Mechanism Of Dexmedetomidine Research Articles

Dexmedetomidine relieves formaldehyde-induced pain in rats through both α2 adrenoceptor and imidazoline receptor

Dexmedetomidine (DEX) is a highly selective α2 adrenergic receptor agonist. In this study, we investigated the analgesic effect and the underlying mechanisms of DEX on inflammatory visceral pain in rats. Twenty-five male Sprague Dawley (SD) rats were randomly divided into 5 groups, including control, sham, low dose DEX, medium dose DEX and high dose DEX group. Pain was induced with 10% formalin and scored every 15min till 2 h-post the induction. Hematoxylin-eosin (HE) staining was used to evaluate the toxicity of DEX on spinal cord neurons. Acetycholine (Ach) and noradrenaline (NA) levels were determined by using ELISA method. The expressions of natural nitric oxide synthase (nNOS), protein kinase γ (PKCγ) and protease-activated receptor 2 (PAR2) were determined by using western blot. DEX treatment relieved formaldehyde-induced pain in rats in a dose-dependent manner. Furthermore, DEX showed little neuro-toxicity on the spinal cord neurons, even at the highest dosage used in our study. Ach level was significantly increased in Sham group compared with control group. DEX treatment decreased NA levels and increased Ach levels in the incubation medium of spinal cord sections. Western blot analysis showed that the expression of nNOS, PKCγ and PAR2 was significantly decreased in DEX group compared with Sham group, whereas these effects of DEX on nNOS, PKCγ and PAR2 were blocked by both yohimbine and idazoxan, indicating that the analgesic effect of DEX is mediated by both α2 adrenergic receptor and imidazoline receptor. Yohimbine and idazoxan treatment significantly enhanced pain scores compared to DEX group, and which antagonizes the effects DEX. In conclusion, our study demonstrated that DEX could inhibit formaldehyde-induced pain by inhibiting nNOS, PKCγ and PAR2 expression through α2 adrenergic receptor and imidazoline receptor.

Dexmedetomidine enhances human lung fluid clearance through improving alveolar sodium transport.

Accumulating evidence shows that dexmedetomidine can attenuate lung edema with acute lung injury in experimental mouse and rat models, but the mechanisms of dexmedetomidine on human alveolar fluid transport are still unknown. We measured the effects of dexmedetomidine on alveolar fluid clearance in human lung lobes ex vivo. Moreover, we measured the regulation of transepithelial Na+ transport by dexmedetomidine in H441 cells by electrophysiological technique and Western blot method. Our results showed that intratracheal instillation of dexmedetomidine markedly increased the reabsorption of 5% bovine serum albumin instillate (19.8 ± 1.4%, P < 0.01 vs. Control, n = 5). Further studies suggested that dexmedetomidine increased amiloride-sensitive short-circuit currents in permeabilized H441 monolayers and whole cell amiloride-sensitive Na+ currents in a dose-dependent fashion. Real-time PCR and Western blot results showed that dexmedetomidine could enhance the mRNA and protein expression of α-ENaC subunit, while inhibiting the phosphorylation of ERK1/2 . These data demonstrate that dexmedetomidine could improve human lung fluid clearance and lung epithelial Na+ channel activity, and these effects may be mediated through the enhancement of α-ENaC expression and inhibition of ERK1/2 pathway.

Effect and mechanism of dexmedetomidine on propofol-induced apoptosis of cortical neurons in rats

Objective To investigate the mechanisms of the protective effects of dexmedetomidine against the propofol-induced neuroapoptosis in primary cultured cortical neurons. Methods The neurons were cultured 7days and then divided into four groups: vehicle-control group (treated with equal volume of intralipid), propofol-treated group (treated with 500 μmol/L propofol), propofol plus dexmedetomidine treated group( treated with 500 μmol/L propofol and 0.1 μmol/L dexmedetomidine), and LY294002 pretreated group( treated with 500 μmol/L propofol , 0.1 μmol/L dexmedetomidine and 10 μmol/L LY294002 ). 12 hours after different treatments, neuron viability was measured by MTT assay, neuroapoptosis was detected by Hoechst33258 staining, and the levels of pAkt and Bcl-2 protein were detected by Western blot. Results Compared with the vehicle-reduced group, propofol reduced neuron viability greatly((53.4±4.2)% vs(99.9±6.3)% ; P<0.01), but increased neuroapoptosis greatly((44.6±4.3)% vs(5.8±0.4)% ; P<0.01). The levels of pAkt((0.41±0.03)vs(0.86±0.07))and Bcl-2 ((0.15±0.02)vs (0.72±0.03)) were decreased greatly (both P<0.01). Compared with propofol treatment group, the neuron viability of propofol plus dexmedetomidine group were increased greatly((86.4±5.3)% , P<0.01), the neuroapoptosis was decreased greatly((23.1±3.5)%, P<0.01), and the levels of pAkt(0.8±0.03)and Bcl-2 (0.52±0.05)were increased greatly (both P<0.01). Compared with propofol plus dexmedetomidine treated group, LY294002 inhibited the protective effects of dexmedetomidine, decreased neuron viability greatly((64.3±5.1)% , P<0.01), increased the number of apoptotic neurons((38.8±4.9)%, P<0.01), and reduced the levels of pAkt(0.52±0.04)and Bcl-2(0.31±0.02) significantly (P<0.01). Conclusion Dexmedetomidine exerts the neuroprotective effects against propofol-induced neuroapoptosis by activating the PI3K-Akt-Bcl-2 signalling pathway. Key words: Propofol; Dexmedetomidine; Primary cultured cortical neurons; Apoptosis; PI3K-Akt -Bcl-2 signalling pathway

Dexmedetomidine Attenuates Blood-Spinal Cord Barrier Disruption Induced by Spinal Cord Ischemia Reperfusion Injury in Rats

Background/Aims: Dexmedetomidine has beneficial effects on ischemia reperfusion (I/R) injury to the spinal cord, but the underlying mechanisms are not fully understood. This study investigated the effects and possible mechanisms of dexmedetomidine on blood-spinal cord barrier (BSCB) disruption induced by spinal cord I/R injury. Methods: Rats were intrathecally pretreated with dexmedetomidine or PBS control 30 minutes before undergoing 14-minute occlusion of aortic arch. Hind-limb motor function was assessed using Tarlov criteria, and motor neurons in the ventral gray matter were counted by histological examination. The permeability of the BSCB was examined using Evans blue (EB) as a vascular tracer. The spinal cord edema was evaluated using the wet-dry method. The expression and localization of matrix metalloproteinase-9 (MMP-9), Angiopoietin-1 (Ang1) and Tie2 were assessed by western blot, real-time polymerase chain reaction, and immunofluorescence. Results: Intrathecal preconditioning with dexmedetomidine minimized the neuromotor dysfunction and histopathological deficits, and attenuated EB extravasation after spinal cord I/R injury. In addition, dexmedetomidine preconditioning suppressed I/R-induced increase in MMP-9. Finally, Dexmedetomidine preconditioning enhanced the Ang1-Tie2 system activity after spinal cord I/R injury. Conclusions: Dexmedetomidine preconditioning stabilized the BSCB integrity against spinal cord I/R injury by inhibition of MMP-9, and enhancing the Ang1-Tie2 system.

The efficacy and mechanism of dexmedetomidine in myocardial apoptosis via the renin-angiotensin-aldosterone system.

Pharmacological preconditioning limits myocardial infarct size after ischemia/reperfusion. Dexmedetomidine is an α2-adrenergic receptor agonist used in anesthesia that may have cardioprotective properties against ischemia/reperfusion injury. We investigated whether dexmedetomidine induces cardioprotection against myocardial apoptosis injury. In order to assess the role of dexmedetomidine on myocardial apoptosis, we established a grave scalding rat model. Blood and myocardial tissue from the ventriculus sinister were harvested, then troponin, myocardial apoptosis, and expression of caspase-12, GRP78, and CHOP were assessed. Dexmedetomidine significantly reduced myocardial apoptosis, improved functional recovery, and reversed myocardial injury induced by grave scalding. The heart rate in the five groups studied was significantly different (p < 0.05). The number of buffy-stained nucleoli in the myocardial cell was highest in the simple scald group. The expression of caspase-12 obviously increased in the simple scald group. The expression of GRP78 and CHOP increased in the simple scald and scald and 50 μg/kg dexmedetomidine groups (p < 0.05). The results show that dexmedetomidine (DEX) produces cardioprotection against myocardial apoptosis injury. DEX is not only a useful sedative, but also plays a pivotal role in anesthetic cardioprotection. The potential benefits of DEX protection in high risk cardiovascular patients undergoing surgery are enormous.

Effects of dexmedetomidine on expression of nNOS and c-fos in lcuos cruleus in a rat model of endotoxic shock

Objective To evaluate the effects of dexmedetomidine on the expression of neuronal nitric oxide synthase (nNOS) and c-fos in the lcuos cruleus (LC) in a rat model of endotoxic shock.Methods Twentyeight male Sprague-Dawley rats,aged 8 weeks,weighing 250-300 g,were randomly divided into 4 groups (n =7 each):control group (group C),endotoxic shock induced by lipopolysaccharide (LPS) group (group L),lowdose dexmedetomidine group (groupLD) and high-dose dexmedetomidine group (group HD).Normal saline 0.5 ml/kg was injected via the tail vein in C and L groups.Dexmedetomidine 0.5 and 4.5μg/kg were injected via the tail vein in group LD and group HD,respectively.Normal saline 0.5 ml/kg was injected via the tail vein 10 min later in C,while LPS 5 mg/kg was injected intravenously 10 min later in the other groups.The rats were sacrificed and their brains were removed for determination of brain water content,the number of nNOS and c-fos positive cells and expression of nNOS and c-fos in the LC by immuno-histochemistry.Results Compared with group C,the brain water content was significantly increased,the number of nNOS and c-fos positive cells in the LC was enlarged,and the expression of nNOS and c-fos in the LC was up-regulated in group L (P ＜ 0.05).The brain water content was significantly lower,the number of nNOS and c-fos positive cells in the LC was smaller,and the expression of nNOS and c-fos in the LC was lower in LD and HD groups than in group L (P ＜ 0.05).The number of nNOS and c-fos positive cells in the LC was significantly smaller,and the expression of nNOS and c-fos in the LC was lower in HD group than in group LD (P ＜ 0.05).Conclusion Dexmedetomidine can down-regulate the expression of nNOS and c-fos in the LC,which may be one of brain-protective mechanisms of dexmedetomidine in a rat model of endotoxic shock. Key words: Dexmedetomidine; Shock, septic; Nitric oxide synthase type Ⅰ ; Proto-oncogene proteins c-fos

Dexmedetomidine ameliorates TNBS-induced colitis by inducing immunomodulator effect

BackgroundSince sedatives are often administered to immune-compromised and critically ill patients, our understanding of immunomodulation by sedation will be critical. Dexmedetomidine, a selective α2-adrenergic receptor agonist, is often used for sedation and analgesia especially in intensive care units. There are conflicting and little data concerning both the effect and the mechanism of dexmedetomidine on immune response. In our study, we aimed to investigate the effect of dexmedetomidine on immune system at two different doses (5 μg.kg−1 and 30 μg.kg−1) during inflammatory bowel disease by using an experimental model, which resembles both systemic and local inflammation. MethodsThe effect of dexmedetomidine on the course of inflammatory bowel disease was investigated by measuring macroscopic and microscopic parameters. We investigated pro-inflammatory Th1, Th2, and Th17 cytokine levels in serum samples to analyze systemic immune response. Following this, local immune response was investigated by measuring cytokine levels in the presence of dexmedetomidine in spleen cell culture. ResultsDexmedetomidine administration led to amelioration of all disease associated pathological manifestations. According to our in vitro and in vivo results, dexmedetomidine shows anti-inflammatory effect by increasing IL-4 and IL-10 levels responsible from anti-inflammatory response via Th2 pathway. Moreover, we showed for the first time in the study that dexmedetomidine administration reduces IL-23, which is responsible from initiation of inflammatory response via Th17 pathway. ConclusionsDexmedetomidine can have beneficial effect on preoperative or postoperative inflammatory bowel disease patients in intensive care units by down-regulating inflammatory immune response not only in systemic circulation but also in tissue-specific manner.

Protective effects and mechanism of dexmedetomidine on lung injury

Background Serious infection,shock and other factors will result in acute lung injury,which is due to excessive and overreacting inflammatory.It could increase the incidence of complications and mortality,and influence the prognosis.Dexmedetomidine (DEX) has satisfactory sedative and analgesic properties.Several trials have proved its advantages on antiinflammatory and organ protective effects.Objective To review the protective effects and mechanism of DEX on lung injury.Content This review summarized the pharmacological characteristics of DEX,the mechanisms of several kinds of lung injury,and protective effects and mechanism of DEX on lung injury.Trend DEX has obvious protection on lung injury.However,this effect is mainly found in animal trials.There are few reports of clinical trials.Further studies are needed to evalauate its clinical effectiveness,in order to expand its clinical application. Key words: Dexmedetomidine; Lung injury; Protective effects

Dexmedetomidine protects against oxygen–glucose deprivation-induced injury through the I2 imidazoline receptor-PI3K/AKT pathway in rat C6 glioma cells

To explore the protection and the mechanism of dexmedetomidine on the oxygen-glucose deprivation (OGD) insults in rat C6 glioma cells. Cells were subjected to OGD then assessed by viability studies. After dexmedetomidine treatment, p-AKT, hypoxia-inducible factor (HIF)-1α, vascular endothelial growth factor (VEGF) and RTP801 expression were measured. Three hours of OGD decreased cell viability to 48.8%, which was reversed to 67.4% by 1 µm dexmedetomidine. Hoechst 33342 and propidium iodide double stains showed that the protection of dexmedetomidine was mainly by an anti-apoptosis effect, which was also strengthened by decreasing caspase-3 expression. Dexmedetomidine protection was mainly blocked by the I2 imidazoline receptor antagonist idazoxan and BU 224, but not by the α(1)-adrenoceptor antagonist prazosin, the α(2)-adrenoceptor antagonist yohimbine and RX 821002, or the I1 imidazoline receptor antagonist efaroxan. On the other hand, dexmedetomidine enhanced AKT phosphorylation. Furthermore, the protection of dexmedetomidine was blocked by the PI3K/AKT inhibitor wortmannin. The proteins of HIF-1α, VEGF and RTP801 were significantly increased by dexmedetomidine treatment. Dexmedetomidine activated the I2 imidazoline receptor-PI3K/AKT pathway, and up-regulated HIF-1α, VEGF and RTP801 expression to protect against OGD-induced injury in rat C6 cells.