Inhibitory Effects of Dexmedetomidine and Propofol on Gastrointestinal Tract Motility Involving Impaired Enteric Glia Ca2+ Response in Mice.

Propofol and dexmedetomidine are popular used for sedation in ICU, however, inadequate attention has been paid to their effect on gastrointestinal tract (GIT) motility. Present study aimed to compare the effect of propofol and dexmedetomidine on GIT motility at parallel level of sedation and explore the possible mechanism. Male C57BL/6 mice (8-10 weeks) were randomly divided into control, propofol and dexmedetomidine group. After intraperitoneal injection of propofol or dexmedetomidine, comparable sedative level was confirmed by sedative score, physiological parameters and electroencephalogram (EEG). Different segments of GIT motility in vivo (gastric emptying, small intestine transit, distal colon bead expulsion, stool weight and number of fecal pellets, gastrointestinal transit and whole gut transit time) and colonic migrating motor complexes (CMMCs) pattern in vitro were evaluated. The Ca2+ response of primary enteric glia was examined under the treatment of propofol or dexmedetomidine. There is little difference in physiological parameters and composite permutation entropy index (CPEI) between administration of 50 mg/kg propofol and 40 µg/kg dexmedetomidine, indicated that parallel level of sedation was reached. Data showed that propofol and dexmedetomidine had significantly inhibitory effect on GIT motility while dexmedetomidine was stronger. Also, the amplitude (ΔF/F0) of Ca2+ response in primary enteric glia was attenuated after treated with the sedatives while the effect of dexmedetomidine was greater than propofol. These findings demonstrated that dexmedetomidine caused stronger inhibitory effects on GIT motility in sedative mice, which may involve impaired Ca2+ response in enteric glia. Hence, dexmedetomidine should be carefully applied especially for potential GIT dysmotility patient.

NDRG2 is expressed on enteric glia and altered in conditions of inflammation and oxygen glucose deprivation/reoxygenation.

Enteric glial cells are more abundant than neurons in the enteric nervous system. Accumulating evidence has demonstrated that enteric glial cells share many properties with astrocytes and play pivotal roles in intestinal diseases. NDRG2 is specifically expressed in astrocytes and is involved in various diseases in the central nervous system. However, no studies have demonstrated the expression of NDRG2 in enteric glial cells. We performed immunostaining of adult mouse tissue, human colon sections, and primary enteric glial cells and the results showed that NDRG2 was widely expressed in enteric glial cells. Meanwhile, our results showed that NDRG2 was upregulated after treatment with pro-inflammatory cytokines and exposure to oxygen glucose deprivation/reoxygenation, indicating that NDRG2 might be involved in these conditions. Moreover, we determined that NDRG2 translocated to the nucleus after treatment with pro-inflammatory cytokines but not after exposure to oxygen glucose deprivation/reoxygenation. This study is the first to show the expression and distribution of NDRG2 in the enteric glia. Our results indicate that NDRG2 might be involved in the pathogenesis of enteric inflammation and ischemia/reperfusion injury. This study shows that NDRG2 might be a molecular target for enteric nervous system diseases.

Muscle-Derived Mitochondrial Transplantation Reduces Inflammation, Enhances Bacterial Clearance, and Improves Survival in Sepsis.

BACKGROUND: Mitochondrial transplantation is a promising strategy for the treatment of several diseases. However, the effects of mitochondrial transplantation on the outcome of polymicrobial sepsis remain unclear. METHODS: The distribution of transplanted mitochondria in cecal ligation and puncture (CLP)-operated mice was detected at 2 and 12 h after intravenous injection in the tail (n = 3). Then, the effects of mitochondrial transplantation on bacterial clearance (n = 7), systemic inflammation (n = 10), organ injury (n = 8), and mortality (n = 19) during CLP-induced sepsis were explored. Microarray analysis (n = 3) was used to testify the molecular changes associated with decreased systemic inflammation and multiorgan dysfunction in sepsis. RESULTS: The extraneous mitochondria were distributed in the lung, liver, kidney, and brain of CLP-operated mice at 2 and 12 h after intravenous injection in the tail. Mitochondrial transplantation increased the survival rate of septic mice, which was associated with decreased bacterial burden, systemic inflammation, and organ injury. Spleen samples were utilized for microarray analysis. Pathway analysis revealed that in polymicrobial sepsis, gene expression was significantly changed in processes related to inflammatory response, complement and coagulation cascades, and rejection reaction. CONCLUSIONS: These data displayed that mitochondrial replenishment reduces systemic inflammation and organ injury, enhances bacterial clearance, and improves the survival rate in sepsis. Thus, extraneous mitochondrial replenishment may be an effective adjunctive treatment to reduce sepsis-related mortality.

Effect of sedation with dexmedetomidine or propofol on gastrointestinal motility in lipopolysaccharide-induced endotoxemic mice.

BACKGROUND: Sepsis often accompanies gastrointestinal motility disorder that contributes to the development of sepsis in turn. Propofol and dexmedetomidine, as widely used sedatives in patients with sepsis, are likely to depress gastrointestinal peristalsis. We queried whether propofol or dexmedetomidine, at sedative doses, aggravated sepsis-induced ileus. METHODS: Sedative/Anesthetic Scores and vital signs of lipopolysaccharide (LPS)-induced endotoxemic mice were measured during sedation with propofol or dexmedetomidine. Endotoxemic mice were divided into 10% fat emulsion, propofol, saline, and dexmedetomidine group. The gastric emptying, small intestinal transit, tests of colonic motility, gastrointestinal transit and whole gut transit were evaluated at 15 mins and 24 h after intraperitoneal injection of sedatives/vehicles respectively. RESULTS: 40 mg·kg- 1propofol and 80 µg·kg- 1 dexmedetomidine induced a similar depth of sedation with comparable vital signs except that dexmedetomidine strikingly decreased heart rate in endotoxemic mice. Dexmedetomidine markedly inhibited gastric emptying (P = 0.006), small intestinal transit (P = 0.006), colonic transit (P = 0.0006), gastrointestinal transit (P = 0.0001) and the whole gut transit (P = 0.034) compared with the vehicle, whereas propofol showed no depression on all parts of gastrointestinal motility 15 mins after administration. The inhibitive effects of dexmedetomidine in these tests vanished 24 h after the administration. CONCLUSIONS: Deep sedation with dexmedetomidine, but not propofol, significantly inhibited gastrointestinal peristalsis in endotoxemic mice while the inhibitory effect disappeared 24 h after sedation. These data suggested that both propofol and dexmedetomidine could be applied in septic patients while dexmedetomidine should be used cautiously in patients with cardiac disease or ileus.