Dexmedetomidine Treatment Research Articles

Dexmedetomidine Attenuates Lung Injury in Toxic Shock Rats by Inhibiting Inflammation and Autophagy

To explore the mechanisms whereby dexmedetomidine reversed lung injury in rats with toxic shock via inhibiting inflammation and autophagy. Thirty-six specific pathogen-free male Sprague Dawley rats with were screened and randomly divided into three groups. Toxic shock was induced by intestinal leakage. The control group received no cecal ligation and the treatment group received dexmedetomidine hydrochloride. Lung tissue morphology was studied by hematoxylin-eosin staining. The expression levels of inflammatory cytokines including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were determined by Reverse Transcription-Polymerase Chain Reaction (RT-PCR). The expression levels of beclin l and LC3 were measured, and the expression levels of apoptosis gene Bax and Bcl-2 were determined. The autophagosomes in lung cells were observed by transmission electron microscopy. Extracellular signal-regulated kinase (ERK) 1/2 expression was determined by Western blotting assays. The results showed that the W/D, total protein and myeloperoxidase (MPO) index in the toxic shock group were 5.45±0.35, 3.21±0.47 and 4.53±0.36, respectively. The W/D (4.02±0.67), total protein (2.01±0.35) and MPO index (2.31±0.59) were significantly lower in the dexmedetomidine group (p <0.05). Similarly, compared with the toxic shock group, the expression of p-ERK1/2 protein in the dexmedetomidine treatment group was significantly decreased (p <0.05). The expression levels of autophagy proteins beclin1 and LC3 in the dexmedetomidine treatment group were not significantly different from those of the control group (p >0.05). Transmission electron microscopy showed that the number of autophagic bodies in lung cells decreased. After induction with dexmedetomidine hydrochloride, the proapoptotic gene Bax was significantly downregulated in the cells. Bax expression levels in each group were 0.36±0.12, 0.67±0.06, and 0.32±0.12, respectively. Compared with the control group, Bax expression in lung tissue significantly increased in the toxic shock group (p <0.05). Dexmedetomidine attenuates lung injury in toxic shock rats by inhibiting inflammation and autophagy.

Dexmedetomidine attenuates sevoflurane‑induced neurocognitive impairment through α2‑adrenoceptors.

It has been reported that sevoflurane induces neurotoxicity in the developing brain. Dexmedetomidine is an α2 adrenoceptor agonist used for the prevention of sevoflurane-induced agitation in children in clinical practice. The aim of the present study was to determine whether dexmedetomidine could prevent sevoflurane-induced neuroapoptosis, neuroinflammation, oxidative stress and neurocognitive impairment. Additionally, the involvement of α2 adrenoceptors in the neuroprotective effect of dexmedetomidine was assessed. Postnatal day (P)6 C57BL/6 male mice were randomly divided into four groups (n=6 in each group). Mice were pretreated with dexmedetomidine, either alone or together with yohimbine, an α2 adrenoceptor inhibitor, then exposed to 3% sevoflurane in 25% oxygen. Control mice either received normal saline alone or with sevoflurane exposure. Following sevoflurane exposure, the expression of cleaved caspase-3 was detected by immunohistochemistry in hippocampal tissue sections. In addition, the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6 and malondialdehyde, as well as superoxide dismutase (SOD) activity in the hippocampus were measured. At P35, the learning and memory abilities were assessed in each mouse using a Morris water maze test. Dexmedetomidine significantly decreased the expression of activated caspase-3 following sevoflurane exposure. Moreover, dexmedetomidine significantly decreased the levels of TNF-α, IL-1β and IL-6 in the hippocampus. SOD activity also increased in a dose-dependent manner in dexmedetomidine-treated mice. MDA decreased in a dose-dependent manner in dexmedetomidine-treated mice. Lastly, sevoflurane-induced learning and memory impairment was reversed by dexmedetomidine treatment. By contrast, co-administration of yohimbine significantly attenuated the neuroprotective effects of dexmedetomidine. These findings suggested that dexmedetomidine exerted a neuroprotective effect against sevoflurane-induced apoptosis, inflammation, oxidative stress and neurocognitive impairment, which was mediated, at least in part, by α2 adrenoceptors.

Dexmedetomidine inhibits inflammatory response and autophagy through the circLrp1b/miR-27a-3p/Dram2 pathway in a rat model of traumatic brain injury.

Circular RNAs (circRNAs) have a regulatory function on inflammation and autophagy, of which rno-circRNA_010705 (circLrp1b) appears to be significantly up-regulated following traumatic brain injury (TBI). Dexmedetomidine (DEX) shows improvement effects in TBI by inhibiting NLRP3/caspase-1. However, whether circLrp1b plays critical roles in DEX-mediated TBI attenuation and the underlying mechanisms remain unclear. After TBI was established in rats by controlled cortical impact (CCI) to cause brain trauma, they received an intracerebroventricular injection of lentiviral vector, followed by intraperitoneal injection of DEX. Administration of DEX ameliorated autophagy in rats following TBI, accompanied by up-regulated circLrp1b and Dram2 and down-regulated miR-27a-3p. DEX promoted the effects of circLrp1b in attenuating TBI-induced neurologic impairment, autophagy, and inflammation, which was significantly reversed by inhibition of miR-27a-3p or Dram2 overexpression. Mechanistically, northern blot and luciferase reporter assays indicated that circLrp1b up-regulated Dram2 expression by functioning as a sponge for miR-27a-3p to promote autophagy involved in TBI, which was reversed by DEX treatment. Collectively, this study demonstrated that DEX inhibits inflammatory response and autophagy involved in TBI in vivo through inactivation of the circLrp1b/miR-27a-3p/Dram2 signaling pathway.

Dexmedetomidine Alleviates Lipopolysaccharide-Induced Acute Kidney Injury by Inhibiting p75NTR-Mediated Oxidative Stress and Apoptosis.

Oxidative stress and apoptosis play a key role in the pathogenesis of sepsis-associated acute kidney injury (AKI). Dexmedetomidine (DEX) may present renal protective effects in sepsis. Therefore, we studied antioxidant effects and the mechanism of DEX in an inflammatory proximal tubular epithelial cell model and lipopolysaccharide- (LPS-) induced AKI in mice. Methods. We assessed renal function (creatinine, urea nitrogen), histopathology, oxidative stress (malondialdehyde (MDA) and superoxide dismutase (SOD)), and apoptosis (TUNEL staining and Cleaved caspase-3) in mice. In vitro experiments including Cleaved caspase-3 and p75NTR/p38MAPK/JNK signaling pathways were evaluated using western blot. Reactive oxidative species (ROS) production and apoptosis were determined using flow cytometry. Results. DEX significantly improved renal function and kidney injury and also revert the substantially increased level of MDA concentrations as well as the reduction of the SOD enzyme activity found in LPS-induced AKI mice. In parallel, DEX treatment also reduced the apoptosis and Cleaved caspase-3 expression evoked by LPS. The expression of p75NTR was increased in kidney tissues of mice with AKI but decreased after treatment with DEX. In cultured human renal tubular epithelial cell line (HK-2 cells), DEX inhibited LPS-induced apoptosis and generation of ROS, but this was reversed by overexpression of p75NTR. Furthermore, pretreatment with DEX significantly downregulated phosphorylation of JNK and p38MAPK in LPS-stimulated HK-2 cells, and this effect was abolished by overexpression of p75NTR. Conclusion. DEX ameliorated AKI in mice with sepsis by partially reducing oxidative stress and apoptosis through regulation of p75NTR/p38MAPK/JNK signaling pathways.

Dexmedetomidine reduces ventilator-induced lung injury via ERK1/2 pathway activation.

Mechanical ventilation (MV) can contribute to ventilator-induced lung injury (VILI); dexmedetomidine (Dex) treatment attenuates MV-related pulmonary inflammation, but the mechanisms remain unclear. Therefore, the present study aimed to explore the protective effect and the possible molecular mechanisms of Dex in a VILI rodent model. Adult male Sprague-Dawley rats were randomly assigned to one of seven groups (n=24 rats/group). Rats were euthanized after 4 h of continuous MV, and pathological changes, lung wet/dry (W/D) weight ratio, the levels of inflammatory cytokines (IL-1β, TNF-α and IL-6) in the bronchoalveolar lavage fluid (BALF), and the expression levels of Bcl-2 homologous antagonist/killer (Bak), Bcl-2, pro-caspase-3, cleaved caspase-3 and the phosphorylation of ERK1/2 in the lung tissues were measured. Propidium iodide uptake and TUNEL staining were used to detect epithelial cell death. The Dex pretreatment group exhibited fewer pathological changes, lower W/D ratios and lower expression levels of inflammatory cytokines in BALF compared with the VILI group. Dex significantly attenuated the ratio of Bak/Bcl-2, cleaved caspase-3 expression levels and epithelial cell death, and increased the expression of phosphorylated ERK1/2. The protective effects of Dex could be partially reversed by PD98059, which is a mitogen-activated protein kinase (upstream of ERK1/2) inhibitor. Overall, dexmedetomidine was found to reduce the inflammatory response and epithelial cell death caused by VILI, via the activation of the ERK1/2 signaling pathway.

Dexmedetomidine Mediates Neuroglobin Up-Regulation and Alleviates the Hypoxia/Reoxygenation Injury by Inhibiting Neuronal Apoptosis in Developing Rats.

BackgroundExploring the effective therapy for neonatal hypoxic-ischemic brain injury is an important goal. This study was designed to investigate how dexmedetomidine (DEX) contribute to hypoxic brain injury.MethodsDeveloping Sprague-Dawley rat models of hypoxia/reoxygenation (H/R) injury were constructed to simulate neonatal hypoxic brain injury for DEX treatment. Immunohistochemistry and western blot were performed to measure neuroglobin (Ngb) protein expression in hippocampal tissues. Hippocampal neuron injury and apoptosis were detected by Nissl staining and TUNEL assay, respectively. A Morris water maze (MWM) test was performed to evaluate the long-term learning and memory function.ResultsThe expression of Ngb was increased following H/R model establishment and up-regulated by medium and high doses of DEX, but not up-regulated by low doses of DEX. Medium and high doses of DEX alleviated the H/R injury as well as induced the reduction of Nissl bodies and apoptosis. Besides, medium and high doses of DEX down-regulated cytosolic Cyt-c, Apaf-1, and caspase-3 in H/R injury model. MWM test showed that medium and high doses of DEX significantly shortened the escape latency and enhanced the number of platform crossings. However, low doses of DEX have no effect on Nissl bodies, mitochondrial apoptosis, expression of apoptosis-related proteins and long-term learning functions.ConclusionsDEX induced Ngb expression in H/R rat models. The neuroprotection of DEX-mediated Ngb up-regulation may be achieved by inhibiting neuronal apoptosis through the mitochondrial pathway. Findings indicated that DEX may be useful as an effective therapy for neonatal hypoxic brain injury.

Effects of intracoelomic alfaxalone–dexmedetomidine on righting reflex in common garter snakes (Thamnophis sirtalis): preliminary data

ObjectiveTo evaluate the effect of dexmedetomidine on alfaxalone immobilization in snakes. Study designNonblinded, crossover study. AnimalsA total of eight mature common garter snakes (Thamnophis sirtalis). MethodsSnakes were administered each of three treatments intracoelomically: alfaxalone (30 mg kg–1; treatment A), alfaxalone (30 mg kg–1) combined with dexmedetomidine (0.05 mg kg–1; treatment AD0.05); and alfaxalone (30 mg kg–1) combined with dexmedetomidine (0.10 mg kg–1; treatment AD0.10). A minimum of 10 days elapsed between experimental trials. Times to loss of righting reflex (LRR) and return of righting reflex (RRR) were recorded. Heart rate (HR) was recorded every 5 minutes throughout the period of LRR and averaged for each snake. Times to LRR and RRR, and mean HR in snakes that achieved LRR were reported. ResultsLRR occurred in eight (100%), five (63%) and three (38%) snakes in treatments A, AD0.05 and AD0.10, respectively. For all treatments, time to LRR ranged 3–20 minutes. Median (range) times to RRR were 39 (30–46), 89 (62–128) and 77 (30–185) minutes for treatments A, AD0.05 and AD0.10, respectively. In animals where righting reflex was lost, mean HR was lower in all dexmedetomidine treatments compared with treatment A. Conclusions and clinical relevanceIn this pilot study, alfaxalone resulted in reliable immobilization, whereas dexmedetomidine and alfaxalone combinations resulted in highly variable durations of immobilization with low HR in immobilized animals. For snakes that achieved LRR, the addition of dexmedetomidine (0.05 mg kg–1) to alfaxalone appeared to extend the period of immobilization compared with alfaxalone alone.

The Protective Effect and Mechanism of Dexmedetomidine on Diabetic Peripheral Neuropathy in Rats.

ObjectiveTo investigate the role of dexmedetomidine (DEX) in the inhibition of diabetic peripheral neuropathy (DPN) and the protection in the nerve damage.MethodsEighty male Sprague-Dawley (SD) rats were randomly allocated to four groups: the control group (C group), DPN model group (DPN group), DEX-treated group (DEX group), and the yohimbine treated group (YOH group). DPN was induced by intraperitoneal administration of streptozocin (STZ) (35 mg/kg). The body weights, blood glucose level, mechanical withdrawal threshold (MWT), thermal withdrawal latency (TWL), the motor, and sensory nerve conduction velocities (MNCV and SNCV) of sciatic nerve were measured. Then the sciatic nerve was isolated for H&E staining and immunohistochemical staining. The oxidative stress makers such as malondialdehyde (MDA), superoxide-dismutase (SOD), and glutathione peroxidase (GSH-Px) and apoptosis related cytokines such as Bax, Bcl-2, and caspase-3 were estimated.ResultsThere was no significant difference of the blood glucose and body weight among the DPN group, DEX group, and YOH group. H&E staining showed that DEX treatment can ameliorate the damage of sciatic nerve cells. In the DPN group, MWT, TWL, MNCV, and SNCV were significantly reduced compared with the C group (P < 0.05). In DEX group rats, MWT, TWL, MNCV, and SNCV were increased significantly (P < 0.05) compared with the DPN group and YOH group rats. Lower SOD and GSH-Px, and higher MDA were found in the DPN group compared with the C group (P < 0.01), and DEX treatment restored SOD, GSH-px, and MDA activity significantly (P < 0.01). The expression levels of Bax and caspase-3 were increased, while that of Bcl-2 was decreased significantly in the DPN group compared with the C group (P < 0.05). In the DEX group, the expression levels of Bax and caspase-3 were decreased significantly (P < 0.05), while that of Bcl-2 was increased significantly (P < 0.05) compared with the DPN group and the YOH group.ConclusionThe results of this study demonstrated that DEX has the inhibitory and protective effects on DPN of rats. This may be associated with its antioxidative and anti-apoptosis responses.

Dexmedetomidine promotes the progression of hepatocellular carcinoma through hepatic stellate cell activation

Dexmedetomidine (DEX) is an anesthetic that is widely used in the clinic, and it has been reported to exhibit paradoxical effects in the progression of multiple solid tumors. In this study, we sought to explore the mechanism by which DEX regulates hepatocellular carcinoma (HCC) progression underlying liver fibrosis. We determined the effects of DEX on tumor progression in an orthotopic HCC mouse model of fibrotic liver. A coculture system and a subcutaneous xenograft model involving coimplantation of mouse hepatoma cells (H22) and primary activated hepatic stellate cells (aHSCs) were used to study the effects of DEX on HCC progression. We found that in the preclinical mouse model of liver fibrosis, DEX treatment significantly shortened median survival time and promoted tumor growth, intrahepatic metastasis and pulmonary metastasis. The DEX receptor (ADRA2A) was mainly expressed in aHSCs but was barely detected in HCC cells. DEX dramatically reinforced HCC malignant behaviors in the presence of aHSCs in both the coculture system and the coimplantation mouse model, but DEX alone exerted no significant effects on the malignancy of HCC. Mechanistically, DEX induced IL-6 secretion from aHSCs and promoted HCC progression via STAT3 activation. Our findings provide evidence that the clinical application of DEX may cause undesirable side effects in HCC patients with liver fibrosis.

MiR-128-3p enhances the protective effect of dexmedetomidine on acute lung injury in septic mice by targeted inhibition of MAPK14.

To investigate the role of miR-128-3p and MAPK14 in the dexmedetomidine treatment of acute lung injury in septic mice. SPF C57BL/6 mice were divided into 8 groups. The pathological changes and wet/dry weight ratio (W/D), PaO2, PaCO2, MDA, SOD and MPO levels in lung tissue and the serum levels of inflammation factors were observed. Dual luciferase reporter assay was used to detect the targeting relationship of miR-128-3p and MAPK14, and qPCR and WB were used to detect the expression of miR-128-3p and MAPK14. Compared with the Normal group, other groups had lower MDA, MPO, inflammatory factors levels and the expression level of MAPK14, while the content of SOD and the expression level of miR-128-3p was significantly decreased (all p < 0.05). Compared with the Model group, the contents of MDA, MPO, inflammatory factors in the DEX group and miR-128-3p mimic group were significantly decreased, and the content SOD was significantly increased, however, opposite results were occurred in oe-MAPK14 group (all p < 0.05). Compared with the DEX group, all the indicators in miR-128-3p mimic+DEX group showed significant improvement (all p < 0.05). Compared with the miR-128-3p mimic group, all the indicators were deteriorated in the miR-128-3p mimic+oe-MAPK14 group (all p < 0.05). The combination of DEX and oe-MAPK14 blocked the protective effect of dexmedetomidine on acute lung injury in septic mice. miR-128-3p can further enhance the protective effect of dexmedetomidine on acute lung injury in septic mice by targeting and inhibiting MAPK14 expression.

Dexmedetomidine Ameliorates Lung Injury Induced by Intestinal Ischemia/Reperfusion by Upregulating Cannabinoid Receptor 2, Followed by the Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway.

Intestinal ischemia/reperfusion (I/R) is a clinical emergency, which often causes lung injury with high morbidity and mortality. Although dexmedetomidine has been identified to have a protective effect on lung injury caused by intestinal I/R, its specific mechanism is still elucidated. In recent years, the cannabinoid (CB2) receptor pathway has been found to be involved in I/R injury of some organs. In the current study, we investigated whether the CB2 receptor pathway contributes to the protective effect of dexmedetomidine on the intestinal I/R-induced lung injury in rats. Dexmedetomidine treatment upregulated the expression of CB2 receptor and suppressed the I/R-induced increases in lung injury scores, inflammatory cell infiltration, lung wet/dry ratio, MPO activity, MDA level, inflammatory cytokines, and caspase-3 expression while augmenting SOD activity and Bcl-2 expression, indicating attenuation of lung injury. Dexmedetomidine treatment also increased the expression of Akt. The protective effects of dexmedetomidine treatment were reversed by the CB2 receptor antagonist AM630 or the PI3K inhibitor wortmannin. And the CB2 receptor antagonist AM630 also downregulated the expression of Akt. Thus, our findings suggest that treatment with dexmedetomidine provides a protective role against lung injury caused by intestinal I/R in rats, possibly due to the upregulation of the CB2 receptor, followed by the activation of the PI3K/Akt pathway.

Dexmedetomidine Improves Locomotor Function and Alleviates Thermal Hyperalgesia Following Sciatic Nerve Crush Injury in Rats.

PurposeThe effects of dexmedetomidine on locomotor function and thermal hyperalgesia in sciatic nerve crush injury (SNCI) were investigated using rats.MethodsAfter exposing the right sciatic nerve, the sciatic nerve was crushed for 1 minute by a surgical clip. One day after nerve injury, dexmedetomidine (5, 25, and 50 µg/kg) was directly applied to the injured sciatic nerve once a day for 14 days. Walking track analysis was used to assess locomotor function and plantar test was conducted to assess thermal pain sensitivity. Immunohistochemistry was performed to determine the expression of c-Fos in the ventrolateral periaqueductal gray (vlPAG) and paraventricular nucleus (PVN). Western blot was used to evaluate the expression level of nerve growth factor (NGF) and myelin basic protein (MBP) in the sciatic nerve.ResultsSNCI resulted in deterioration of locomotor function and increased thermal pain sensitivity. The level of c-Fos expression in the PVN and vlPAG was increased and the level of NGF and MBP expression in the sciatic nerve was enhanced by SNCI. Dexmedetomidine treatment improved locomotor function and upregulated expression of NGF and MBP in the sciatic nerve of SNCI. Dexmedetomidine treatment alleviated thermal hyperalgesia and downregulated expression of c-Fos in the vlPAG and PVN after SNCI.ConclusionsDexmedetomidine may be used as a potential new treatment drug for recovery of locomotion and control of pain in peripheral nerve injury.

Assessment of the sedative effects of dexmedetomidine and propofol treatment in patients undergoing mechanical ventilation in the ICU and relationship between treatment and occurrence of ventilator-associated pneumonia and detection of pathogenic bacteria.

The present study aimed to investigate the sedative effects of dexmedetomidine combined with propofol in patients undergoing mechanical ventilation in the intensive care unit (ICU), and to reveal the risk factors of ventilator-associated pneumonia (VAP). A retrospective analysis of 322 patients who had been subject to mechanical ventilation in the ICU ward was performed. Subjects were divided into two groups: A group treated with dexmedetomidine and propofol (combined group) and a group treated with dexmedetomidine alone (monotherapy group). Clinical data, sedative effects, the number of VAP patients and the distribution of VAP pathogens were assessed. Multivariate analysis and receiver operating characteristic (ROC) curves were used to predict VAP. Significant differences in the sedative effects between the two groups were observed (P<0.001). The incidence of VAP was significantly higher in the monotherapy group compared with the combined group (P<0.05). Multivariate logistic regression analysis demonstrated that age, acute physiology chronic health evaluation score, consciousness, invasive operations, recovery time, extubation time and sedation regimen were independent risk factors for VAP in the ICU during mechanical ventilation. ROC curves indicated that the areas under the curve for age, acute physiology chronic health score, consciousness, invasive operations, recovery time, extubation time and sedation regimen were 0.934, 0.870, 0.632, 0.677, 0.865, 0.950 and 0.603, respectively. In summary, dexmedetomidine combined with propofol can shorten the recovery and extubation times of mechanical ventilation patients in the ICU. Different sedation schemes are also independent risk factors for VAP during mechanical ventilation in the ICU.

Dexmedetomidine protects intestinal ischemia-reperfusion injury via inhibiting p38 MAPK cascades

Intestinal ischemia-reperfusion (I/R) is a life-threatening condition associated with high morbidity and mortality. Dexmedetomidine (DEX), an agonist of α2-adrenoceptor with sedation and analgesia effect, has recently been identified with protective function against I/R injury in multiple organs. However, the mechanism underlying the beneficial effect of DEX on intestine after I/R injury remained poorly understood. In the present study, using in both in vitro and in vivo models, we found that intestinal I/R injury was associated with the activation of p38 MAPK cascade, while DEX was capable of deactivating p38 MAPK and thus protect intestinal cells from apoptosis by inhibiting p38 MAPK-mediated mitochondrial depolarization and cytochrome c (Cyto C) release. Moreover, through inhibiting p38 MAPK activity, the downstream production of pro-inflammatory cytokines-regulated by NF-κB was also suppressed by DEX treatment, leading to the resolution of I/R-induced inflammation in intestine. In general, our study provided evidence that DEX protected intestine from I/R injury by inhibiting p38 MAPK-mediated mitochondrial apoptosis and inflammatory response.

Dexmedetomidine suppresses the progression of esophageal cancer via miR-143-3p/epidermal growth factor receptor pathway substrate 8 axis

Esophageal cancer is one of the fatal cancers around the world. Dexmedetomidine (DEX) is widely used during anesthesia of esophageal cancer surgery. Nevertheless, the role of DEX in the progression of esophageal cancer remains barely known. The proliferation, apoptosis and metastasis of esophageal cancer cells were detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry, transwell migration and invasion assays and Western blot assay. The expression of miR-143-3p was measured by quantitative real-time PCR in esophageal cancer tissues and cells. The binding sites between miR-143-3p and epidermal growth factor receptor pathway substrate 8 (EPS8) were predicted by Starbase online software, and the combination was verified by dual-luciferase reporter assay. The murine xenograft model was established using KYSE150 cells to verify the function of DEX in vivo. DEX inhibited the proliferation and metastasis while accelerated the apoptosis of esophageal cancer cells. The abundance of miR-143-3p was lower in esophageal cancer tissues and cells than that in paring normal tissues and normal esophageal mucosal cells Het-1A. MiR-143-3p could be induced by DEX treatment in esophageal cancer cells, and miR-143-3p also suppressed the development of esophageal cancer. EPS8 was a functional target of miR-143-3p, and it played an oncogenic role in esophageal cancer. DEX inhibited the growth of tumor via miR-143-3p/EPS8 in vivo. DEX suppressed the growth and metastasis while facilitated the apoptosis of esophageal cancer cells through upregulating the abundance of miR-143-3p and reducing the level of EPS8 in vivo and in vitro, providing promising target for the treatment of esophageal cancer.

Dexmedetomidine Protects against Ischemia and Reperfusion-Induced Kidney Injury in Rats.

Acute kidney injury (AKI), a clinical syndrome, is a sudden onset of kidney failure that severely affects the kidney tubules. One potential treatment is dexmedetomidine (DEX), a highly selective α2-adrenoreceptor agonist that is used as an anesthetic adjuvant. It also has anti-inflammatory, neuroprotective, and sympatholytic qualities. The aim of this study was to establish whether DEX also offers protection against ischemia and reperfusion- (I/R-) induced AKI in rats. An intraperitoneal injection of DEX (25 μg/kg) was administered 30 min prior to the induction of I/R. The results indicate that in the I/R rats, DEX played a protective role by reducing the damage to the tubules and maintaining renal function. Furthermore, in response to I/R, the DEX treatment reduced the mRNA expression of TNF-α, IL-1β, IL-6, and MCP-1 in the kidney tissues and the serum levels of TNF-α, IL-1β, IL-6, and MCP-1. DEX also reduced the levels of oxidative stress and apoptosis in the tubular cells. These results indicate that in response to I/R kidney injury, DEX plays a protective role by inhibiting inflammation and tubular cell apoptosis, reducing the production of reactive oxygen species, and promoting renal function.

Therapeutic effect of dexmedetomidine on myocardial ischemia reperfusion injury in type 2 diabetic rat model under P13K/Akt pathway

This research aims to study the therapeutic effect of dexmedetomidine on type 2 diabetic rats reperfusion injury model. A rat model of type 2 diabetes was induced by high-fat and high-sugar feed, and a reperfusion rat model was obtained by ligating the left anterior descending branch and reperfusion. The diabetic rat model sham operation group was used as the control group (DM-S), the rats were divided into diabetic reperfusion group (DM-IR) and dexmedetomidine treatment group (DM-D), dexmedetomidine combined with DM-DW (DM-DW), and Wortmannin treatment group (DM-W). In this study, the MB isoenzyme of creatine kinase (CK-MB) concentration was determined by ELISA competition method, superoxide dismutase (SOD) activity in rat plasma was detected by superoxide dismutase WST-1, and the content of malonaldehyde (MDA) in rat plasma was determined by thiobarbituric acid method. Besides, Western Blot was used to detect the expression changes of Akt, P-Akt, GSK-3β, and P-GSK-3β in rat myocardial tissue. The results showed that the content of CK-MB and SOD in DM-D group was significantly higher than that in DM-IR group (P < 0.05), and the content of MAD was significantly lower than that in DM-IR group (P < 0.05). The content of CK-MB and SOD in DM-DW group and DM-W group were significantly higher than that in DM-D group (P < 0.05), and the content of MDA was significantly lower than that in DM-D group (P < 0.05). However, expression of p-Akt and p-GSK-3β protein in DM-D group was significantly higher than that in DM-DW group and DM-W group (p < 0.05). Accordingly, dexmedetomidine can play a role in treating myocardial ischemia-reperfusion injury in type 2 diabetes by regulating the expression of related genes in the P13K/Akt signaling pathway.

Dexmedetomidine Pharmacokinetics in Neonates with Hypoxic-Ischemic Encephalopathy Receiving Hypothermia.

Dexmedetomidine is a promising sedative and analgesic for newborns with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). Pharmacokinetics and safety of dexmedetomidine were evaluated in a phase I, single-center, open-label study to inform future trial strategies. We recruited 7 neonates ≥36 weeks' gestational age diagnosed with moderate-to-severe HIE, who received a continuous dexmedetomidine infusion during TH and the 6 h rewarming period. Time course of plasma dexmedetomidine concentration was characterized by serial blood sampling during and after the 64.8 ± 6.9 hours of infusion. Noncompartmental analysis yielded descriptive pharmacokinetic estimates: plasma clearance of 0.760 ± 0.155 L/h/kg, steady-state distribution volume of 5.22 ± 2.62 L/kg, and mean residence time of 6.84 ± 3.20 h. Naive pooled and population analyses according to a one-compartment model provided similar estimates of clearance and distribution volume. Overall, clearance was either comparable or lower, distribution volume was larger, and mean residence time or elimination half-life was longer in cooled newborns with HIE compared to corresponding estimates previously reported for uncooled (normothermic) newborns without HIE at comparable gestational and postmenstrual ages. As a result, plasma concentrations in cooled newborns with HIE rose more slowly in the initial hours of infusion compared to predicted concentration-time profiles based on reported pharmacokinetic parameters in normothermic newborns without HIE, while similar steady-state levels were achieved. No acute adverse events were associated with dexmedetomidine treatment. While dexmedetomidine appeared safe for neonates with HIE during TH at infusion doses up to 0.4 μg/kg/h, a loading dose strategy may be needed to overcome the initial lag in rise of plasma dexmedetomidine concentration.

Sleep-restriction Inhibits Neurogenesis Through Decreasing the Infiltration of CD169+ Macrophages to Ischemic Brain After Stroke

Chronic sleep-restriction (SR) is shown to be correlated with neurodevelopmental disorders. However, the effects of SR during stroke recovery on neurorepair remain unclear. In this study, mice were subjected to 60 min of cerebral ischemia followed by reperfusion. The SR protocol was accomplished by depriving mice of sleep for 20 h/day for 14 days starting at 14 days post-ischemia. We found that SR increased CD169+ macrophages infiltration into the ischemic brain parenchyma and inhibited neurogenesis and functional recovery. SR decreased CD169+ macrophages infiltration into the choroid plexus (CP) and cerebrospinal fluid (CSF), accompanied by increased expression of Chemokine C-X3-C-Motif Ligand 1 (CX3CL1) and intercellular adhesion molecule (ICAM-1) via IFN-γ/IFN-γR signaling in the CP. When splenic CD169+ macrophages sorted from Kaede transgenic mice were administered into CSF of C57BL/6 mice, they homed to the ischemic brain parenchyma. Moreover, blockade of IFN-γ/IFN-γR signaling, CX3CL1 or ICAM-1 decreased CD169+ macrophages infiltration into the CP, CSF and ischemic brain parenchyma, as well as decreasing neurogenesis and functional recovery after SR. The promoting roles of infiltrated CD169+ macrophages in post-stroke neurogenesis were due to increasing regulatory T cells (Tregs) in the ischemic brain parenchyma. Furthermore, dexmedetomidine treatment during SR increased CD169+ macrophages infiltration into the CP, CSF and ischemic brain parenchyma, and promoted neurogenesis and functional recovery. Taken together, our results showed that SR during stroke recovery decreased Tregs in the ischemic brain parenchyma by decreasing CD169+ macrophages infiltration to the ischemic brain parenchyma across the CP, which inhibited neurogenesis and functional recovery.

Protective Effect of Dexmedetomidine on Acute Lung Injury via the Upregulation of Tumour Necrosis Factor-α-Induced Protein-8-like 2 in Septic Mice.

The aim of the present study was to investigate whether TIPE2 participates in the protective actions of dexmedetomidine (DEX) in a mouse model of sepsis-induced acute lung injury (ALI). We administered TIPE2 adeno-associated virus (AAV-TIPE2) intratracheally into the lungs of mice. Control mice were infected with an adeno-associated virus expressing no transgene. Three weeks later, an animal model of caecal ligation-perforation (CLP)-induced sepsis was established. DEX was administered intravenously 30 min after CLP. Twenty-four hours after sepsis, lung injury was assayed by lung histology, the ratio of polymorphonuclear leukocytes (PMNs) to total cells in the bronchoalveolar lavage fluid (BALF), myeloperoxidase (MPO) activity, BALF protein content and the lung wet-to-dry (W/D) weight ratio. Proinflammatory factor levels in the BALF of mice were measured. The protein expression levels in lung tissues were analysed by Western blotting. The results showed that DEX treatment markedly mitigated sepsis-induced lung injury, which was characterized by the deterioration of histopathology, histologic scores, the W/D weight ratio and total protein levels in the BALF. Moreover, DEX markedly attenuated sepsis-induced lung inflammation, as evidenced by the decrease in the number of PMNs in the BALF, lung MPO activity and proinflammatory cytokines in the BALF. In addition, DEX dramatically prevented sepsis-induced pulmonary cell apoptosis in mice, as reflected by decreases in the number of TUNEL-positive cells, the protein expression of cleaved caspase-9 and cleaved caspase 3 and the Bax/Bcl-2 ratio. In addition, evaluation of protein expression showed that DEX blocked sepsis-activated JNK phosphorylation and NF-κB p65 nuclear translocation. Similar results were also observed in the TIPE2 overexpression group. Our study demonstrated that DEX inhibits acute inflammation and apoptosis in a murine model of sepsis-stimulated ALI via the upregulation of TIPE2 and the suppression of the activation of the NF-κB and JNK signalling pathways.