Effects and mechanism of dexmedetomidine on neuronal cell injury induced by hypoxia-ischemia.

BACKGROUND: The present study aims to investigate the protective effects of dexmedetomidine (DMED) on hypoxia ischemia injury induced by oxygen and glucose deprivation (OGD) in PC12 and primary neuronal cells. METHODS: PC12 cells exposed to OGD was used to establish ischemia model. The OGD-induced cell injury was evaluated by alterations of cell viability, apoptosis and expressions of apoptosis-associated proteins. Oxidative stress and expressions of neurotrophic factors after OGD and DMED treatments were also explored. The activation of possible involved signaling pathways were studied after OGD and DMED treatments, along with the addition of inhibitors of these pathways. Finally, the effects of DMED on primary neuronal cells were verified according to the alterations of inflammatory cytokines release and oxidative stress. RESULTS: DMED obviously increased cell viability and reduced cell apoptosis as well as ratio of Bax/Bcl-2 in OGD-treated PC12 cells. Then, the OGD-induced changes of LDH, MDA, SOD and GSH-Px as well as decreases of neurotrophic factors were all ameliorated by DMED treatment. Key kinases in Notch/NF-κB signaling pathway were up-regulated by OGD, whereas the up-regulations were decreased by DMED. In addition, inhibitor of Notch or NF-κB could augment the effects of DMED on OGD-induced cell injury. Finally, the protective effects of DMED were verified in primary neuronal cells. CONCLUSION: DMED had protective effect on OGD-induced PC12 cell injury, depending on its anti-apoptotic, anti-oxidative activity and the inhibition of Notch/NF-κB activation. Our findings suggested that DMED could be used as a potential therapeutic drug for cerebral ischemia.

Undiagnosed giant cystic pheochromocytoma: A case report.

Giant cystic pheochromocytomas (GPCCs) are rare adrenal tumors and the majority of them present as asymptomatic. As a result GPCCs often remain undiagnosed until surgery and therefore the surgical team face a greater challenge in perioperative management. The present study describes the case of a 36 year-old woman with an undiagnosed GPCC, which was successfully resected despite the occurrence of perioperative cardiovascular events, including hypertension, hypotension, ventricular arrhythmias, acute heart failure, acute myocardial infarction, and the patient was discharged home without any recurrence. It should be considered in retroperitoneal tumour of patients with nonspecific symptoms and given adequate treatment to promote the perioperative safety.

Intraoperative intravenous lidocaine exerts a protective effect on cell-mediated immunity in patients undergoing radical hysterectomy.

Surgical procedures cause a decrease in lymphocyte proliferation rate, an increase in apoptosis and shifts the balance of T­helper (Th)1/Th2 cells towards anti­cell­mediated immunity (CMI) Th2 dominance, which is relevant to the immunosuppressive effects of CMI, postoperative septic complications and the formation of tumor metastasis. Previous studies have revealed that lidocaine exhibits antibacterial actions; regulating inflammatory responses, reducing postoperative pain and affecting the duration spent in hospital. Thus, the present study hypothesized that lidocaine may exert a protective effect on the CMI of patients undergoing surgery for the removal of a primary tumor. A total of 30 adult female patients diagnosed with cervical cancer were recruited to the present study and were randomized into two groups. The lidocaine group received an intravenous bolus dose of 1.5 mg/kg lidocaine, followed by continuous infusion at 1.5 mg/kg/h until discharge from the operating room. The control group received the same volume of normal saline. A 10 ml sample of venous blood was drawn, and the lymphocytes were isolated using Ficoll­paque 1 day prior to surgery, at discharge from the operating room and 48 h post­surgery. The proliferation rate of the lymphocytes was assessed using a Cell Counting Kit­8 assay and was found to be higher in the lidocaine group. The early apoptosis of lymphocytes was attenuated following lidocaine treatment at 48 h post­surgery, as detected using flow cytometry with Annexin V­fluorescein isothiocyanate/propidium iodide staining. The level of interferon (IFN)­Î³ in the serum at 48 h was significantly decreased following surgery in the control group, compared with the pre­surgical values (3.782 ± 0.282, vs. 4.089 ± 0.339 pg/ml, respectively) and the ratio of IFN­Î³ to interleukin­4 was well preserved in the lidocaine group. In conclusion, the present study demonstrated that the intraoperative systemic administration of lidocaine exerted a protective effect on CMI in patients with cervical cancer undergoing radical hysterectomy. This may be beneficial in reducing the occurrence of postoperative septic complications and tumor metastasis formation.

Doxapram hastens the recovery following total intravenous anesthesia with dexmedetomidine, propofol and remifentanil.

Dexmedetomidine is a suitable sedative for awake fiberoptic intubation in patients with obstructive sleep apnea (OSA). However, previous studies have shown that dexmedetomidine delays recovery from propofol-remifentanil anesthesia. This study aimed to determine whether doxapram may hasten the recovery following dexmedotomidine-propofol-remifentanil anesthesia. Sixty patients scheduled for uvulopalatopharyngoplasty with total intravenous anesthesia were randomized to two groups according to the medicine given at the end of surgery. These were the doxapram (1 mg/kg) and control (normal saline) groups (n=30 per group). The primary outcome was the time to eye opening on verbal command. The time to return to spontaneous breathing, to hand squeezing in response to verbal command, to extubation of the trachea, and the heart rate (HR), bispectral index (BIS) values, respiratory rate (RR) and pulse oximetry values were also recorded and compared. The time to return to spontaneous breathing (5.2±2.9 vs. 11.7±3.4 min, P<0.001), eye opening (9.3±4.7 vs. 15.9±6.3 min, P<0.001), hand squeeze to command (11.8±6.5 vs. 17.6±7.7 min, P=0.0026) and extubation (14.2±7.8 vs. 19.2±9.6 min, P=0.0308) were significantly shorter in the doxapram group compared with the control group. BIS scores (at 3-14 min), RR (at 4-10 min) and HR (at 2-13 min) were significantly higher in the doxapram group compared with those in the control group (P<0.05). Doxapram hastens the recovery from dexmedetomidine-propofol-remifentanil anesthesia in patients undergoing uvulopalatopharyngoplasty, and may benefit patients with OSA.

Intraoperative systemic lidocaine inhibits the expression of HMGB1 in patients undergoing radical hysterectomy.

Surgery stressors trigger inflammatory response and excessive inflammatory response leads to organ failure or even septic shock. HMGB1 as a later inflammatory cytokines and a critical mediator of severe sepsis is always associated with the aggravation of organ failure. Previous study shows that lidocaine can inhibit the expression of HMGB1 in macrophage of septic rats and protect animals from organ failure. The present study sought to determine whether intraoperative systemic lidocaine could attenuate the level of HMGB1 by inhibiting it expression in PBMC from patients underwent radical hysterectomy. Thirty patients were recruited and divided randomly into two groups according to the difference of study medicine. Patients in lidocaine group received an intravenous bolus infusion of 1.5 mg/kg of lidocaine followed by a continuous infusion of 1.5 mg/kg/h till discharged from operating room, and those in the control group received normal saline. Peripheral blood sample was drawn at pre-surgery, discharge from operating room and 48 h post-surgery. Monocytes were isolated and cultured with medium alone or with LPS. HMGB1 protein in serum or in supernatant of PBMC was detected with ELISA, while the HMGB1 mRNA in PBMC was determined by real-time quantitative PCR. The result showed that lidocaine not only attenuated the level of HMGB1 protein in serum and supernatant, but inhibited the transcription of HMGB1 mRAN in PBMC. The present study of us demonstrated that intraoperative systemic lidocaine can attenuate the level of HMGB1 and inhibit its expression in PBMC from patients underwent radical hysterectomy. Therefore, lidocaine may play an important role in many other clinical diseases by inhibiting HMGB1.

HMGB1 enhances smooth muscle cell proliferation and migration in pulmonary artery remodeling.

HMGB1 is a necessary and critical mediator of acute lung injury and can act as a chemoattractant and anti-apoptosis factor in injury or repair in diseases. In this study we sought to determine whether HMGB1 is involved in the remodeling of pulmonary artery and investigate the mechanism. A rat model of pulmonary artery remodeling was successful induced with LPS infusion and the increasing of pulmonary arteries media was obviously inhibited in rats treated with thrice inject of HMGB1 neutralizing antibody. The percent of areas of tunica media to total artery wall was (0.53 ± 0.15), (0.81 ± 0.10) and (0.59 ± 0.11) in control, LPS and antibody group respectively (p<0.05). Meanwhile, treatment with HMGB1 neutralizing antibody not only decreased the level of HMGB1 mRNA and protein significantly, but inhibited the expression of PCAN and Bcl-2 as well. On the contrary, Bax, a gen which represented the apoptosis, revealed an absolutely reversed trend to Bcl-2 in pulmonary arteries. Experiments in vitro showed that HMGB1 could stimulate the proliferation of hPASMC in MTT test and increase the number of migrated cells in a concentration-dependent manner in chemotaxis assay using modified Boyden chambers. In conclusion, data from this study support the concept that HMGB1 is involved in the remodeling of pulmonary artery by enhancing proliferation and migration of smooth muscle cell. Inhibiting HMGB1 may be a new target to deal with the remodeling of pulmonary artery.

The protective effect of lidocaine on septic rats via the inhibition of high mobility group box 1 expression and NF-κB activation.

Lidocaine, a common local anesthetic drug, has anti-inflammatory effects. It has demonstrated a protective effect in mice from septic peritonitis. However, it is unknown whether lidocaine has effects on high mobility group box 1 (HMGB1), a key mediator of inflammation. In this study, we investigated the effect of lidocaine treatment on serum HMGB1 level and HMGB1 expression in liver, lungs, kidneys, and ileum in septic rats induced by cecal ligation and puncture (CLP). We found that acute organ injury induced by CLP was mitigated by lidocaine treatment and organ function was significantly improved. The data also demonstrated that lidocaine treatment raised the survival of septic rats. Furthermore, lidocaine suppressed the level of serum HMGB1, the expression of HMGB1, and the activation of NF-κB p65 in liver, kidneys, lungs, and ileum. Taken together, these results suggest that lidocaine treatment exerts its protective effection on CLP-induced septic rats. The mechanism was relative to the inhibitory effect of lidocaine on the mRNA expression level of HMGB1 in multiple organs, release of HMGB1 to plasma, and activation of NF- κB.

The inhibitory effect of lidocaine on the release of high mobility group box 1 in lipopolysaccharide-stimulated macrophages.

BACKGROUND: High mobility group box 1 (HMGB1), a key mediator of inflammation, has been shown to inhibit phagocytosis of apoptotic cells in sepsis. Lidocaine has been proven to protect macrophages in mice with septic peritonitis by attenuating the production of cytokines. However, it is currently unknown whether lidocaine also affects HMGB1. In this study, we sought to detect the effect of lidocaine on the release of HMGB1 from RAW264.7 macrophages after lipopolysaccharide (LPS) stimulation. METHODS: The levels of HMGB1 in the supernatant of RAW264.7 cells incubated with LPS and different concentrations of lidocaine were measured by enzyme-linked immunosorbent assays. HMGB1 mRNA expression was assessed by real-time polymerase chain reaction. The immunocytochemistry was used to detect the release and translocation of HMGB1 from the nucleus to cytoplasm. Nuclear factor (NF)-κB levels in the nuclear fraction of RAW264.7 cells were measured with the Active Motif NF-κB family kit. RESULTS: We found that lidocaine suppressed the translocation of HMGB1 from the nucleus to cytoplasm and decreased the expression of HMGB1 mRNA in RAW264.7 cells induced by LPS. Furthermore, the LPS-stimulated translocation of NF-κB from the cytoplasm to nucleus was inhibited by lidocaine in a dose-dependent manner. CONCLUSIONS: Our data suggest that lidocaine functions as an antiinflammatory by inhibiting expression of HMGB1 mRNA, and translocating both HMGB1 and NF-κB from the nucleus to cytoplasm. The mechanism of these effects might be involved, at least partly, in the inhibition of the NF-κB signal pathway.