Triptolide Alleviates Neuropathic Pain by Inhibiting the Activation of Microglial Toll-Like Receptor 3.

BACKGROUND: Current data indicates the incidence of neuropathic pain after surgical nerve injury is as high as 50%, thus representing a major problem for patients and for the medical system. Triptolide, a traditional Chinese herb, has anti-inflammatory effects on various neurodegenerative and neuroinflammatory diseases. This agent also reduces peripheral nerve injury-induced neuropathic pain, although the mechanism underlying this effect is still unknown. MATERIALS AND METHODS: The effects of triptolide on spinal nerve ligation (SNL) injury-induced neuropathic pain was studied in an animal model using behavioral, morphological and molecular biological methods. RESULTS: Repeated administration of intrathecal triptolide was found to alleviate SNL- or Poly(I:C) (toll-like receptor 3 agonist) injection-induced mechanical allodynia without any motor impairment. The mechanism by which triptolide reduces SNL- and Poly(I:C) injection-induced microglial activation appears to be via the inhibition of OX42 expression, which is a microglial-specific marker. Intrathecal triptolide also suppressed SNL- and Poly(I:C) injection-induced expression of spinal TRIF. TRIF transmits signals from activated TLR3 and is the downstream adaptor of TLR3 in microglia. In addition, intrathecal triptolide inhibited the expression of spinal pro-inflammatory IL-1 ß following SNL or Poly(I:C) injection. CONCLUSIONS: Intrathecal triptolide can suppress the TLR3/TRIF/IL-1 ß pathway in spinal microglia following SNL. This could be the underlying mechanism by which triptolide alleviate neuropathic pain induced by peripheral nerve injury.

Remifentanil up-regulates HIF1α expression to ameliorate hepatic ischaemia/reperfusion injury via the ZEB1/LIF axis.

Ischaemia/reperfusion (I/R)-induced hepatic injury is regarded as a main reason of hepatic failure after transplantation or lobectomy. The current study aimed to investigate how the opioid analgesic remifentanil treatment affects I/R-induced hepatic injury and explore the possible mechanisms related to HIF1α. Initially, an I/R-induced hepatic injury animal model was established in C57BL/6 mice, and an in vitro hypoxia-reoxygenation model was constructed in NCTC-1469 cells, followed by remifentanil treatment and HIF1α silencing treatment. The levels of blood glucose, lipids, alanine transaminase (ALT) and aspartate transaminase (AST) in mouse serum were measured using automatic chemistry analyser, while the viability and apoptosis of cells were detected using CCK8 assay and flow cytometry. Our results revealed that mice with I/R-induced hepatic injury showed higher serum levels of blood glucose, lipids, ALT and AST and leukaemia inhibitory factor (LIF) expression, and lower HIF1α and ZEB1 expression (P < .05), which were reversed after remifentanil treatment (P < .05). Besides, HIF1α silencing increased the serum levels of blood glucose, lipids, ALT and AST (P < .05). Furthermore, hypoxia-induced NCTC-1469 cells exhibited decreased HIF1α and ZEB1 expression, reduced cell viability, as well as increased LIF expression and cell apoptosis (P < .05), which were reversed by remifentanil treatment (P < .05). Moreover, HIF1α silencing down-regulated ZEB1 expression, decreased cell viability, and increased cell apoptosis (P < .05). ZEB1 was identified to bind to the promoter region of LIF and inhibit its expression. In summary, remifentanil protects against hepatic I/R injury through HIF1α and downstream effectors.

Hyperoxygenated hydrogen-rich solution suppresses shock- and resuscitation-induced liver injury.

BACKGROUND: It is not known whether simultaneous delivery of hydrogen and oxygen can reduce injury caused by hemorrhagic shock and resuscitation (HSR). This study investigated the therapeutic potential of hyperoxygenated hydrogen-rich solution (HHOS), a combined hydrogen/oxygen carrier, in a rat model of HSR-induced liver injury. MATERIALS AND METHODS: Rats (n = 60) were randomly divided into 5 groups (n = 6 per group at each time point). One group underwent sham operation, and the others were subjected to severe hemorrhagic shock and then treated with lactated Ringer's solution (LRS), hydrogen-rich solution, hyperoxygenated solution, or HHOS. At 2 and 6 h after resuscitation, blood samples (n = 6) were collected from the femoral artery and serum concentrations of alanine aminotransferase and aspartate aminotransferase (AST) were measured. Rats were then sacrificed, and histopathological changes in the liver were evaluated by quantifying the percentage of apoptotic cells by caspase-3 immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick-end labeling. Inflammation was assessed by assessing malondialdehyde content and tumor necrosis factor-α, and interleukin (IL)-6 expression. RESULTS: Compared to lactated Ringer's solution, hydrogen-rich solution, or hyperoxygenated solution groups, serum AST and alanine aminotransferase levels and IL-6, tumor necrosis factor-α, and malondialdehyde expression in liver tissue were decreased by HHOS treatment. The number of caspase-3- and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells was decreased (P < 0.05) by HHOS treatment, 2 and 6 h after resuscitation. CONCLUSIONS: HHOS has protective effects against liver injury in a rat model of HSR.

Depressing interleukin-1ß contributed to the synergistic effects of tramadol and minocycline on spinal nerve ligation-induced neuropathic pain.

Our previous study indicated that coadministration of tramadol and minocycline exerted synergistic effects on spinal nerve ligation (SNL)-induced neuropathic mechanical allodynia. However, the underlying mechanisms are still unclear. Recent reports indicated that spinal proinflammatory factor interleukin-1ß (IL-1ß) contributed to the development of neuropathic pain and the positive feedback communication between neuron and glia. Therefore, the present research is to confirm whether spinal IL-1ß-related pathway response contributes to the synergistic effects of tramadol and minocycline on SNL-induced neuropathic pain. Real-time RT-PCR demonstrated IL-1ß up-expression in the ipsilateral spinal dorsal horn 3 days after lesion, which could be significantly decreased by tramadol and minocycline coadministration. Immunofluorescence and Western blot indicated that SNL-induced microglial phosphorylated p38 (p-p38) upregulation was also inhibited by tramadol and minocycline coapplication. Meanwhile, intrathecal administration of p38 inhibitor SB203580 markedly alleviated mechanical allodynia whilst reducing IL-1ß and Fos expression induced by SNL. Moreover, intrathecal neutralized antibody of IL-1ß could depress SNL-induced mechanical allodynia and Fos expression. These results suggest that depressing SNL-induced aberrant activation of the spinal dorsal horn IL-1ß-related pathway contributes to the underlying mechanism of the synergistic effects of tramadol and minocycline coadministration on SNL-induced neuropathic mechanical allodynia.

The combined use of serum Raman spectroscopy and D dimer testing for the early diagnosis of acute aortic dissection.

Objectives: Acute aortic dissection (AAD) is an extremely life-threatening medical emergency, often misdiagnosed in its early stages, resulting in prolonged wait times for rescue. This study aims to identify potential serum biomarkers that can assist in the accurate diagnosis of AAD and effectively differentiate it from other conditions causing severe chest pain. Methods: A total of 122 patients with AAD and 129 patients with other severe chest pain disorders were included in the study. Serum samples were analyzed by measuring the peak intensities of Raman spectra. For each measurement, the Raman spectrum was accumulated by two accumulations (3 s per acquisition). Logistic regression and nomogram models were developed using these peak intensities as well as D-dimer levels to predict the occurrence of AAD. The clinical utilities of these models were assessed through receiver operating characteristics (ROC) curve analysis, net reclassification improvement (NRI), integrated discrimination improvement (IDI), and decision curve analysis (DCA) in both training and internal test cohorts. Results: The D-dimer levels of AAD patients were significantly increased, as well as higher intensities at specific Raman peaks, including 505 cm-1, 842 cm-1, 947 cm-1, 1254 cm-1, 1448 cm-1, and 1655 cm-1 when compared to non-AAD patients. Conversely, decreased intensities were observed at Raman peaks such as 750 cm-1, 1004 cm-1, 1153 cm-1, 1208 cm-1, and 1514 cm-1 in AAD patients. Least absolute shrinkage and selection operator regression analysis on the training cohort identified eight potential predictors: D-dimer along with intensity measurements at peaks such as 505 cm-1, 750 cm-1, 1153 cm-1, 1208 cm-1, 1254 cm-1, 1448 cm-1, and 1655 cm-1. The combination of these eight potential predictors demonstrated a good discriminatory performance, with an area under the curve (AUC) value of 0.928 in the training cohort and an AUC of 0.936 in the internal test cohort, outperforming the use of D-dimer alone. Furthermore, DCA curve analysis revealed that leveraging this combination of eight potential predictors would provide substantial net benefits for clinical application. Moreover, this combination significantly augmented discrimination power, as evidenced by a continuous NRI of 39.8 % and IDI of 9.95 % in the training cohort, as well as a continuous NRI of 27.1 % and IDI of 9.95 % in the internal test cohort. Conclusions: The employment of this combination of eight potential predictors effectively rules out AAD to a greater extent. This study presents a promising diagnostic strategy for early detection using optical diagnostic techniques such as Raman spectroscopy.

Olanzapine for the prevention of postoperative nausea and vomiting after gynecologic laparoscopic surgery: a randomized controlled trial.

Purpose: This study was designed to investigate the prophylactic effect of oral olanzapine in postoperative nausea and vomiting after gynecologic laparoscopic surgery. Methods: ASA I-II, aged 18-75 years, planned to undergo gynecologic laparoscopic surgery with general anesthesia in adult female patients. Using the randomized numbers table, the patients were placed in two groups. Oral olanzapine 5 mg or placebo was given 1 h before anesthesia. All patients received standard antiemetic prophylaxis with dexamethasone and granisetron. The primary outcome was nausea and/or vomiting in the 24 h after the postoperative. Results: A total of 250 patients were randomized, and 241 were analyzed. The primary outcome occurred in 10 of 120 patients (8.3%) in the olanzapine group and 23 of 121 patients (19.2%) in the placebo group (p = 0.014). According to Kaplan-Meier analysis, the probabilities of nausea and/or vomiting in the 24 h after the postoperative in the olanzapine group were lower than in the placebo group (log-rank p = 0.014). In a multivariate Cox analysis, the variables of use of olanzapine [hazard ratio (HR): 0.35, 95% confidence interval (CI): 0.16-0.79; p = 0.012] and use of vasoactive drugs (HR: 2.48, 95% CI: 1.07-5.75; p = 0.034) were independently associated with nausea and/or vomiting in the 24 h after the postoperative. Conclusion: Our data suggest that olanzapine relative to placebo decreased the risk of nausea and/or vomiting in the 24 h after gynecologic laparoscopic surgery. Trial registration: The trial was registered prior to patient enrollment at The Chinese Clinical Trial Registry (https://www.chictr.org.cn/showproj.html?proj=166900, link to registry page, Principal investigator: Nanjin Chen, Date of registration: 25 April 2022).

Preventing nausea and vomiting after laparoscopic gynecological surgery: the benefits of using olanzapine Why was this study done? Despite the use of antiemetics, postoperative nausea and vomiting remain prevalent. Furthermore, patients who undergo gynecological laparoscopic surgery are at an increased risk. Therefore, this study investigated whether oral Olanzapine could reduce the incidence of nausea and vomiting after gynaecological Laparoscopy? What did the researchers do? The research team examined patients who underwent gynecological laparoscopic surgery under general anesthesia. They observed the occurrence of nausea and vomiting within 24 hours after surgery in patients who either received or did not receive Olanzapine treatment. The goal was to assess the effectiveness of Olanzapine in reducing postoperative nausea and vomiting. What did the researchers find? The addition of Olanzapine, when combined with granisetron and dexamethasone, resulted in a decreased risk of nausea and/or vomiting within the 24 hours following gynecologic laparoscopic surgery, as compared to the placebo. Administering oral Olanzapine at a dosage of 5 mg reduced the incidence of nausea and vomiting after gynecological laparoscopy from 19.2% to 8.3%. What do the findings mean? This study has identified a safe and effective medication for preventing postoperative nausea and vomiting. Implementing Olanzapine as a preventive measure can significantly reduce the incidence of nausea and vomiting following surgery, thereby enhancing the overall medical experience for patients.

Combination of tramadol with minocycline exerted synergistic effects on a rat model of nerve injury-induced neuropathic pain.

Neuropathic pain is a refractory clinical problem. Certain drugs, such as tramadol, proved useful for the treatment of neuropathic pain by inhibiting the activity of nociceptive neurons. Moreover, studies indicated that suppression or modulation of glial activation could prevent or reverse neuropathic pain, for example with the microglia inhibitor minocycline. However, few present clinical therapeutics focused on both neuronal and glial participation when treating neuropathic pain. Therefore, the present study hypothesized that combination of tramadol with minocycline as neuronal and glial activation inhibitor may exert some synergistic effects on spinal nerve ligation (SNL)-induced neuropathic pain. Intrathecal tramadol or minocycline relieved SNL-induced mechanical allodynia in a dose-dependent manner. SNL-induced spinal dorsal horn Fos or OX42 expression was downregulated by intrathecal tramadol or minocycline. Combination of tramadol with minocycline exerted powerful and synergistic effects on SNL-induced neuropathic pain also in a dose-dependent manner. Moreover, the drug combination enhanced the suppression effects on SNL-induced spinal dorsal horn Fos and OX42 expression, compared to either drug administered alone. These results indicated that combination of tramadol with minocycline could exert synergistic effects on peripheral nerve injury-induced neuropathic pain; thus, a new strategy for treating neuropathic pain by breaking the interaction between neurons and glia bilaterally was also proposed.

The Inhibition of Spinal Astrocytic JAK2-STAT3 Pathway Activation Correlates with the Analgesic Effects of Triptolide in the Rat Neuropathic Pain Model.

Neuropathic pain (NP) is an intractable clinical problem without satisfactory treatments. However, certain natural products have been revealed as effective therapeutic agents for the management of pain states. In this study, we used the spinal nerve ligation (SNL) pain model to investigate the antinociceptive effect of triptolide (T10), a major active component of the traditional Chinese herb Tripterygium wilfordii Hook F. Intrathecal T10 inhibited the mechanical nociceptive response induced by SNL without interfering with motor performance. Additionally, the anti-nociceptive effect of T10 was associated with the inhibition of the activation of spinal astrocytes. Furthermore, intrathecal administration of T10 attenuated SNL-induced janus kinase (JAK) signal transducers and activators of transcription 3 (STAT3) signalling pathway activation and inhibited the upregulation of proinflammatory cytokines, such as interleukin-6, interleukin-1 beta, and tumour necrosis factor-α, in dorsal horn astrocytes. Moreover, NR2B-containing spinal N-methyl D-aspartate receptor (NMDAR) was subsequently inhibited. Above all, T10 can alleviate SNL-induced NP via inhibiting the neuroinflammation in the spinal dorsal horn. The anti-inflammation effect of T10 may be related with the suppression of spinal astrocytic JAK-STAT3 activation. Our results suggest that T10 may be a promising drug for the treatment of NP.

Inhibition of spinal astrocytic c-Jun N-terminal kinase (JNK) activation correlates with the analgesic effects of ketamine in neuropathic pain.

BACKGROUND: We have previously reported that inhibition of astrocytic activation contributes to the analgesic effects of intrathecal ketamine on spinal nerve ligation (SNL)-induced neuropathic pain. However, the underlying mechanisms are still unclear. c-Jun N-terminal kinase (JNK), a member of mitogen-activated protein kinase (MAPK) family, has been reported to be critical for spinal astrocytic activation and neuropathic pain development after SNL. Ketamine can decrease lipopolysaccharide (LPS)-induced phosphorylated JNK (pJNK) expression and could thus exert its anti-inflammatory effect. We hypothesized that inhibition of astrocytic JNK activation might be involved in the suppressive effect of ketamine on SNL-induced spinal astrocytic activation. METHODS: Immunofluorescence histochemical staining was used to detect SNL-induced spinal pJNK expression and localization. The effects of ketamine on SNL-induced mechanical allodynia were confirmed by behavioral testing. Immunofluorescence histochemistry and Western blot were used to quantify the SNL-induced spinal pJNK expression after ketamine administration. RESULTS: The present study showed that SNL induced ipsilateral pJNK up-regulation in astrocytes but not microglia or neurons within the spinal dorsal horn. Intrathecal ketamine relieved SNL-induced mechanical allodynia without interfering with motor performance. Additionally, intrathecal administration of ketamine attenuated SNL-induced spinal astrocytic JNK activation in a dose-dependent manner, but not JNK protein expression. CONCLUSIONS: The present results suggest that inhibition of JNK activation may be involved in the suppressive effects of ketamine on SNL-induced spinal astrocyte activation. Therefore, inhibition of spinal JNK activation may be involved in the analgesic effects of ketamine on SNL-induced neuropathic pain.

Ketamine depresses toll-like receptor 3 signaling in spinal microglia in a rat model of neuropathic pain.

Reports suggest that microglia play a key role in spinal nerve ligation (SNL)-induced neuropathic pain, and toll-like receptor 3 (TLR3) has a substantial role in the activation of spinal microglia and the development of tactile allodynia after nerve injury. In addition, ketamine application could suppress microglial activation in vitro, and ketamine could inhibit proinflammatory gene expression possibly by suppressing TLR-mediated signal transduction. Therefore, the present study was designed to disclose whether intrathecal ketamine could suppress SNL-induced spinal microglial activation and exert some antiallodynic effects on neuropathic pain by suppressing TLR3 activation. Behavioral results showed that intrathecal ketamine attenuated SNL-induced mechanical allodynia, as well as spinal microglial activation, in a dose-dependent manner. Furthermore, Western blot analysis displayed that ketamine application downregulated SNL-induced phosphorylated-p38 (p-p38) expression, which was specifically expressed in spinal microglia but not in astrocytes or neurons. Besides, ketamine could reverse TLR3 agonist (polyinosine-polycytidylic acid)-induced mechanical allodynia and spinal microglia activation. It was concluded that intrathecal ketamine depresses TLR3-induced spinal microglial p-p38 mitogen-activated protein kinase pathway activation after SNL, probably contributing to the antiallodynic effect of ketamine on SNL-induced neuropathic pain.

Neuronal NR2B-containing NMDA receptor mediates spinal astrocytic c-Jun N-terminal kinase activation in a rat model of neuropathic pain.

Spinal N-methyl d-aspartate receptor (NMDAR) plays a pivotal role in nerve injury-induced central sensitization. Recent studies suggest that NMDAR also contributes to neuron-astrocyte signaling. c-Jun N-terminal kinase (JNK) is persistently and specifically activated (indicated by phosphorylation) in spinal cord astrocytes after nerve injury and thus it is considered as a dependable indicator of pain-related astrocytic activation. NMDAR-mediated JNK activation in spinal dorsal horn might be an important form of neuron-astrocyte signaling in neuropathic pain. In the present study, we observed that intrathecal injection of MK-801, a noncompetitive NMDA receptor antagonist, or Ro25-6981 and ifenprodil, which are selective antagonists of NR2B-containing NMDAR each significantly reduced nerve injury-induced JNK activation. Double immunostaining showed that NR2B was highly expressed in neurons, indicating the effect of NMDAR antagonists on JNK activation was indirect. We further observed that intrathecal injection of NMDA (twice a day for 3 days) significantly increased spinal JNK phosphorylation. Besides, NMDAR-related JNK activation could be blocked by a neuronal nitric oxide synthase (nNOS) selective inhibitor (7-nitroindazole sodium salt) but not by a nNOS sensitive guanylyl cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one). Finally, real-time RT-PCR and immunostaining showed that nerve injury-induced interleukin-1beta expression was dependent on astrocytic JNK activation. Treatments targeting NMDAR-nNOS pathway also influenced interleukin-1beta expression, which further confirmed our hypothesis. Taken together, our results suggest that neuronal NMDAR-nNOS pathway could activate astrocytic JNK pathway. Excitatory neuronal transmission initiates astrocytic activation-induced neuroinflammation in this way, which contributes to nerve injury-induced neuropathic pain.

Pre-anesthetic clinic internship: new teaching method of pre-anesthesia evaluation for undergraduates.

BACKGROUND: This study aimed to observe the effect of internship in a pre-anesthetic clinic on the teaching quality of pre-anesthesia evaluation for undergraduates. METHODS: A total of 120 undergraduates from July 2017 to July 2018 in the anesthesia department of our hospital were randomly divided into two groups: pre-anesthetic clinic internship teaching group (n = 60) and traditional teaching group (n = 60). The knowledge in the pre-anesthesia evaluation teaching chapters was evaluated between the two groups of undergraduates. RESULTS: There were no significant differences in the demographic information between the two groups. The scores in the case analysis and theoretical knowledge test in the pre-anesthetic clinic internship teaching group were significantly higher than those in the traditional teaching group. In addition, the students' satisfaction with the curriculum design was significantly higher in the pre-anesthetic clinic internship teaching group than in the traditional teaching group. CONCLUSION: Pre-anesthetic clinic internships can improve the quality of pre-anesthesia assessment teaching for undergraduates.

Combining ketamine with astrocytic inhibitor as a potential analgesic strategy for neuropathic pain ketamine, astrocytic inhibitor and pain.

BACKGROUND: Neuropathic pain is an intractable clinical problem. Intrathecal ketamine, a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist, is reported to be useful for treating neuropathic pain in clinic by inhibiting the activity of spinal neurons. Nevertheless, emerging studies have disclosed that spinal astrocytes played a critical role in the initiation and maintenance of neuropathic pain. However, the present clinical therapeutics is still just concerning about neuronal participation. Therefore, the present study is to validate the coadministration effects of a neuronal noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine and astrocytic cytotoxin L-α-aminoadipate (LAA) on spinal nerve ligation (SNL)-induced neuropathic pain. RESULTS: Intrathecal ketamine (10, 100, 1000 µg/kg) or LAA (10, 50, 100 nmol) alleviated SNL-induced mechanical allodynia in a dose-dependent manner respectively. Phosphorylated NR1 (pNR1) or glial fibrillary acidic protein (GFAP) expression was down-regulated by intrathecal ketamine (100, 1000 µg/kg) or LAA (50, 100 nmol) respectively. The combination of ketamine (100 µg/kg) with LAA (50 nmol) showed superadditive effects on neuropathic pain compared with that of intrathecal administration of either ketamine or LAA alone. Combined administration obviously relieved mechanical allodynia in a quick and stable manner. Moreover, down-regulation of pNR1 and GFAP expression were also enhanced by drugs coadministration. CONCLUSIONS: These results suggest that combining NMDAR antagonist ketamine with an astrocytic inhibitor or cytotoxin, which is suitable for clinical use once synthesized, might be a potential strategy for clinical management of neuropathic pain.

Inhibiting astrocytic activation: a novel analgesic mechanism of ketamine at the spinal level?

Although ketamine is widely used as an analgesic agent and has an anti-allodynic effect on neuropathic pain, the underlying analgesic mechanisms are not fully explained by the modern 'neuronal-based' theories. As emerging studies have focused on the critical role of spinal astrocytes in the pathological pain states, we have hypothesized that there exist some 'astrocytes-related' mechanisms in the analgesic function of ketamine. In the present study, using the spinal nerve ligation (SNL) pain model, we investigated the anti-nociceptive effects of intraperitoneal or intrathecal ketamine on SNL-induced neuropathic pain response, meanwhile, we investigated the astrocytic activation after ketamine administration on SNL rats. Behavioral data showed that either intraperitoneal or intrathecal ketamine inhibited SNL-induced allodynia, however, immunohistochemistry showed that SNL induced astrocytic activation was suppressed by intrathecal but not intraperitoneal ketamine. Using quantitative Western blot analysis, our report showed that intrathecal ketamine down-regulated glial fibrillary acidic protein expression, suggesting inhibition of SNL-induced astrocytic activation, which wasn't influenced by intraperitoneal administration. We conclude that intraperitoneal ketamine could alleviate SNL-induced neuropathic pain via the classical 'neuronal-based' mechanisms, but in addition, 'astrocytes-related' mechanisms were also important underlying the anti-allodynic effect of intrathecal ketamine.

Blocking conversion of GABAergic inhibition as a potential mechanism of propofol-mediated brain protection following resuscitation.

Animal experiments and clinical studies have indicated that propofol pretreatment significantly improves post-resuscitation recovery of neuronal functions. However, current theories on how propofol enhances the inhibitory effects of gamma-aminobutyric acid (GABA) cannot fully explain its protective action on the brain. Recent studies have suggested that during the process of resuscitation, the effect of GABA is converted from inhibitory to excitatory, via a mechanism that is closely associated with activation of microglia and downregulation of the K(+)-Cl(-) cotransporter 2 (KCC2). We propose a hypothesis that propofol protects the brain through inhibiting the conversion of GABAergic inhibition into excitation during resuscitation. Activation of microglia, downregulation of KCC2, and correlations between these effects and the protective actions of propofol, may reveal the molecular mechanisms of propofol-mediated brain protection. Further investigations into the protective mechanisms of general anesthetics on the brain represented by propofol will help to guide rational clinical drug use, and will contribute to the discovery and development of novel brain-protective drugs to prevent perioperative cardiopulmonary resuscitation-associated brain injury.

Probenecid Relieves Cerebral Dysfunction of Sepsis by Inhibiting Pannexin 1-Dependent ATP Release.

Acute brain dysfunction and the following neurological manifestation are common complications in septic patients, which are associated with increased morbidity and mortality. However, the therapeutic strategy of this disorder remains a major challenge. Given the emerging role of a clinically approved drug, probenecid (PRB) has been recently identified as an inhibitor of pannexin 1 (PANX1) channel, which restrains extracellular ATP release-induced purinergic pathway activation and inflammatory response contributing to diverse pathological processes. In this study, we explored whether PRB administration attenuated neuroinflammatory response and cognitive impairment during sepsis. In mice suffered from cecal ligation and puncture (CLP)-induced sepsis, treatment with PRB improved memory retention and lessened behavioral deficits. This neuroprotective effect was coupled with restricted overproduction of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and interleukin (IL)-1ß in the hippocampus. Since this damped neuroinflammation was replicated by inhibition of ATP release, it suggested that PANX1 channel modulates a purinergic-related pathway contributing to the neurohistological damage. Therefore, we identified PRB could be a promising therapeutic approach for the therapy of cerebral dysfunction of sepsis.

Systemic Injection of Thalidomide Prevent and Attenuate Neuropathic Pain and Alleviate Neuroinflammatory Response in the Spinal Dorsal Horn.

BACKGROUND AND OBJECTIVE: Thalidomide (Tha) has been shown to exert immunomodulatory and anti-inflammatory properties. Whether Tha can alleviate spinal nerve ligation (SNL)-induced neuropathic pain (NP) is still unclear. This study aimed to investigate the therapeutic effect of Tha on the SNL-induced NP and further explore the potential analgesic mechanisms of Tha. METHODS: The effects of Tha on SNL-induced mechanical allodynia were assessed by pain behavioral testing. The expressions of the astrocyte marker glial fibrillary acidic protein (GFAP) and the microglia marker Iba1 in the spinal dorsal horn were evaluated by immunofluorescence histochemistry. Protein expressions of the tumor necrosis factor alpha (TNF-α) in the spinal dorsal horn were tested by Western blot assay. Data were analyzed using one-way ANOVA or two-way ANOVA. RESULTS: By the pretreatment with a single intraperitoneal injection, the PWMT in SNL+Tha group was significantly increased from day 1 to day 2 after SNL (P < 0.05 compared with SNL+Veh group). By the posttreatment with a single intraperitoneal injection, the PWMT in SNL+Tha group was also significantly increased from day 3 to day 4 after SNL (P < 0.05 compared with SNL+Veh group). By the posttreatment with multiple intraperitoneal injection, both the PWMT and the PWTL in SNL+Tha group were similarly significantly increased from day 3 to day 14 after SNL (P < 0.05 compared with SNL+Veh group). Furthermore, the GFAP and Iba1 expressions and TNF-α levels of the ipsilateral spinal dorsal horn in SNL+Tha group were significantly weaker from day 3 to day 14 after SNL than those in SNL+Veh group (P < 0.05). CONCLUSION: Tha can significantly alleviate NP induced by SNL. The analgesic mechanism may be related to inhibition of astrocyte and microglia activation as well as down-regulation of TNF-α levels in the spinal dorsal horn.

The effect of pre- and after-treatment of sevoflurane on central ischemia tolerance and the underlying mechanisms.

In recent years, with continuous research efforts targeted at studying the effects of pre- and after-treatment of inhaled anesthetics, significant progress has been made regarding the common clinical use of low concentrations of inhaled sevoflurane and its effect on induced central ischemia tolerance by pre- and post-treatment. In this study, we collected, analyzed, classified, and summarized recent literature regarding the effect of sevoflurane on central ischemia tolerance and its related mechanisms. In addition, we provide a theoretical basis for the clinical application of sevoflurane to protect the central nervous system and other important organs against ischemic injury.

Cause analysis, prevention, and treatment of postoperative restlessness after general anesthesia in children with cleft palate.

Cleft palate is one of the most common congenital malformations of the oral and maxillofacial region, with an incidence rate of around 0.1%. Early surgical repair is the only method for treatment of a cleft lip and palate. However, because of the use of inhalation anesthesia in children and the physiological characteristics of the cleft palate itself combined with the particularities of cleft palate surgery, the incidence rate of postoperative emergence agitation (EA) in cleft palate surgery is significantly higher than in other types of interventions. The exact mechanism of EA is still unclear. Although restlessness after general anesthesia in children with cleft palate is self-limiting, its effects should be considered by clinicians. In this paper, the related literature on restlessness after surgery involving general anesthesia in recent years is summarized. This paper focuses on induction factors as well as prevention and treatment of postoperative restlessness in children with cleft palate after general anesthesia. The corresponding countermeasures to guide clinical practice are also presented in this paper.