Dexmedetomidine attenuates acute alcoholic hepatic injury in mice

AIM: To investigate the effects of dexmedetomidine (DEX) on acute alcoholic hepatic injury in mice and to explore the possible mechanisms. METHODS: Kunming mice (n=50) were randomly divided into 5 groups (n=10): normal saline control (NS) group, acute alcoholic hepatic injury model (E) group, low-dose (10 μg/kg) DEX (E+L) group, medium-dose (50 μg/kg) DEX (E+M) group and high-dose (100 μg/kg) DEX (E+H) group. The animals were sacrificed at 6 h after gavage of alcohol or normal saline. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD) were measured. The livers were removed for evaluation of histological characteristics and determining the content of tumor necrosis factor-α (TNF-α) amd interleukin-1β (IL-1β) in the liver tissues by ELISA. The expression levels of cytochrome P450 2E1 (CYP2E1) and nuclear factor-κB (NF-κB) in the liver tissues were evaluated by Western blot. RESULTS: Compared with NS group, the levels of ALT, AST and TG were obviously increased in E group, which were obviously decreased in E+M and E+H groups. Compared with NS group, the levels of TNF-α, IL-1β and MDA were obviously increase in E group, which were obviously decreased in E+M and E+H groups. Compared with NS group, the activity of SOD and the content of GSH were obviously decreased in E group, which were obviously increased in E+M and E+H groups. Compared with NS group, the expression of CYP2E1 and NF-κB was obviously increase in E group, which was obviously decreased in E+M and E+H groups. Compared with NS group, ethanol induced marked liver histological injury, which was less pronounced in E+M and E+H groups. CONCLUSION: DEX has a protective effect on mouse liver with acute alcoholic injury by the involvement in the processes of antioxidation and antiinflammation, and its mechanism may be associated with the inhibition of CYP2E1 and NF-κB expression.     

Cardiorespiratory and anaesthetic effects of two continuous rate infusions of dexmedetomidine in alfaxalone anaesthetized dogs

Six Beagles were used in this prospective randomised crossover experimental study. Dexmedetomidine was administered at 0, 1 or 2 μg/kg IV for group C, LDA and HDA, respectively. Animals were induced and maintained with alfaxalone at 0.07 mg/kg/min with a CRI dexmedetomidine dose of 0, 0.5 or 1 μg/kg/h for group C, LDA and HDA, respectively. Cardiorespiratory variables, arterial blood gases and depth of anaesthesia were recorded. The recovery times and quality of recovery were scored. Group HDA produced a greater increase in the depth of anaesthesia than LDA. However, with both protocols, CI was halved compared to normal values in dogs. The use of oxygen before and during the anaesthetic maintenance is advisable, mainly if dexmedetomidine is going to be use as a pre-medicant and maintenance agent. The quality of recovery was better in groups receiving dexmedetomidine, without causing an increase in recovery time.     

Dexmedetomidine reduced isoflurane-induced neuroapoptosis by inhibiting activation of p38 and JNK proteins in hippocampus of neonatal rats

AIM：To investigate the effect of dexmedetomidine (Dex) on neuronal apoptosis induced by isoflurane (Iso) and its relationship with the expression of p38 mitogen-activated protein kinase (p38) and c-Jun N-terminal kinase (JNK) proteins in the hippocampus of neonatal rats. METHODS：Forty-eight neonatal SD rats at postnatal day 7 were randomly divided into control group (Con), Dex group, Iso group and Iso combined with Dex (Iso+Dex) group. Rats in Iso and Iso+Dex groups were exposed to 0.75% Iso for 6 h, while rats in Con and Dex groups were exposed to air for 6 h. Rats were intraperitoneally injected with 25 μg·kg-1 Dex (Dex and Iso+Dex groups) or 150 μL saline (Con and Iso groups) 20 min before exposure and 2 and 4 h after exposure. After the termination of anesthesia, the neuronal apoptosis in hippocampal CA1 region was detected by TUNEL staining, and the protein expression of cleaved caspase-3, phospho-p38 (p-p38), p38, phospho-JNK (p-JNK) and JNK in hippocampal tissues was detected by Western blotting. RESULTS：The number of TUNEL positive cells in hippocampal CA1 region of the rats in Iso group was increased by 447.57% (P<0.01) compared with Con group, while Dex significantly inhibited the increased TUNEL positive cells in Iso group by 75.18% (P<0.01). The expression of cleaved caspase-3 protein in Iso group was increased by 126.29% (P<0.01) compared with Con group, while Dex reversed the increased cleaved caspase-3 protein expression (P<0.01). Iso significantly increased the phosphorylation of p38 and JNK proteins (P<0.01), while Dex reversed the increased p-p38 and p-JNK proteins (P<0.01). CONCLUSION：Dex attenuates Iso-induced neuroapoptosis in the hippocampus of neonatal rats through inhibiting the phosphorylation of p38 and JNK proteins.     

Protective effect of dexmedetomidine-ulinastatin combination on lipopolysaccharide-induced acute lung injury in rats

AIM：To investigate the effects of dexmedetomidine-ulinastatin combination on acute lung injury induced by lipopolysaccharide (LPS) in rats. METHODS：Male Wistar rats were randomly divided into 5 groups: saline control group (NS group) was given saline (5 mL/kg, iv) alone; LPS group (L group) was given LPS (10 mg/kg, over 10 min); dexmedetomidine+LPS group (L+D group) was treated with the additional administration of dexmedetomidine (1 μg·kg -1·h -1) immediately after LPS injection; ulinastatin+LPS group (L+U group) was treated with the addi-tional administration of ulinastatin (50 000 U/kg, ip) immediately after LPS injection; dexmedetomidine+ulinastatin+LPS group (L+D+U group) received dexmedetomidine (1 μg·kg -1·h -1) and ulinastatin (50 000 U/kg) immediately after LPS injection. The animals were sacrificed at 6 h after LPS or NS administration. Partial pressure of arterial oxygen (PaO 2), pH and base excess (BE) were measured, and the lungs were removed for evaluation of histological characteristics and determining the concentrations of TNF-α, IL-1β, macrophage inflammatory protein 2 (MIP-2), malondialdehyde (MDA), nitric oxide (NO), prostaglandin E 2 (PGE 2) and myeloperoxidase (MPO) in lung tissues, lung wet/dry weight ratio (W/D), and albumin in brochoalveolar lavage fluid (BLAF). The pulmonary expression of nuclear factor kappa B (NF-κB) p65 was evaluated by Western blotting. RESULTS：Compared with NS group, PaO 2, pH and BE was lower in L group, which was increased by treatment with dexmedetomidine-ulinastatin combination but not by dexmedetomidine or ulinastatin alone. Compared with NS group, LPS induced marked lung histological injury, which was less pronounced in the animals treated with dexmedetomidine-ulinastatin combination but not dexmedetomidine or ulinastatin alone. The levels of IL-1β, IL-6, MIP-2, MDA, NO and PGE 2 in the lung tissues increased in L group compared with NS group, which were reduced by dexmedetomidine-ulinastatin combination but not by dexmedetomidine or ulinastatin alone. The MPO activity, MDA level and W/D increased in the lung tissues in L group compared with NS group, which was reduced by dexmedetomidine-ulinastatin combination but not by dexmedetomidine or ulinastatin alone. Compared with NS group, the albumin concentration in the BLAF increased, which was reduced by dexmedetomidine-ulinastatin combination but not by dexmedetomidine or ulinastatin alone. Compared with NS group, the expression of NF-κB p65 increased in L group, which was reduced by dexmedetomidine-ulinastatin combination but not by dexmedetomidine or ulinastatin alone.CONCLUSION：Dexmedetomidine-ulinastatin combination has a protective effect on LPS-induced acute lung injury in the rats.     

Dexmedetomidine reduces renal injury induced by lung ischemia/reperfusion in mice through inhibiting endoplasmic reticulum stress response

AIM:To investigate the effect of dexmedetomidine (DEX) on renal injury induced by lung ischemia/reperfusion (I/R) in mice and its relationship with endoplasmic reticulum stress response.METHODS:Healthy SPF male C57BL/6J mice,weighing 20~24 g,aged 8~10 weeks,were randomly divided into 5 groups (n=10 each):sham operation group (sham group),I/R group,atipamezole (Atip) group,DEX group,and DEX+Atip group.In vivo lung I/R model was established by occlusion of the left pulmonary artery for 30 min followed by 180 min of reperfusion in the mice.The Atip (250 μg/kg),DEX (20 μg/kg) and DEX+Atip were intraperitoneally infused into the mice before left pulmonary hilus was blocked in Atip group,DEX group and DEX+Atip group,and other operations were the same as I/R group.After experiment,the mice were killed,and the renal tissues were harvested to observe the morphological changes.The enzymatic activity of caspase-3,serum creatinine and blood urea nitrogen,and cell apoptotic index of the renal cells were also analyzed.The expression of c-Jun N-terminal kinase (JNK),caspase-12,CCAAT/enhancer-binding protein homdogous protein (CHOP) and glucose-regulated protein 78(GRP78) at mRNA and protein levels in the renal tissues was determined by RT-PCR and Western blot.RESULTS:Compared with sham group,the enzymatic activity of caspase-3,serum creatinine and blood urea nitrogen,renal cell apoptotic index,and the mRNA and protein levels of JNK,caspase-12,CHOP and GRP78 in I/R group were significantly increased (P<0.01),and the renal tissues had obvious damage under light microscope.Compared with I/R group,Atip group and DEX+Atip group,the enzymatic activity of caspase-3,serum creatinine and blood urea nitrogen,renal cell apoptotic index,and the mRNA and protein levels of JNK,caspase-12 and CHOP in DEX group were significantly decreased,and the expression level of GRP78 significantly increased (P<0.01).Furthermore,the renal tissue damage was obvious reduced.CONCLUSION:DEX effectively relieves the renal injury induced by lung I/R in mice,which may be associated with exciting α₂-adrenergic receptor and inhibiting endoplasmic reticulum stress response.     

Effect of dexmedetomidine on astrocytes in rats with focal cerebral ischemia-reperfusion

AIM: To investigate the effects of dexmedetomidine on astrocytes in rats with focal cerebral ischemia-reperfusion. METHODS: Sixty female SD rats, weighing 230~250 g, were randomly divided into sham operation group, ischemia-reperfusion group, dexmedetomidine preconditioning group 1 and dexmedetomidine preconditioning group 2. The model of middle cerebral artery occlusion (MCAO) was established by thread embolism of middle cerebral artery. In sham operation group, the carotid arteries were exposed without performing MCAO. In ischemia-reperfusion group, NS was injected intraperitoneally 30 min before focal cerebral ischemia-reperfusion. The rats in dexmedetomidine preconditioning group 1 and dexmedetomidine preconditioning group 2 received intraperitoneal injection of dexmedetomidine at doses of 20 μg/kg and 40 μg/kg, respectively. The neurological scores were studied, and the pathological changes were observed under microscope with HE staining. The expression of glial fibrillary acidic protein (GFAP) and tumor necrosis factor α (TNF-α) in astrocytes was detected by the methods of immunohistochemistry and immunoblotting 24 h after cerebral ischemia-reperfusion. RESULTS: No neurological change was observed in sham operation group. The neurological deficiency scores in ischemia-reperfusion group were markedly higher than those in dexmedetomidine preconditioning group 1 and group 2 (P<0.05). Compared with sham operation group, the expression of GFAP and TNF-α in astrocytes and the level of GFAP increased significantly 24 h after focal cerebral ischemia-reperfusion. Pretreatment with dexmedetomidine significantly attenuated the expression of GFAP and reduced the infarct size and inflammation. CONCLUSION: Dexmedetomidine has a neuroprotective effect on focal cerebral ischemia-reperfusion injury by inhibiting the astrocytes.     

Comparative Effect of Epidural Administration of Xylazine or Dexmedetomidine on Echocardiographic Dimensions and Cardiac Indices in Clinically Healthy Donkeys (Equus asinus)

The aim of the present study was to assess and compare the changes of the echocardiographic dimensions and cardiac function indices after epidural injection of xylazine or dexmedetomidine in clinically healthy donkeys. In an experimental prospective randomized cross-over study, 10 healthy adult donkeys were injected with saline solution, xylazine (0.20 mg kg⁻¹), and dexmedetomidine (0.005 mg kg⁻¹) into the epidural space between the second and third coccygeal vertebrae. Echocardiographic dimensions as well as cardiac function indices were assessed using a 2–3.9 MHz sector transducer, at the left paracostal ultrasonographic window, at zero, 15, 30, 60, 90, 120, and 180 minutes after administration of these medications. Epidural injection of xylazine or dexmedetomidine produced moderate sedation, complete bilateral perineal analgesia, and mild ataxia in all studied donkeys. There was a significant (P < .05) decrease in the interventricular septum thickness at end systole 60 minutes, stroke volume 30–120 minutes, fractional shortening 120 minutes, and ejection fraction 90–120 minutes after administration of xylazine or dexmedetomidine when compared with saline solution. Left ventricular end diastolic volume was significantly (P < .05) increased 60 minutes following epidural injection of dexmedetomidine compared with xylazine and saline solution. There was a significant (P < .05) increase in the left ventricular internal diameter at end diastole 90–120 minutes and left ventricular end systolic volume 60–180 minutes after administration of xylazine or dexmedetomidine in comparison with saline solution. In conclusion, epidural use of xylazine or dexmedetomidine in donkeys induced mild and transient effect on echocardiographic dimensions as well as cardiac function indices. Therefore, care should be taken when such medications are to be administered into the epidural space in donkeys with a pre-anesthetic cardiovascular compromise.     

Two doses of dexmedetomidine in combination with buprenorphine for premedication in dogs; a comparison with acepromazine and buprenorphine

ObjectiveTo assess as premedicants, the sedative, cardiorespiratory and propofol-sparing effects in dogs of dexmedetomidine and buprenorphine compared to acepromazine and buprenorphine.Study designProspective, randomised, blinded clinical studyAnimalsSixty healthy dogs (ASA grades I/II). Mean (SD) body mass 28.0 ± 9.1 kg, and mean age 3.4 ± 2.3 years.MethodsDogs were allocated randomly to receive 15 μg kg^?1 buprenorphine combined with either 30 μg kg^?1 acepromazine (group 1), 62.5 μg m^?2 dexmedetomidine (group 2), or 125 μg m^?2 dexmedetomidine (group 3) intramuscularly. After 30 minutes, anaesthesia was induced using a propofol target controlled infusion. Heart rate, respiratory rate, and oscillometric arterial blood pressure were recorded prior to induction, at endotracheal intubation and at 3 and 5 minutes post-intubation. Induction quality and pre-induction sedation were scored on 4 point scales. Propofol target required for endotracheal intubation was recorded. Data were analysed using Chi-squared tests, Kruskal-Wallis, one way and general linear model anova (p < 0.05).ResultsAge was significantly lower in group 1 (1.0 (1.0–3.8) years) than group 2 (5.0 (2.0–7.0) years), (median, (IQR)). There were no significant differences in sedation or quality of induction between groups. After premedication, heart rate was significantly lower and arterial blood pressures higher in groups 2 and 3 than group 1, but there was no significant difference between groups 2 and 3. Propofol targets were significantly lower in group 3 (1.5 (1.0–2.5) μg mL^?1) than group 1 (2.5 (2.0–3.0) μg mL^?1); no significant differences existed between group 2 (2.0 (1.5–2.5) μg mL^?1) and the other groups (median, (interquartile range)).Conclusions and Clinical relevanceWhen administered with buprenorphine, at these doses, dexmedetomidine had no advantages in terms of sedation and induction quality over acepromazine. Both doses of dexmedetomidine produced characteristic cardiovascular and respiratory effects of a similar magnitude.     

Effects of dexmedetomidine on behaviors and expression of BDNF and mTOR in hippocampus of depressive rats

AIM: To investigate the effects of dexmedetomidine (DEX) on the behaviors and the expression of brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR) in the hippocampus of depressive rats. METHODS: Sprague-Dawley (SD) rats were randomly divided into 5 groups: sham operation group, model group, and DEX (2.5, 5 and 10 μg/kg) groups. The rats were randomly selected in each group (n=12). The rat depression model was established by chronic unpredictable mild stress and ovariectomy. The rats in DEX groups received daily DEX treatment via intraperitoneal injection for 21 d. The forced swimming immobility time (FSIT) and open-field test were used to evaluate the antidepressant effect of DEX. Escape latency and times of crossing the flat were evaluated by Morris water maze. The histological changes of hippocampal neurons were determined by Nissl staining. The mRNA levels of interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) were detected by RT-qPCR. The protein expression of IL-1β, IL-6, TNF-α and BDNF, and the phosphorylation levels of protein kinase A (PKA), cAMP response element-binding protein (CREB), tropomyosin-related kinase B (TrkB), phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt) and mTOR in hippocampus were evaluated by Western blot. RESULTS: Compared with model group, the FSIT was significantly reduced and the spontaneous activity was markedly increased in DEX groups. The damage of the hippocampal neurons was obviously attenuated, the escape latency was obviously decreased, and times of crossing the flat were markedly increased (P<0.05 or P<0.01). The levels of IL-1β, IL-6 and TNF-α were obviously decreased, and the protein levels of p-PKA, p-CREB, BDNF, p-TrkB and p-PI3K, p-Akt, p-mTOR in hippocampal tissues were obviously increased (P<0.05 or P<0.01). CONCLUSION: Dexmedetomidine improves the behaviors and the spatial learning and memory ability of depressive model rats, which may be related to its anti-inflammatory effects, as well as up-regulating the protein levels of BDNF and p-TrkB, and activating PI3K/Akt/mTOR signaling pathway in the hippocampus.