PDTC ameliorates neuropathic pain by inhibiting microglial activation via blockage of the TNFα-CX3CR1 pathway.

Previous studies have suggested that pyrrolidine dithiocarbamate (PDTC), a nuclear factor κB (NF-κB) inhibitor, play a role in deterring nerve injury-induced neuropathic pain (NP) The activation of NF-κB pathway may contribute to spinal microglial activation, CX3CR1 and tumor necrosis factor-alpha (TNF-a) up-regulation. The aim of this study was to clarify whether PDTC could inhibit the development of neuropathic pain via decreasing TNF-a-induced CX3CR1 up-regulation. Sprague-Dawley rats were randomly divided into sham group and NP group. Rats in each group were treated with intrathecal infusion of PDTC (100 or 1000 pmol/d) or saline. The sciatic nerve chronic constriction injury (CCI) model was used to induce NP in rats. Mechanical stimuli and radiant heat were used to evaluate mechanical allodynia and thermal hyperalgesia. Spinal microglial marker OX42 and TNF-a were detected by immunohistochemistry. In vitro BV-2 microglia activation was induced by TNF-a incubation, and the levels of CX3CR1 were assessed by Western blot and reverse transcription-polymerase chain reaction. Pain behavior and immunohistochemistry results showed that intrathecal infusion of PDTC at 100 or 1000 pmol/d prevented the development of mechanical and thermal hyperalgesia, spinal microglial activation and TNF-a expression induced by sciatic nerve CCI in rats. In vitro experiment results showed that PDTC inhibited the TNF-a-induced CX3CR1 up-regulation in BV-2 microglial cells. In conclusion, intrathecal infusion of PDTC could attenuate the pain-related behaviors induced by sciatic nerve CCI through suppressing the spinal microglia activation and TNF-a up-regulation in rats. The NF-κB activation might be responsible for TNF-a-induced CX3CR1 up-regulation in microglia.

Association between the variability of cerebral oxygen saturation during cardiopulmonary bypass and delayed postoperative neurocognitive recovery in cardiac valve surgical patients: A pilot study.

AIMS OF THE STUDY: The association between regional cerebral oxygen saturation (rSO2) and postoperative cognitive decline is controversial. In this study, we investigated the association between the real variability of regional cerebral oxygen saturation during cardiopulmonary bypass (CPB) and postoperative delayed neurocognitive recovery in patients undergoing heart valve surgery. METHODS USED TO CONDUCT THE STUDY: A total of 71 patients who underwent cardiac valve surgery were enrolled in this study. Patients were assessed for cognitive function using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment Scale (MOCA) on the day before surgery and the 7th day after surgery. The real variability of regional cerebral oxygen saturation (rSO2), real variability of the brain bispectral index of EEG (BIS), real variability of mean arterial pressure (MAP) and body temperature were monitored during CPB. Patients were divided into two groups according to neural cognitive function scores to explore the relationship between postoperative delayed neurocognitive recovery and the real variability of cerebral oxygen saturation, BIS, MAP, and body temperature during CPB. RESULTS OF THE STUDY: Twenty-seven patients were diagnosed with postoperative delayed neurocognitive recovery. The occurrence of postoperative delayed neurocognitive recovery after surgery was closely related to the large variability of rSO2 during the rewarming phase of CPB (P < .05). Logistic analysis showed that preoperative arrhythmia, a lower level of serum albumin after surgery and greater rSO2 variability during the rewarming phase were risk factors for postoperative delayed neurocognitive recovery (P < .05). In this study, there was no correlation between postoperative delayed neurocognitive recovery and BIS, MAP or body temperature variability (P > .05). CONCLUSIONS DRAWN FROM THE STUDY AND CLINICAL IMPLICATIONS: The real variability of rSO2 during the CPB rewarming phase was related to postoperative delayed neurocognitive recovery in patients who underwent cardiac surgery.

Outcomes of Infant Cardiac Surgery for Congenital Heart Disease Concomitant With Persistent Pneumonia: A Retrospective Cohort Study.

OBJECTIVES: There is still controversy about whether an infant should have cardiac surgery concomitant with ongoing persistent pneumonia. This study analyzes the outcome of surgical treatment for infants with left-to-right shunt congenital heart disease accompanied with persistent pneumonia and discusses the perioperative management strategies for these cases. DESIGN: This is a retrospective cohort study. SETTING: This study was conducted in an academic hospital and is a single-center study. PARTICIPANTS: In this study, the authors analyzed the data of 94 infants admitted to our hospital from January 2014 to May 2016 who underwent surgical correction for left-to-right shunt congenital heart disease. INTERVENTIONS: Fifty cases without pneumonia were included as a control group, and 44 cases with unresolved persistent pneumonia were included as a study group. The clinical characteristics between the 2 groups were compared, and the perioperative safety and short-term prognosis were evaluated. MEASUREMENTS AND MAIN RESULTS: There was no significant difference in sex composition between the 2 groups. Infants in the pneumonia group were younger and had a lower body weight (p < 0.001). There was a significant difference in types of congenital heart disease between the 2 groups (p < 0.001). Preoperative body temperature and heart rate of infants in the pneumonia group were higher than those in the control group (p < 0.001). The cardiopulmonary bypass time in the pneumonia group was significantly longer than that of the control group (p = 0.001). Perioperative major complications were not significantly different between the 2 groups. The postoperative ventilator-assisted time, duration of intensive care unit stay, and length of hospital stay were longer in the pneumonia group (p < 0.001). Only 1 patient in the control group died of severe low cardiac output syndrome. CONCLUSION: The authors conclude that in the presented cases, no mortality or major morbidity was observed related to the practice of performing surgery in infants with signs of persistent pneumonia. The authors conclude that it is likely to be safe and effective for infants to receive cardiac surgery for left-to-right shunt congenital heart disease in the presence of persistent pneumonia.

Enhanced recovery after surgery pathway for patients undergoing cardiac surgery: a randomized clinical trial.

OBJECTIVES: Enhanced recovery after surgery (ERAS) pathways have not been reported in cardiac surgery. The aim of this study was to evaluate the clinical effectiveness and safety profile of ERAS pathways compared with routine care for patients undergoing cardiac valvular surgery. METHODS: A randomized clinical trial was conducted between July 2015 and November 2016. A total of 226 patients who underwent elective valvular surgery were randomly assigned to the ERAS pathway or routine care (control) group. The ERAS protocol consisted of an evidence-based systematic optimization approach for managing perioperative patients. The control group received routine care. The primary end-point was readiness for hospital discharge. The secondary outcomes were duration of intensive care unit (ICU) stay, length of postoperative vasoactive drug support, duration of mechanical ventilation, time to first bowel movement, removal of surgical drain, overall medical costs and complication rate. RESULTS: Postoperative time to readiness for discharge was significantly shorter in the ERAS group (6.0 (2.0∼14.0) days) than the control group (7.0 (4.0∼16.0) days, P = 0.01), and the duration of ICU stay and duration of mechanical ventilation were significantly shorter in the ERAS group (20.9 (13.5∼69.3) h, 7.2 (0.0∼22.3) h, respectively) than the control group (22.0 (13.4∼212.3) h, P = 0.001; 8.8 (3.7∼44.9) h, respectively; P < 0.0001). The overall treatment cost of the ERAS group (69202 (52089∼123823) CNY) was significantly lower than that of the control group (77058 (51390∼144290) CNY, P = 0.002). CONCLUSIONS: ERAS pathways reduce the length of ICU and hospital stay, postoperative complications and cost for patients undergoing cardiac surgery. Clinical trial registration: ClinicalTrials.gov: NCT02479581.

Suppression of HDAC2 in Spinal Cord Alleviates Mechanical Hyperalgesia and Restores KCC2 Expression in a Rat Model of Bone Cancer Pain.

Epigenetic modulation participates in the mechanism of multiple types of pathological pain, so targeting the involved regulators may be a promising strategy for pain treatment. Our previous research identified the analgesic effect of the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) on mechanical hyperalgesia in a rat model of bone cancer pain (BCP) via restoration of µ-opioid receptor (MOR) expression. However, the specific types of HDACs contributing to BCP have not been explored. The present study investigated the expression pattern of some common HDACs and found that HDAC2 was up-regulated in a time-dependent manner in the lumbar spinal cord of BCP rats. TSA application suppressed HDAC2 expression in cultured PC12 cells and reversed the augmented HDAC2 in BCP rats. An RNA-interfering strategy confirmed the essential role of HDAC2 in the modulation of mechanical hyperalgesia following tumor cell inoculation, and we further examined its possible downstream targets. Notably, HDAC2 knock-down did not restore MOR expression, but it robustly reversed the down-regulation of potassium-chloride cotransporter 2 (KCC2). The impaired KCC2 expression is a vital mechanism of many types of pathological pain. Therefore, our results demonstrated that HDAC2 in spinal cord contributed to the mechanical hyperalgesia in BCP rats, and this effect may be associated with KCC2 modulation.

Inhibition of Rac1 ameliorates neuronal oxidative stress damage via reducing Bcl-2/Rac1 complex formation in mitochondria through PI3K/Akt/mTOR pathway.

Although the neuroprotective effects of Rac1 inhibition have been reported in various cerebral ischemic models, the molecular mechanisms of action have not yet been fully elucidated. In this study, we investigated whether the inhibition of Rac1 provided neuroprotection in a diabetic rat model of focal cerebral ischemia and hyperglycemia-exposed PC-12 cells. Intracerebroventricular administration of lentivirus expressing the Rac1 small hairpin RNA (shRNA) and specific Rac1 inhibitor NSC23766 not only decreased the infarct volumes and improved neurologic deficits with a correlated significant activation of mitochondrial DNA specific proteins, such as OGG1 and POLG, but also elevated Bcl-2 S70 phosphorylation in mitochondria. Furthermore, the levels of p-PI3K, p-Akt and p-mTOR increased, while 8-OHdG, ROS production and Bcl-2/Rac1 complex formation in mitochondria reduced in both Rac1-shRNA- and NSC23766-treated rats. Moreover, to confirm our in vivo observations, inhibition of Rac1 activity by NSC23766 suppressed the interactions between Bcl-2 and Rac1 in the mitochondria of PC-12 cells cultured in high glucose conditions and protected PC-12 cells from high glucose-induced neurotoxicity. More importantly, these beneficial effects of Rac1 inhibition were abolished by PI3K inhibitor LY294002. In contrast to NSC23766 treatment, LY294002 had little effect on the decrement of p-PTEN level. Taken together, these findings revealed novel neuroprotective roles of Rac1 inhibition against cerebral ischemic reperfusion injury in vivo and high glucose-induced neurotoxicity in PC-12 cells in vitro, by reducing Bcl-2/Rac1 complex formation in mitochondria through the activation of PI3K/Akt/mTOR survival pathway.

[Perioperative safety of Tibetan children with congenital heart disease undergoing cardiac surgery and anesthesia in low-altitude area].

OBJECTIVE: To observe the clinical parameters and short-term prognosis of Tibetan high-altitude area children with congenital heart disease undergoing surgery and anaesthesia in low-altitude area, and to investigate the perioperative safety of the treatment.
 Methods: From January, 2016 to December, 2016, 14 children with congenital heart disease who underwent surgery were assigned into 2 groups (n=7 each): the high-altitude area group (X group, children from Tibetan Autonomous Region) and the low-altitude area group (H group, children from Hunan Province). Echocardiography data, perioperative hemodynamic changes, postoperative recovery, complication and perioperative serum N terminal pro B type natriuretic peptide (NT-proBNP) levels were recorded.
 Results: There were no significant differences in cardiac structure and function between the 2 groups, while the incidence of pulmonary hypertension in the X group was significantly higher than that in the H group (P<0.05). There were no significant differences in perioperative hemodynamics between the 2 groups (P>0.05), while the duration in ICU in the X group was longer than that in the H group and the serum NT-proBNP level in the X group was higher than that in the H group (P<0.05).
 Conclusion: For children with congenital heart disease in Tibetan high-altitude area, undergoing surgery in low-altitude area contributes to a steady perioperative hemodynamics and helps to increase the perioperative safety. There may be a higher risk of postoperative cardiac dysfunction in Tibetan children than that in low-altitude area.

Etanercept decreases HMGB1 expression in dorsal root ganglion neuron cells in a rat chronic constriction injury model.

In the present study, we examined the effect of etanercept on high mobility group box 1 (HMGB1) expression in dorsal root ganglion (DRG) neuron cells in a rat model of chronic constriction injury (CCI) of the sciatic nerve, with the aim of exploring the molecular mechanism underlying the therapeutic effect of etanercept on sciatica-related nociception and the potential interaction between tumor necrosis factor-α (TNF-α) and HMGB1 in DRG neuron cells. A rat CCI model was employed and the animals were randomly assigned to seven groups (n=20/group): untreated, sham only, sham/saline, sham/etanercept, CCI only, CCI/saline and CCI/etanercept. Our results revealed that compared with the sham/saline and sham/etanercept groups, thermal hyperalgesia and mechanical hyperalgesia, as well as HMGB1 expression at both the mRNA and protein levels in the DRG neuron cells, were induced by CCI, and were significantly inhibited by etanercept. Although etanercept showed no significant effect on the sham group, it significantly reduced the phosphorylated p38 mitogen-activated protein kinase (MAPK) levels induced by CCI in the DRG neuron cells. In conclusion, we demonstrated that etanercept significantly decreased the HMGB1 expression induced by CCI in the DRG neuron cells. This study not only explored the molecular mechanisms underlying the therapeutic effect of etanercept on sciatica-related nociception, but also provided indirect evidence for an interaction between TNF-α and HMGB1 in DRG neuron cells.

Intrathecal infusion of pyrrolidine dithiocarbamate for the prevention and reversal of neuropathic pain in rats using a sciatic chronic constriction injury model.

BACKGROUND AND OBJECTIVES: Recent studies have suggested that nuclear factor κB (NF-κB) may play a role in mediating nerve injury-induced neuropathic pain. Here, we examined the effects of intrathecal pyrrolidine dithiocarbamate (PDTC), a NF-κB inhibitor, on the development of neuropathic pain, spinal microglial activation, and CX3CR1 expression induced by sciatic chronic constriction injury (CCI) model in rats. METHODS: Under chloral hydrate anesthesia, male Sprague-Dawley rats (300-350 g) fitted with intrathecal catheters underwent either sciatic CCI or sham surgery. Intrathecal saline or PDTC (100 or 1000 pmol/d) was infused 1 day before or 3 days after CCI (n = 8). The rat hind-paw withdrawal threshold to mechanical stimuli and withdrawal latency to radiant heat were determined before surgery and from days 1 to 7 after CCI. Spinal microglial activation was evaluated with OX-42 immunoreactivity, and spinal CX3CR1 expression was assessed by Western blotting. RESULTS: Chronic constriction injury induced mechanical allodynia and thermal hyperalgesia and microglial activation as demonstrated by OX-42 expression. Whereas it had no apparent effect on spinal cord histology, intrathecal administration of PDTC prevented the development of the mechanical and thermal hyperalgesia and inhibited nerve injury-induced microglial activation and spinal CX3CR1 expression. CONCLUSIONS: In this study, we have shown the protective effect of intrathecal PDTC on the development of nociceptive behaviors induced by CCI in rats. The activation of NF-κB pathway may contribute to spinal microglial activation and CX3CR1 up-regulation.

[Sevoflurane preconditioning induced delayed neuroprotection against focal cerebral ischemia in rats].

OBJECTIVE: To investigate whether the reactive oxygen species (ROS) and mitochondrial ATP-sensitive potassium (mitoKATP) channels were involved in delayed neuroprotection induced by sevoflurane on tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels. METHODS: Eighty-four male SD rats weighing 250 approximately 280 g, undergoing thread embolism of the right middle cerebral artery occlusion (MCAO) to cause focal ischemia for 2 h and then undergoing 24 h reperfusion, were randomly divided into 7 groups (n=12, each): a sham group(S), an ischemia-reperfusion group (I/R), a sevoflurane preconditioning group (Sevo), a 2-mercaptopropionylglycine (ROS scavenger)+sevoflurane group (MPG+Sevo), a 5-hydroxydecanoate (a mitoK(ATP) blocker) + sevoflurane group (5-HD+Sevo), an MPG group, and a 5-HD group. The protein level of TNF-alpha and IL-1beta in the cerebral issue was detected by enzyme linked immunosorbent assay (ELISA) and the expression of mRNA was measured by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Apoptosis index (AI), the protein level and the mRNA expression of TNF-alpha and IL-1beta were significantly higher in the I/R group than those of Group S. Pre-administration of sevoflurane could inhibit the increase of the protein level and the expression of mRNA of TNF-alpha, and IL-1beta and attenuate the cerebral damage induced by ischemia-reperfusion. Neuroprotection of sevoflurane preconditioning was abolished by MPG and 5-HD. However, MPG and 5-HD alone had no effect. CONCLUSION: Sevoflurane can produce delayed protection against cerebral ischemia-reperfusion injury by down-regulating TNF-alpha, IL-1beta protein, and mRNA expression.