Dexmedetomidine facilitates autophagic flux to promote liver regeneration by suppressing GSK3ß activity in mouse partial hepatectomy.

INTRODUCTION: Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist, is widely used for sedation and anesthesia in patients undergoing hepatectomy. However, the effect of DEX on autophagic flux and liver regeneration remains unclear. OBJECTIVES: This study aimed to determine the role of DEX in hepatocyte autophagic flux and liver regeneration after PHx. METHODS: In mice, DEX was intraperitoneally injected 5 min before and 6 h after PHx. In vitro, DEX was co-incubated with culture medium for 24 h. Autophagic flux was detected by LC3-II and SQSTM1 expression levels in primary mouse hepatocytes and the proportion of red puncta in AML-12 cells transfected with FUGW-PK-hLC3 plasmid. Liver regeneration was assessed by cyclinD1 expression, Edu incorporation, H&E staining, ki67 immunostaining and liver/body ratios. Bafilomycin A1, si-GSK3ß and Flag-tagged GSK3ß, α2-ADR antagonist, GSK3ß inhibitor, AKT inhibitor were used to identify the role of GSK3ß in DEX-mediated autophagic flux and hepatocyte proliferation. RESULTS: Pre- and post-operative DEX treatment promoted liver regeneration after PHx, showing 12 h earlier than in DEX-untreated mice, accompanied by facilitated autophagic flux, which was completely abolished by bafilomycin A1 or α2-ADR antagonist. The suppression of GSK3ß activity by SB216763 and si-GSK3ß enhanced the effect of DEX on autophagic flux and liver regeneration, which was abolished by AKT inhibitor. CONCLUSION: Pre- and post-operative administration of DEX facilitates autophagic flux, leading to enhanced liver regeneration after partial hepatectomy through suppression of GSK3ß activity in an α2-ADR-dependent manner.

Differential effects of propofol and dexmedetomidine on neuroinflammation induced by systemic endotoxin lipopolysaccharides in adult mice.

Propofol and dexmedetomidine are commonly used in clinical situations where neuroinflammation may be imminent or even established but comparative data on their effects on neuroinflammatory and cognitive parameters are lacking. Using a murine model of neuroinflammation induced by systemic lipopolysaccharide (LPS), this study compared the effects of these two agents on cognitive function, neuroinflammatory parameters, oxidative stress and neurotransmission. Male adult C57BL/6 N mice were anaesthetised with propofol or dexmedetomidine prior to intraperitoneal injection of LPS. Cognitive and motor function were assessed by the Y-maze and Rotarod tests respectively. Inflammatory responses were evaluated by relative levels of cytokine mRNA and immunoreactivity of glia cells. LPS caused a marked elevation in IL-1ß and TNF-α levels both peripherally and in the brain, together with microglia activation (p < 0.05) and cognitive impairment. These changes were accompanied by an increase in 8-hydroxy-2'-deoxyguanosine (8-OHdG) (p < 0.05). Dexmedetomidine attenuated microglia activation (p < 0.05) and the elevation in 8-OHdG level (p < 0.05). Propofol did not affect cognition. However, both drugs lowered the number of vesicular glutamate transporter 1 (VGLUT 1), but was associated with higher levels of apoptosis and 8-OHdG (p < 0.05). Data from this study suggest dexmedetomidine and propofol have different anti-neuroinflammatory and neuroprotective profiles. However, neither drug can fully attenuate the effects of LPS induced cognitive impairment.

Evidence of the impact of systemic inflammation on neuroinflammation from a non-bacterial endotoxin animal model.

BACKGROUND: Systemic inflammation induces neuroinflammation and cellular changes such as tau phosphorylation to impair cognitive function, including learning and memory. This study uses a single model, laparotomy without any pathogen, to characterize these changes and their responses to anti-inflammatory treatment in the intermediate term. METHODS: In a two-part experiment, wild-type C57BL/6N mice (male, 3 month old, 25 ± 2 g) were subjected to sevoflurane anesthesia alone or to a laparotomy. Cognitive performance, systemic and neuroinflammatory responses, and tau phosphorylation were evaluated on postoperative days (POD) 1, 3, and 14. The effect of perioperative ibuprofen intervention (60 mg/kg) on these changes was then assessed. RESULTS: Mice in the laparotomy group displayed memory impairment up to POD 14 with initial high levels of inflammatory cytokines in the liver, frontal cortex (IL-1ß, IL-6, and TNF-α), and hippocampus (IL-1ß and IL-8). On POD 14, although most circulating and resident cytokine levels returned to normal, a significant number of microglia and astrocytes remained activated in the frontal cortex and microglia in the hippocampus, as well as abnormal tau phosphorylation in these two brain regions. Perioperative ibuprofen improved cognitive performance, attenuated systemic inflammation and glial activation, and suppressed the abnormal tau phosphorylation both in the frontal cortex and hippocampus. CONCLUSIONS: Our results suggest that (1) cognitive dysfunction is associated with an unbalanced pro-inflammatory and anti-inflammatory response, tauopathy, and gliosis; (2) cognitive dysfunction, gliosis, and tauopathy following laparotomy can persist well beyond the immediate postoperative period; and (3) anti-inflammatory drugs can act rapidly to attenuate inflammatory responses in the brain and negatively modulate neuropathological changes to improve cognition. These findings may have implications for the duration of therapeutic strategies aimed at curtaining cognitive dysfunction following surgery.

Changes in Prevalence, Outcomes, and Help-seeking Behavior of Chronic Pain in an Aging Population Over the Last Decade.

BACKGROUND: Chronic pain is expected to increase as the population ages. This study aimed to investigate the changes in prevalence, patterns, and help-seeking behavior of chronic pain and prevalence of neuropathic pain of an aging population in Hong Kong. METHODS: A cross-sectional, telephone interview with a structured questionnaire was conducted in a randomly selected sample of adults with acute or chronic pain of any kind in the general population to estimate the prevalence of chronic and neuropathic pain, and to describe sociodemographics and help-seeking behavior. Results were compared with a similar study conducted in 1999. RESULTS: Totally, 1,570 people were interviewed. Chronic pain was experienced by 28.7% of all respondents, compared to 10.8% in 1999. Joint (45.5%), muscle (27.1%), and back (25.2%) pain were the most common, similar to findings in 1999. Of those with chronic pain, 83.1% reported pain in more than one body site (63.4% in 1999, P = 0.0023). More respondents reported their average pain as being intense (51.57% vs. 33.0% in 2013 and 1999, respectively, P = 0.0098). A downward trend of respondents taking medications for chronic pain (34.9% in 2013 vs. 47.6% in 1999, P = 0.019) was seen. Neuropathic pain was present in 9.03% of the population and 14.7% of chronic pain sufferers. CONCLUSION: The prevalence of neuropathic pain in Hong Kong is high and is described here for the first time. The number of chronic pain sufferers has tripled in the past decade. Significant changes in the patterns and help- seeking behavior of chronic pain sufferers are also seen.

Effect of Continuous Propofol Infusion in Rat on Tau Phosphorylation with or without Temperature Control.

Several studies suggest a relationship between anesthesia-induced tau hyperphosphorylation and the development of postoperative cognitive dysfunction. This study further characterized the effects of continuous propofol infusion on tau protein phosphorylation in rats, with or without temperature control. Propofol was administered intravenously to 8-10-week-old male Sprague-Dawley rats and infused to the loss of the righting reflex for 2 h continuously. Proteins from cortex and hippocampus were examined by western blot and immunohistochemistry. Rectal temperature was significantly decreased during propofol infusion. Propofol with hypothermia significantly increased phosphorylation of tau at AT8, AT180, Thr205, and Ser199 in cortex and hippocampus except Ser396. With temperature maintenance, propofol still induced significant elevation of AT8, Thr205, and Ser199 in cortex and hippocampus; however, increase of AT180 and Ser396 was only found in hippocampus and cortex, respectively. Differential effects of propofol with or without hypothermia on multiple tau related kinases, such as Akt/GSK3ß, MAPK pathways, or phosphatase (PP2A), were demonstrated in region-specific manner. These findings indicated that propofol increased tau phosphorylation under both normothermic and hypothermic conditions, and temperature control could partially attenuate the hyperphosphorylation of tau. Further studies are warranted to determine the long-term impact of propofol on the tau pathology and cognitive functions.

A double-blind randomized crossover study to evaluate the timing of pregabalin for third molar surgery under local anesthesia.

PURPOSE: This double-blind randomized crossover study compared the analgesic efficacy of pre- and postoperative administration of oral pregabalin 75 mg using a postsurgical dental pain model. MATERIALS AND METHODS: Patients requiring third molar surgery in 2 separate stages under local anesthesia were recruited. They were given pregabalin 75 mg either 1 hour before or after their first surgical extraction. They then received the same dose of pregabalin at their second surgical extraction, but those who received it before surgery received it postsurgery, and vice versa. Postoperative analgesic effects were assessed at postoperative hours 2, 4, 8, 12, 24, 48, and 72. Time to first analgesic, analgesic consumption and adverse events were also evaluated. RESULTS: Forty patients were recruited, and 34 completed the study. The area under curves for numerical rating scale pain scores 1 to 24 hours were significantly lower at rest but not during mouth opening for patients receiving postoperative pregabalin (P < .048). Pain relief was similar for the period of 24 to 72 hours. No significant difference was found in time to first analgesic, total analgesic consumption, and side effects between preoperative and postoperative groups. No difference in the incidence of adverse events was noticed in relation to the timing of pregabalin administration. CONCLUSIONS: Postoperative administration of oral pregabalin 75 mg appears to offer better analgesic efficacy than preoperative administration after third molar surgery under local anesthesia.

Evaluation of the analgesic efficacy of local dexmedetomidine application.

OBJECTIVES: To determine the analgesic effects of locally applied dexmedetomidine in third molar surgery under general anesthesia. METHODS: Patients undergoing bilateral third molar surgery under general anesthesia were recruited into this double-blind, randomized, controlled study and were allocated to 3 study groups. Group D received preincision intravenous dexmedetomidine (1 mcg/kg) and direct infiltration of normal saline to the surgical wounds at the end of the surgery. Group P received preincision intravenous normal saline and direct infiltration of dexmedetomidine (1 µg /kg) to the surgical wounds at the end of the surgery. A control group (group N) received normal saline at both time points. Postoperative analgesic effects, analgesic consumption, global pain satisfaction score, vital signs, adverse events, and postoperative recovery were assessed. RESULTS: Thirty-three patients from each group were studied. Postoperative resting pain numerical rating scale scores were similar in all the groups. However, the areas under curves of numerical rating scale pain scores during mouth opening for 1 to 72 hours were significantly lower in group P than in group N (P=0.012). Both heart rate and systolic blood pressure in the immediate postoperative period were significantly lower in groups D and P than in group N (P<0.001). Patients from groups D and P were also more sedated than patients in group N (P=0.013 and P=0.007, respectively) but no difference in psychomotor recovery was observed. Respiratory rate, oxygen saturation, common side effects, wound infection rate, and global pain satisfaction scores were similar among the groups. CONCLUSIONS: Dexmedetomidine seems to have an antihyperalgesic effect when administered locally after bilateral third molar surgery. There is no delay in psychomotor recovery or increase in postoperative clinically significant adverse events.

Interaction between spinal opioid and adenosine receptors in remote cardiac preconditioning: effect of intrathecal morphine.

OBJECTIVES: Intrathecal morphine is cardioprotective and also triggers spinal adenosine release. This study investigated the role of spinal and peripheral adenosine receptors in intrathecal morphine cardioprotection. DESIGN: A randomized, prospective study. SETTING: A university research laboratory. PARTICIPANTS: Seventy-two male Sprague-Dawley rats. INTERVENTIONS: Anesthetized, open-chest, male Sprague-Dawley rats were assigned to 1 of 10 treatment groups 3 days after intrathecal catheter placement. Intrathecal morphine cardioprotection was induced with 3 µg/kg of morphine. Intrathecal normal saline was used as the control. The adenosine-receptor antagonist 8-(p-sulfophenyl) theophylline (50 µg/kg or 7.5 mg/kg) was given via intrathecal or intravenous routes, respectively, either 10 minutes before or immediately after morphine or saline. Ischemia reperfusion injury then was induced by 30 minutes of left coronary artery occlusion followed by 120 minutes of reperfusion. MEASUREMENTS AND MAIN RESULTS: Infarct size, as a percentage of the area at risk, was determined by 2,3,5-triphenyltetrazolium chloride staining. This was reduced significantly in the morphine group (25% ± 5%) compared with the control (58% ± 3%, p < 0.05). The addition of intravenous 8-SPT either before or after morphine significantly attenuated the cardioprotective effect. In comparison, intrathecal administration of 8-(p-sulfophenyl) theophylline before but not after morphine attenuated the cardioprotective effects of intrathecal morphine. CONCLUSIONS: Both central and peripheral adenosine receptors are involved in the signaling of intrathecal morphine preconditioning. Central receptors are important in the initiation of the process, whereas peripheral receptors have a role in ongoing mediation of the protective effect.