Effects of dexmedetomidine on oxygenation and inflammatory factors in patients undergoing uvulopalatopharyngoplasty: a prospective, randomized, placebo-controlled trial.

PURPOSE: Uvulopalatopharyngoplasty (UPPP) can aggravate lung inflammatory reactions in patients with obstructive sleep apnoea syndrome (OSAS). Dexmedetomidine (Dex) is a selective α-2 adrenoreceptor agonist that can alleviate lung injury. This study was designed to investigate the effects of Dex on oxygenation and inflammatory factors in patients undergoing UPPP in the early perioperative period. METHODS: Patients with OSAS undergoing UPPP were randomly allocated to the Dex Group or Control Group. Arterial blood gas analyses were performed, and the respiratory index (RI) and oxygenation index (OI) were calculated upon entering the operating room (T0) and immediately after surgery (T3). The inflammatory factors tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10) were measured at T0 and T3. RESULTS: A total of 44 patients with OSAS were randomized. There was no significant difference in basic patient characteristics between the two groups. The preoperative RI and OI were not significantly different between the two groups, but they were altered immediately after surgery relative to the corresponding preoperative value (p < 0.05). Compared with the Control Group, the RI was significantly lower at T3 in the Dex Group (p < 0.001). However, there was no significant difference in the OI between the two groups (p = 0.128). The inflammatory factors TNF-α (p < 0.001) and IL-6 (p = 0.018) were lower, while IL-10 was higher in the Dex Group than in the Control Group (p < 0.001). CONCLUSION: Dexmedetomidine can improve the oxygenation and inhibit the inflammatory response in patients undergoing UPPP in the early perioperative period. TRIAL REGISTRATION: The present clinical study has been registered at Clinical Trials under number NCT03612440.

The effect of dilution with glucose and prolonged injection time on dexamethasone-induced perineal irritation - A randomized controlled trial.

Dexamethasone can be used to prevent nausea and vomiting after surgery, but there is concern that it may induced perineal irritation. The aim of this study was to investigate the attenuation effect of dilution and slow injection on dexamethasone-induced perineal irritation. In this prospective, randomized, double-blind study, a total of 400 patients were enrolled and allocated into four groups: Group I, receiving 2 mL dexamethasone (5 mg/mL), Group II, receiving 5 mL dexamethasone (2 mg/mL), Group III, receiving 10 mL dexamethasone (1 mg/mL), and Group IV receiving 20 mL dexamethasone (0.5 mg/mL). Dexamethasone was diluted with 5% glucose. The injection time of dexamethasone was less than 2 s in Group I, while it was 30 s in Groups II, III, and IV. The incidence, onset, duration, and severity of perineal irritation were recorded. The incidence of dexamethasone-induced perineal irritation was 49, 33, 17, and 15% in Groups I, II, III, and IV, respectively. Group IV had less severity than Group I in mild and moderate perineal irritation (P < 0.008). The onset and duration of perineal irritation of Groups II, III, and IV were significantly improved compared to Group I (P < 0.001). Dexamethasone-induced perineal irritation can be alleviated by dilution of dexamethasone to 0.5 mg/mL with 5% glucose combined with prolonged injection time of 30 s.

Analgesic effect of nobiletin against neuropathic pain induced by the chronic constriction injury of the sciatic nerve in mice.

Neuropathic pain is chronic pain resulting from central or peripheral nerve damage that remains difficult to treat. Current evidence suggests that nobiletin, isolated from Citrus reticulata Blanco, possesses analgesic and neuroprotective effects. However, its effect on neuropathic pain has not been reported. This study evaluated the analgesic effect of nobiletin on neuropathic pain induced by chronic constriction injury (CCI) in mice. In vivo, mice were intragastrically administered with nobiletin (30, 60, 120 mg/kg) for eight consecutive days, respectively. Our study indicated that nobiletin ameliorated mechanical allodynia, cold allodynia and thermal hyperalgesia on CCI mice at doses that do not induce significant sedation. Moreover, nobiletin could ameliorate axonal and myelin injury of the sciatic nerve and further restore abnormal sciatic nerve electrical activity on CCI mice. In vitro studies indicated that nobiletin could suppress the proteins and mRNA expression of the IRF5/P2X4R/BDNF signalling pathway in fibronectin-induced BV2 cells. Overall, our results indicated that nobiletin might exert an analgesic effect on CCI-induced neuropathic pain in mice by inhibiting the IRF5/P2X4R/BDNF signalling pathway in spinal microglia. This study provided a novel potential therapeutic drug for neuropathic pain and new insights into the pharmacological action of nobiletin.

Bupivacaine reduces GlyT1 expression by potentiating the p-AMPKα/BDNF signalling pathway in spinal astrocytes of rats.

Bupivacaine, a local anaesthetic, is widely applied in the epidural or subarachnoid space to clinically manage acute and chronic pain. However, the underlying mechanisms are complex and unclear. Glycine transporter 1 (GlyT1) in the spinal cord plays a critical role in various pathologic pain conditions. Therefore, we sought to determine whether bupivacaine exerts its analgesic effect by regulating GlyT1 expression and to determine the underlying mechanisms of regulation. Primary astrocytes prepared from the spinal cord of rats were treated with bupivacaine. The protein levels of GlyT1, brain-derived neurotrophic factor (BDNF) and phosphorylated adenosine 5'-monophosphate (AMP)-activated protein kinase α (p-AMPKα) were measured by western blotting or immunofluorescence. In addition, 7,8-dihydroxyflavone (7,8-DHF, BDNF receptor agonist) and AMPK shRNA were applied to verify the relationship between the regulation of GlyT1 by bupivacaine and the p-AMPKα/BDNF signalling pathway. After treatment with bupivacaine, GlyT1 expression was diminished in a concentration-dependent manner, while the expression of BDNF and p-AMPK was increased. Moreover, 7,8-DHF decreased GlyT1 expression, and AMPK knockdown suppressed the upregulation of BDNF expression by bupivacaine. Finally, we concluded that bupivacaine reduced GlyT1 expression in spinal astrocytes by activating the p-AMPKα/BDNF signalling pathway. These results provide a new mechanism for the analgesic effect of intrathecal bupivacaine in the treatment of acute and chronic pain.

Effects of alkaloids on peripheral neuropathic pain: a review.

Neuropathic pain is a debilitating pathological pain condition with a great therapeutic challenge in clinical practice. Currently used analgesics produce deleterious side effects. Therefore, it is necessary to investigate alternative medicines for neuropathic pain. Chinese herbal medicines have been widely used in treating intractable pain. Compelling evidence revealed that the bioactive alkaloids of Chinese herbal medicines stand out in developing novel drugs for neuropathic pain due to multiple targets and satisfactory efficacy. In this review, we summarize the recent progress in the research of analgesic effects of 20 alkaloids components for peripheral neuropathic pain and highlight the potential underlying molecular mechanisms. We also point out the opportunities and challenges of the current studies and shed light on further in-depth pharmacological and toxicological studies of these bioactive alkaloids. In conclusion, the alkaloids hold broad prospects and have the potentials to be novel drugs for treating neuropathic pain. This review provides a theoretical basis for further applying some alkaloids in clinical trials and developing new drugs of neuropathic pain.

The effects of different doses of dexmedetomidine on the requirements for propofol for loss of consciousness in patients monitored via the bispectral index: a double-blind, placebo-controlled trial.

BACKGROUND: The α2-adrenergic agonist dexmedetomidine (DEX) is a sedative and can be used as an adjunct to hypnotics. The study sought to evaluate the effects of different doses of DEX on the requirements for propofol for loss of consciousness (LOC) in patients monitored via the bispectral index (BIS). METHODS: In this randomized, double-blind, three arm parallel group design and placebo-controlled trial, 73 patients aged between 18 and ~ 65 years with a BMI range of 18.0-24.5 kg·m- 2 and an American Society of Anesthesiologists (ASA) grade I or II who were scheduled for general anesthesia at the General Hospital of Ningxia Medical University were included in this study. Anesthesiologists and patients were blinded to the syringe contents. All patients were randomly assigned in a 1:1:1 ratio to receive a 0.5 µg·kg- 1 DEX infusion (0.5 µg·kg- 1 DEX group; n = 24), a 1.0 µg·kg- 1 DEX infusion (1.0 µg·kg- 1 DEX group; n = 25) or a saline infusion (control group; n = 24) for 10 min. Propofol at a concentration of 20 mg·kg- 1·h- 1 was then infused at the end of the DEX or saline infusion. The propofol infusion was stopped when the patient being infused lost consciousness. The primary endpoint were propofol requirements for LOC and BIS value at LOC. RESULTS: The data from 73 patients were analyzed. The propofol requirements for LOC was reduced in the DEX groups compared with the control group (1.12 ± 0.33 mg·kg- 1 for the 0.5 µg·kg- 1 DEX group vs. 1.79 ± 0.39 mg·kg- 1 for the control group; difference, 0.68 mg·kg- 1 [95% CI, 0.49 to 0.87]; P = 0.0001) (0.77 ± 0.27 mg·kg- 1 for the 1.0 µg·kg- 1 DEX group vs. 1.79 ± 0.39 mg·kg- 1 for the control group; difference, 1.02 mg·kg- 1 [95% CI, 0.84 to 1.21]; P = 0.0001). The propofol requirements for LOC was lower in the 1.0 µg·kg- 1 DEX group than the 0.5 µg·kg- 1 DEX group (0.77 ± 0.27 mg·kg- 1 vs. 1.12 ± 0.33 mg·kg- 1, respectively; difference, 0.34 mg·kg- 1 [95% CI, 0.16 to 0.54]; P = 0.003). At the time of LOC, the BIS value was higher in the DEX groups than in the control group (67.5 ± 3.5 for group 0.5 µg·kg- 1 DEX vs. 60.5 ± 3.8 for the control group; difference, 7.04 [95% CI, 4.85 to 9.23]; P = 0.0001) (68.4 ± 4.1 for group 1.0 µg·kg- 1 DEX vs. 60.5 ± 3.8 for the control group; difference, 7.58 [95% CI, 5.41 to 9.75]; P = 0.0001). CONCLUSION: The study showed that DEX (both 0.5 and 1.0 µg·kg- 1 DEX) reduced the propofol requirements for LOC. DEX pre-administration increased the BIS value for LOC induced by propofol. CLINICAL TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (trial ID: NCT02783846 on May 26, 2016).

Neuroprotective Effect of Swertiamain on Cerebral Ischemia/Reperfusion Injury by Inducing the Nrf2 Protective Pathway.

Oxidative stress plays a vital role in the development of cerebral ischemic/reperfusion (I/R). Targeting oxidative stress is proposed to be an effective strategy to treat cerebral I/R injury. Gentiana macrophylla Pall is reported to have a potential protective effect against stroke. Swertiamarin (Swe), an active secoiridoid glycoside compound isolated from Gentiana macrophylla Pall, has been reported to possess antioxidative potential. This study is to explore whether Swe could prevent brain from I/R injury, and the related mechanisms of oxidative stress are also elucidated using mice middle cerebral artery occlusion (MCAO) model and primary hippocampal neurons oxygen-glucose deprivation/reperfusion (OGD/R) model. Swe (25, 100, or 400 mg/kg) was pretreated intraperitoneally for 7 days until establishment of the MCAO model, while hippocampal neurons were maintained in Swe (0.1, 1, or 10 µM) in the entire process of reoxygenation. The results indicated that Swe pretreatment markedly decreased infarct volume, apoptotic neurons, and oxidative damage and promoted neurologic recovery in vivo. It also decreased reactive oxygen species (ROS) and increased cell viability in vitro. Western blot analyses and immunofluorescence staining demonstrated that Swe pretreatment promoted Nrf2 nuclear translocation from Keap1-Nrf2 complex and enhanced the expressions of NAD(P)H: quinone oxidoreductase-1 (NQO1) and heme oxygenase-1 (HO-1) both in vivo and in vitro, while the expressions could be reversed by a Nrf2 inhibitor. The binding mode of Keap1 with Swe was also proposed by covalent molecular docking. Collectively, Swe could be considered as a promising protective agent against cerebral I/R injury through suppressing oxidative stress by activation of the Nrf2 protective pathway.

Neuroprotective Effect of Anethole Against Neuropathic Pain Induced by Chronic Constriction Injury of the Sciatic Nerve in Mice.

Neuropathic pain is an intractable disease with few definitive therapeutic options. Anethole (AN) has been confirmed to possess potent anti-inflammatory and neuroprotective properties, but its effect on neuropathic pain has not been reported. The present study was designed to investigate the antinociceptive effect of AN on chronic constriction injury (CCI)-induced neuropathic pain in mice. AN (125, 250, and 500 mg/kg) and pregabalin (40 mg/kg) were intragastric administered for 8 consecutive days from the 7th day post-surgery. Behavioral parameters were measured on different days, namely, 0, 7, 8, 10, 12, and 14, from CCI operation. Additionally, electrophysiological and histopathological changes were analyzed on the 14th day. Afterward, immunofluorescence and Western blot were utilized to examine the activation of glial cells and the expression of inflammatory cytokines, respectively. AN treatment of CCI mice considerably alleviated hyperalgesia and allodynia, ameliorated abnormal sciatic nerve conduction, and restored injured sciatic nerves in a dose-dependent manner. Furthermore, AN suppressed the activation of glial cells, down-regulated pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL-6, and IL-1ß), and up-regulated the anti-inflammatory cytokine (IL-10). These assays first indicated that AN exerted an antinociceptive effect on CCI-induced neuropathic pain, and might be attributed to the anti-inflammatory and neuroprotective activities of AN.

Effects of intrathecal bupivacaine on the NR2B/CaMKIIα/CREB signaling pathway in the rat lumbar spinal cord.

Neuraxial anesthesia produces an anesthetic-sparing, sedative effect. The mechanism underlying this effect potentially involves decreased spinal afferent input. However, the neurochemical mechanisms at the spinal level remain unknown. The N­methyl­D­aspartate receptor 2B subunit/calcium­calmodulin­dependent protein kinase II α/cAMP response element­binding protein (NR2B/CaMKIIα/CREB) signaling pathway serves an important role in regulating the transmittance of peripheral noxious stimulation to supraspinal regions in the process of nociception. The present study investigated the effects of intrathecal bupivacaine on the NR2B/CaMKIIα/CREB signaling pathway. Following catheterization, 36 male Sprague­Dawley rats were randomly assigned to a normal saline (NS) or bupivacaine treatment group, in which each rat intrathecally received 20 µl normal saline or 0.5% bupivacaine, respectively. The expression levels of NR2B, CaMKIIα/p­CaMKIIα, and CREB/phosphorylated (p)­CREB in the lumbar spinal cord were investigated by western blotting, reverse transcription-quantitative polymerase chain reaction and immunohistochemistry (IHC). Following bupivacaine treatment, western blot analysis demonstrated that the protein expression levels of NR2B, p­CaMKIIα, and p­CREB in the spinal cord were reduced by approximately 54, 56 and 33%, respectively, compared with NS control rats. Similar alterations in expression were observed by IHC analysis. Additionally, mRNA expression levels of NR2B, CaMKIIα, and CREB were also downregulated following the intrathecal administration of bupivacaine. Therefore, the sedative effect of subarachnoid blockade with bupivacaine possibly occurs through de­afferentation, which may reduce cortical arousal by downregulating the spinal NR2B/CaMKIIα/CREB pathway in vivo, however further investigation is required in order to verify this.

Enhanced sedative efficacy and delayed recovery in propofol anesthesia in a rat model of hepatic cirrhosis.

PURPOSE: The sedative efficacy of propofol anesthesia is enhanced in patients with hepatic cirrhosis. Establish a rat model to investigate the efficacy of propofol. METHODS: 100 healthy Sprague-Dawley rats were divided into three groups and administered Phenobarbital sodium, carbon tetrachloride and ethanol solution for 0 (control), 9 (mild cirrhosis, M1), or 12 (severe cirrhosis, M2) weeks to induce hepatic cirrhosis. Propofol was infused via the caudal vein and the ED50 of the sedative effect and the recovery time were assessed according to the loss and recovery of the righting reflex. The effect of propofol on circulating cells and platelets, blood biochemistry and neurotransmitter content of the brain were measured. RESULTS: Cirrhosis was achieved in 25 of 35 M1 and 27 of 45 M2 rats. The propofol ED50 was significantly lower in M1 and M2 (5.8 ± 1.2 and 4.8 ± 1.1 mg/kg, respectively) than in control rats (6.2 ± 1.1 mg/kg, P < 0.05), and the time to recovery of righting reflex was significantly longer in M1 and M2 (370.0 ± 108.2 s and 501.6 ± 100.1 s, respectively) than in control rats (275.0 ± 90.3 s, P < 0.05). In M1 and M2 rats white and red blood cell and platelet counts were reduced, but ALT and AST activity was increased. In M1 and M2 rats the cerebral content of Gly and GABA increased but Glu and Asp were reduced. CONCLUSION: The sedative efficacy of propofol anesthesia is enhanced in rats with hepatic cirrhosis, perhaps due to reduced hepatic functional reserve, enhancement of inhibitory neurotransmitters and reduction of excitatory neurotransmitters.

Effects of glucose administered with lidocaine solution on spinal neurotoxicity in rats.

To investigate whether intrathecal administration of 10% glucose increases functional impairment and histologic damage in rats when mixed with 5% lidocaine. After implanted intrathecal catheter, 32 male Sprague-Dawley rats were randomly assigned to one of four groups: lidocaine group (Group L, n=8) received 5% lidocaine 20 µL, lidocaine with glucose group (Group LG, n=8) received 5% lidocaine with 10% glucose 20 µL, glucose group (Group G, n=8) received 10% glucose 20 µL and normal saline group received normal saline 20 µL (Group NS, n=8). Four days after intrathecal injection, sensory impairments of rats in the four groups were evaluated by using the tail-flick test. The histologic changes of spinal cord and nerve roots were observed by electron microscopy and light microscopy. There was no significant difference in baseline tail-flick latencies between the four groups (P=0.284). On the 4th day after intrathecal injection, the assessment result of sensory function was similar to baseline (P=0.217) in saline-treated animals. Sensory impairment occurred after intrathecal administration of 5% lidocaine, and 10% glucose with 5% lidocaine worsen this satiation (P=0.0001); histologic changes in 10% glucose with 5% lidocaine-treated group has differ significantly from lidocaine-treated group (P=0.001). Sensory function after intrathecal administration of 10% glucose was similar to baseline and did not differ from the saline group (P=0.995); histologic changes in 10% glucose-treated rats did not differ significantly from saline controls (P=0.535). These results suggest that 5% lidocaine can induce spinal neurotoxicity and 10% glucose with 5% lidocaine could worsen spinal neurotoxicity.

Oxysophocarpine induces anti-nociception and increases the expression of GABAAα1 receptors in mice.

Oxysophocarpine (OSC) is an alkaloid extracted from Siphocampylus verticillatus. The aim of this study was to investigate the anti-nociceptive effects of OSC through systemic and intracerebroventricular administration in mice. Moreover, to evaluate its effectiveness and mechanism of action, this study investigated whether OSC altered the expression of γ-aminobutyric acid type A α1 (GABAAα1) receptors in the central nervous system. Thermal and chemical behavioral models of nociception were used to assess the anti­nociceptive action of OSC. The warm water tail-flick test, the hot­plate test, acetic acid-induced abdominal constriction and formalin­induced pain were used in mice. OSC was administered intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.). Results showed that OSC (80 mg/kg, i.p.) significantly increased the tail withdrawal threshold with a peak effect of 25.46% maximal possible effect (MPE) at 60 min (P﹤0.01). Additionally, OSC (80 mg/kg) increased the positive staining of GABAAα1 receptors in cells. In conclusion, OSC administration is suggested to have anti-nociceptive effects on the central and peripheral nervous systems. The involvement of GABAA receptors in the anti-nociceptive activity of OSC is currently being investigated.

ED50 and recovery times after propofol in rats with graded cirrhosis.

BACKGROUND: Patients with end-stage liver disease have increased sensitivity to general anesthetics. In this study, we sought to quantify sensitivity to propofol as a function of the degree of liver disease, in a rat model of cirrhosis. METHODS: Liver disease was induced by carbon tetrachloride (CCl(4)) injections for 6, 9, or 12 weeks in 3 study groups. Control rats received saline injections on the same schedule as CCl(4)-injected rats. A second control (comparison) group was treated with phenobarbital for a week followed by 9 weeks of phenobarbital and 10% ethanol in drinking water. Liver function was assessed by liver function tests and pathologic scoring of liver histology. RESULTS: Progressively worse cirrhosis was associated with longer CCl(4) treatment by histologic criteria, by hypersplenism, liver to body weight ratios, and liver function tests. The major findings were that mild liver disease (either steatosis or fibrosis) was not associated with increased propofol sensitivity, but recovery times after propofol bolus and propofol infusion were significantly increased in rats with more severe liver fibrosis. CONCLUSION: Propofol sensitivity is not significantly affected in the setting of mild liver disease, similar to clinical observations, but end-stage liver disease (fibrosis) is associated with significantly prolonged time to recovery after propofol infusion. The progressive liver disease model used in these studies is useful for rigorously studying anesthetic sensitivity as a function of degree of hepatocellular-fibrotic liver disease.

Comparison of minimum alveolar concentration between intravenous isoflurane lipid emulsion and inhaled isoflurane in dogs.

BACKGROUND: As in inhaled isoflurane anesthesia, when isoflurane lipid emulsion (ILE; 8%, vol/vol) is intravenously administered, the primary elimination route is through the lungs. This study was designed to determine the minimum alveolar concentration (MAC) and the time course of washout of isoflurane for intravenously infused ILE by monitoring end-tidal isoflurane concentration. METHODS: Twelve healthy adult mongrel dogs were assigned randomly to an intravenous anesthesia group with 8% ILE or to an inhalation anesthesia group with isoflurane vapor. An up-and-down method and stimulation of tail clamping were used to determine MAC of 8% ILE by intravenous injection in the intravenous anesthesia group and MAC by the inhaled approach in the inhalation anesthesia group, respectively. Isoflurane concentration and partial pressure in end-tidal gas, femoral arterial blood, and jugular venous blood were measured simultaneously just before each tail clamping and during washout. RESULTS: The induction time in the intravenous anesthesia group (105 +/- 24 s) was shorter than that in the inhalation anesthesia group (378 +/- 102 s; P < 0.01). MAC of 8% ILE by intravenous injection (1.12 +/- 0.18%) was significantly less than MAC by the inhaled approach (1.38 +/- 0.16%; P < 0.05). No significant difference was found between the two groups in the time course of washout of isoflurane. CONCLUSION: The MAC of intravenous anesthesia with 8% ILE was less than that of inhalation anesthesia with isoflurane vapor in dogs.