung tissues were significantly attenuated, and the number of Clara cells was increased in group DEX. Conclusion The mechanism by which dexmedetomidine pretreatment reduces endotoxin-induced ALI may be related to up-regulating CC16 expression in rats. Key words: Dexmedetomidine; Lipopolysaccharide; Acute lung injury; Clara cell

Effect of dexmedetomidine pretreatment on hippocampus Bcl-2, Bax expression and cognitive function in endotoxemia rat

Objective To investigate the effects of dexmedetomidine(Dex) pretreatment on endotoxemia rats cognitive function and the expression of Bcl-2 and Bax in hippocampus. Methods A total of twenty-four pathogen-free male SD rats, aged 6 weeks, weighing 200-250 g, were randomly divided into 3 groups(n=8): control group(group C), lipopolysaccharide(LPS) group(group E) and Dex group(group D). Dex 50 μg/kg was injected intraperitoneally and LPS 5 mg/kg was injected via caudal vein 30 min later in group D. Normal saline 2 ml was injected intraperitoneally and LPS 5 mg/kg was injected via the caudal vein in 30 min later in group E. Normal saline 2 ml was injected intraperitoneally and then injected via the caudal vein 30 min later in group C. After administration of 12 h, the cognitive function of rats were tested by Morris maze, the rats were sacrificed and hippocampal were harvest at each group. Terminal-deoxynucleotidyl transfering mediated nick end labeling was applied to evaluate the apoptosis index(AI). The expression of protein Bcl-2 and Bax were detected by immunohistochemical method. Results Compared with group C, the latency and swimming distance were increased and numbers of crossing the platform were decreased in group E and D(P 0.05) while Bax immunopositivity was increased. The Bcl-2/Bax ratio was decreased(P<0.05), the expression of Bcl-2 and Bax were upregulated in group D, Bcl-2/Bax ratio was increased(P<0.05). Compared with group E, the AI index was decreased, Bcl-2 expression was upregulated while Bax expression was downregulated, Bcl-2/Bax ratio was increased in group D(P<0.05). Conclusions Dex can improve the cognitive function of rats with endotoxemia. Its mechanism is related to the regulating expression level of Bcl-2 and Bax with a result of decreasing the neuronal apoptosis in hippocampus. Key words: Dexmedetomidine; Endotoxemia; Bcl-2; Bax

The effects of dexmedetomidine pretreatment on the pro- and anti-inflammation systems after spinal cord injury in rats

Excessive inflammatory responses play important roles in the aggravation of secondary damage to an injured spinal cord. Dexmedetomidine (DEX), a selective α2-adrenoceptor agonist, has recently been implied to be neuroprotective in clinical anesthesia, but the underlying mechanism is elusive. As signaling through Toll-like receptor 4 (TLR4) and nicotinic receptors (nAChRs, notably α7nAChR) play important roles in the pro- and anti-inflammation systems in the central nervous system, respectively, this study investigated whether and how they were modulated by DEX pretreatment in a rat model of spinal cord compression. The model was used to mimic perioperative compressive spinal cord injury (SCI) during spinal correction. DEX preconditioning improved locomotor scores after SCI, which was accompanied by increased α7nAChR and acetylcholine (Ach, an endogenous ligand of α7nAChR) expression as well as PI3K/Akt activation. However, there was a decrease in Ly6h (a negative regulator for α7nAChR trafficking), TLR4, PU.1 (a critical transcriptional regulator of TLR4), HMGB1 (an endogenous ligand of TLR4), and caspase 3-positive cells, which was prevented by intrathecal preconditioning with antagonists of either α2R, α7nAChR or PI3K/Akt. In addition, application of an α7nAChR agonist produced effects similar to those of DEX after SCI, while application of an α7nAChR antagonist reversed these effects. Furthermore, both α7nAChR and TLR4 were mainly co-expressed in NeuN-positive cells of the spinal ventral horn, but not in microglia or astrocytes after SCI. These findings imply that the α2R/PI3K/Akt/Ly6h and α7nAChR/PI3K/Akt/PU.1 cascades are required for upregulated α7nAChR and downregulated TLR4 expression by DEX pretreatment, respectively, which provided a unique insight into understanding DEX-mediated neuroprotection.

Effect of dexmedetomidine pretreatment on activation of JAK/STAT signaling pathway during intestinal injury in rats undergoing liver transplantation

Objective To evaluate the effect of dexmedetomidine pretreatment on activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway during intestinal injury in rats undergoing liver transplantation. Methods Thirty-two pathogen-free healthy adult male Sprague-Dawley rats, weighing 220-250 g, aged 8-10 weeks, were divided into 4 groups (n=8 each) using a random number table: sham operation group (S group), liver transplantation group (LT group), dexmedetomidine pretreatment group (D group) and dexmedetomidine plus atipamezole (specific α2-adrenergic receptor antagonist) group (D+ A group). The model of liver transplantation was established in LT, D and D+ A groups except group S. In group D, dexmedetomidine 50 μg/kg was injected intraperitoneally at 30 min before skin incision.In group D+ A, atipamzole 250 μg/kg was injected intraperitoneally at 5 min before administration of dexmedetomidine.At 6 h of reperfusion, blood samples were collected from the inferior vena cava for determination of serum concentrations of intestinal fatty acid binding protein (iFABP), lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-α) and high-mobility group box 1 protein (HMGB1). Intestinal specimens were then obtained for examination of the pathological changes of intestinal tissues (under light microscope) and for determination of the expression of activated caspase-3, phosphorylated JAK2 (p-JAK2), phosphorylated STAT1 (p-STAT1) and phosphorylated STAT3 (p-STAT3). Intestinal damage was assessed and scored.Wet/dry weight ratio (W/D ratio) was calculated. Results Compared with group S, the concentrations of iFABP, LPS, TNF-α and HMGB1 in serum, intestinal damage scores and W/D ratio were significantly increased, and the expression of activated caspase-3, p-JAK2, p-STAT1 and p-STAT3 in intestinal tissues was up-regulated in LT and D groups (P<0.05). Compared with group LT, the concentrations of iFABP, LPS, TNF-α and HMGB1 in serum, intestinal damage scores and W/D ratio were significantly decreased, and the expression of activated caspase-3, p-JAK2, p-STAT1 and p-STAT3 in intestinal tissues was down-regulated in group D (P<0.05). Compared with group D, the concentrations of iFABP, LPS, TNF-α and HMGB1 in serum, intestinal damage scores and W/D ratio were significantly increased, and the expression of activated caspase-3, p-JAK2, p-STAT1 and p-STAT3 in intestinal tissues was up-regulated in group D+ A (P<0.05). The pathological changes of intestinal tissues were significantly attenuated in group D as compared with group LT. Conclusion The mechanism by which dexmedetomidine pretreatment reduces intestinal injury may be related to inhibition of JAK/STAT signaling pathway activation in rats undergoing liver transplantation. Key words: Janus kinases; STAT transcription factors; Dexmedetomidine; Reperfusion injury; Liver transplantation; Intestines

Effect of dexmedetomidine pretreatment on ERK pathway during acute lung injury in a rat model of liver transplantation

Objective To evaluate the effects of dexmedetomidine pretreatment on extracellular signal-regulated kinase (ERK) pathway during acute lung injury in a rat model of liver transplantation. Methods Sixty male Sprague-Dawley rats, weighing 235-250 g, were divided into 4 groups (n=15 each) using a random number table: sham operation group (group S), liver transplantation group (group LT), low-dose dexmedetomidine pretreatment group (group LD) and high-dose dexmedetomidine pretreatment group (group HD). In LT, LD and HD groups, the model of orthotopic liver transplantation was established, and the operation time was about 4 h. Dexmedetomidine 2.5 and 5.0 μg·kg-1·h-1 were intravenously infused for 1 h starting from 1 h prior to clipping the hepatic artery and portal vein in LD and HD groups, respectively.The rats were sacrificed after the end of operation, and the lungs were removed for determination of wet to dry weight ratio (W/D ratio), cell apoptosis and expression of ERK mRNA, ERK, phosphorylated ERK (p-ERK), Bcl-2 and Bax in lung tissues and for examination of the pathological changes (with light microscope) and ultrastructure of lung tissues (with transmission electron microscope). The injured alveolus rate (IAR), apoptosis index (AI) and ratio of Bcl-2 to Bax expression (Bcl-2/Bax ratio) were calculated. Results Compared to group S, the W/D ratio, IAR, AI, expression of ERK-1 mRNA, ERK-2 mRNA, p-ERK, Bcl-2 and Bax and Bcl-2/Bax ratio were significantly increased in LT, LD and HD groups (P<0.05). Compared to group LT, the W/D ratio, IAR and AI were significantly decreased, the expression of ERK-1 mRNA, ERK-2 mRNA, p-ERK and Bcl-2 and Bcl-2/Bax ratio were significantly increased, and the expression of Bax was significantly down-regulated in LD and HD groups (P<0.05). Compared to group LD, the W/D ratio, IAR and AI were significantly decreased, the expression of ERK-1 mRNA, ERK-2 mRNA, p-ERK and Bcl-2 and Bcl-2/Bax ratio were significantly increased, and the expression of Bax was significantly down-regulated in group HD (P<0.05). The pathological changes of lung tissues were significantly attenuated in LD and HD groups as compared with group LT, and in group HD as compared with group LD. Conclusion The mechanism by which dexmedetomidine pretreatment mitigates cell apoptosis during acute lung injury is related to activation of ERK pathway in a rat model of liver transplantation. Key words: Dexmedetomidine; Liver transplantation; Respiratory distress syndrome, adult; Extracellular signal-regulated MAP kinases

The effect of dexmedetomidine pretreatment on the median effective bolus dose of propofol for facilitating laryngeal mask airway insertion.

We designed this study to investigate the effect of dexmedetomidine (1μg/kg) pretreatment on the median effective dose (ED50) of propofol for facilitating successful laryngeal mask airway (LMA) insertion compared to propofol alone. Forty patients were randomized to either the control group (n=21) or the dexmedetomidine group (n=19). After infusion of normal saline or dexmedetomidine 1µg/kg over 10min, 1% lidocaine 0.5mg/kg, followed by propofol 2.5mg/kg was administered and the laryngeal mask airway was inserted without muscle relaxants. The ED50 of propofol for successful LMA insertion was determined by the modified Dixon's up-and-down method. The ED50 and ED95 were also calculated using an isotonic regression method, based on the pooled adjacent-violators algorithm-adjusted response rate, and the confidential interval (CI) was estimated using a bootstrap approach. The ED50 of propofol for smooth insertion of the LMA was significantly higher in the control group than in the dexmedetomidine group (3.1±0.4 vs 1.9±0.3mg/kg, P<0.001). From isotonic regression analysis using a bootstrap approach, the ED50 and ED95 of propofol was 2.9mg/kg (83% CI 2.5-3.3mg/kg) and 3.9mg/kg (95% CI 3.5-4.0mg/kg) in the control group, and 1.8mg/kg (83% CI 1.8-2.1mg/kg) and 2.4mg/kg (95% CI 2.0-2.5mg/kg) in the dexmedetomidine groups, respectively. The apnea time was not significantly different between the two groups. Pretreatment with dexmedetomidine 1μg/kg could reduce the propofol requirement by 38% for facilitating LMA insertion without prolonged respiratory depression and hemodynamic instability.

Effect of dexmedetomidine pretreatment on expression of caspase-12 in lung tissues undergoing one-lung ventilation in rats

Objective To investigate the effect of dexmedetomidine pretreatment on the expression of caspase-12 in lung tissues undergoing one-lung ventilation(OLV)in rats. Methods Thirty male Sprague-Dawley rats, aged 6–8 weeks, weighing 180–220 g, were randomly allocated into 3 groups(n=10 each)using a random number table: two-lung ventilation(TLV)group, OLV group and dexmedetomidine group(Dex group). Bilateral lungs were ventilated for 2 h in group TLV.In OLV and Dex groups, unilateral lung was ventilated for 1.5 h followed by 0.5 h TLV.In group Dex, dexmedetomidine was infused intravenously at a rate of 3.0 μg·kg–1·h–1 over 60 min starting from 60 min prior to OLV.The equal volume of normal saline was given instead of dexmedetomidine in OLV and TLV groups.Peak airway pressure(Ppeak)and mean airway pressure(Paw)were recorded at 45 min of OLV and 15 min of TLV in OLV and Dex groups, and at 15 min of TLV in group TLV.The rats were then sacrificed, and left lungs were removed for microscopic examination of the pathologic changes(using HE staining)and the ultrastructure of lung tissues(with transmission electron microscope)and for determination of wet to dry lung weight ratio(W/D ratio), cell apoptosis in lung tissues(by TUNEL), caspase-12 mRNA expression(using real-time reverse transcriptase-polymerase chain reaction), and caspase-12 expression(by Western blot). Results Ppeak and Paw were significantly lower at 15 min of TLV than at 45 min of OLV in OLV and Dex groups(P<0.05). Compared to group TLV, W/D ratio and AI were significantly increased, and the expression of caspase-12 protein and mRNA was up-regulated in OLV and Dex groups(P<0.01). Compared to group OLV, W/D ratio and AI were significantly decreased, and the expression of caspase-12 protein and mRNA was down-regulated in group Dex(P<0.01). The pathologic changes of lung tissues were significantly alleviated in group Dex as compared with group OLV. Conclusion The mechanism by which dexmedetomidine pretreatment alleviates acute lung injury caused by OLV is associated with down-regulated expression of caspase-12 and inhibited cell apoptosis in rats. Key words: Dexmedetomidine; Respiration, artificial; Respiratory distress syndrome, adult; Caspase 12