Histamine 2/3 receptor agonists alleviate perioperative neurocognitive disorders by inhibiting microglia activation through the PI3K/AKT/FoxO1 pathway in aged rats.

BACKGROUND: Microglia, the principal sentinel immune cells of the central nervous system (CNS), play an extensively vital role in neuroinflammation and perioperative neurocognitive disorders (PND). Histamine, a potent mediator of inflammation, can both promote and prevent microglia-related neuroinflammation by activating different histamine receptors. Rat microglia express four histamine receptors (H1R, H2R, H3R, and H4R), among which the histamine 1 and 4 receptors can promote microglia activation, whereas the role and cellular mechanism of the histamine 2 and 3 receptors have not been elucidated. Therefore, we evaluated the effects and potential cellular mechanisms of histamine 2/3 receptors in microglia-mediated inflammation and PND. METHODS: This study investigated the role of histamine 2/3 receptors in microglia-induced inflammation and PND both in vivo and in vitro. In the in vivo experiments, rats were injected with histamine 2/3 receptor agonists in the right lateral ventricle and were then subjected to exploratory laparotomy. In the in vitro experiments, primary microglia were pretreated with histamine 2/3 receptor agonists before stimulation with lipopolysaccharide (LPS). Cognitive function, microglia activation, proinflammatory cytokine production, NF-κb expression, M1/M2 phenotypes, cell migration, and Toll-like receptor-4 (TLR4) expression were assessed. RESULTS: In our study, the histamine 2/3 receptor agonists inhibited exploratory laparotomy- or LPS-induced cognitive decline, microglia activation, proinflammatory cytokine production, NF-κb expression, M1/M2 phenotype transformation, cell migration, and TLR4 expression through the PI3K/AKT/FoxO1 pathway. CONCLUSION: Based on our findings, we conclude that histamine 2/3 receptors ameliorate PND by inhibiting microglia activation through the PI3K/AKT/FoxO1 pathway. Our results highlight histamine 2/3 receptors as potential therapeutic targets to treat neurological conditions associated with PND.

Correction to: Mild endoplasmic reticulum stress ameliorates lipopolysaccharide-induced neuroinflammation and cognitive impairment via regulation of microglial polarization.

An amendment to this paper has been published and can be accessed via the original article.

Pro-inflammatory role of high-mobility group box-1 on brain mast cells via the RAGE/NF-κB pathway.

High-mobility group box-1 (HMGB-1) acts as a pro-inflammatory cytokine contributing to the occurrence of many central inflammatory and infectious disorders. Brain mast cells (MCs) are the first responders to peripheral inflammatory stimulation because of their rapid response to external stimuli coupled with their release of preformed and newly synthesized reactive chemicals. Little is known about the involvement of brain MCs in the pro-inflammatory effects of HMGB-1 on the central nervous system (CNS). Thus, we investigated the activation process of MCs by HMGB-1 and explored whether this process is involved in the pro-inflammatory effects of HMGB-1 on the CNS. In this study, we used P815 cells to study the activating role of HMGB-1 on MCs and to explore its potential mechanism in vitro. In an in vivo study, adult male Sprague-Dawley rats received i.c.v. injection of sterile saline or cromoglycate (stabilizer of MCs) 30 min prior to i.p. injection of HMGB-1. Increased levels of tumor necrosis factor and IL-1ß were observed in the P815 cells, as well as in the rats' brains, after HMGB-1 treatment. Pretreatment with the receptor of advanced glycation endproducts (RAGE)-siRNA inhibited the HMGB-1-induced inflammatory process in the P815 cells. Activation of the RAGE/nuclear factor-κB (NF-κB) pathway was observed in both the P815 cells and rats' brains. In addition, HMGB-1 induced the accumulation of brain MCs in the hippocampal CA1 region, and the blood-brain barrier was disrupted. Pretreatment with cromoglycate, a stabilizer of MCs, mitigated these HMGB-1-induced pro-inflammatory processes in rats. These findings indicate that brain MCs are involved in the pro-inflammatory effect of HMGB-1 on the CNS, probably via activating the RAGE/NF-κB pathway.

Effect of tryptase on mouse brain microvascular endothelial cells via protease-activated receptor 2.

BACKGROUND: Mast cells (MCs), the 'first responders' in brain injury, are able to disrupt the blood-brain barrier (BBB), but the underlying mechanism is not well understood. Tryptase is the most abundant MC secretory product. Protease-activated receptor 2 (PAR-2) has been identified as a specific receptor for tryptase, which is abundantly expressed in brain microvascular endothelial cells. The BBB comprises brain microvascular endothelial cells that display specialised molecular properties essential for BBB function and integrity. Therefore, the purpose of the present study was to investigate the effects of tryptase on mouse brain microvascular endothelial cell line bEnd3 and its potential mechanisms of action. METHODS: Induction of mouse brain microvascular endothelial cell activation by tryptase was examined. Then, mouse brain microvascular endothelial cells were pretreated with a PAR-2 antagonist and stimulated with tryptase. Cellular activation, proinflammatory cytokine production, expression of PAR-2, Toll-like receptors (TLRs) and mitogen-activated protein kinases (MAPK), nuclear factor kappa B (NF-kappa B) phosphorylation were assessed. RESULTS: Tryptase upregulated the production of VCAM-1, MMPs (MMP9 and MMP2), TLR4 and TNF-α and downregulated the expression of the tight junction proteins occludin and claudin-5 in mouse brain microvascular endothelial cell. Among the MAPK and NF-kappa B pathway, ERK and NF-kappa B were activated by tryptase. All of these effects could be eliminated by the PAR-2 inhibitor. CONCLUSION: Based on our findings, we conclude that tryptase can trigger brain microvascular endothelial cell activation and proinflammatory mediator release. These findings may further clarify the involvement and mechanism of tryptase in BBB disruption.

Mild endoplasmic reticulum stress ameliorates lipopolysaccharide-induced neuroinflammation and cognitive impairment via regulation of microglial polarization.

BACKGROUND: Neuroinflammation, which ultimately leads to neuronal loss, is considered to play a crucial role in numerous neurodegenerative diseases. The neuroinflammatory process is characterized by the activation of glial cells such as microglia. Endoplasmic reticulum (ER) stress is commonly associated with impairments in neuronal function and cognition, but its relationship and role in neurodegeneration is still controversial. Recently, it was confirmed that nonharmful levels of ER stress protected against experimental Parkinson's disease. Here, we investigated mild ER stress-based regulation of lipopolysaccharide (LPS)-driven neuroinflammation in rats and in primary microglia. METHODS: Male Sprague-Dawley (SD) rats received the intracerebroventricular injection of the ER stress activator tunicamycin (TM) with or without intraperitoneal injection of the ER stress stabilizer sodium 4-phenylbutyrate (4-PBA) 1 h before LPS administration. The levels of neuroinflammation and memory dysfunction were assessed 24 h after treatment. In addition, the effect of mild ER stress on microglia was determined in vitro. RESULTS: Here, we found that low doses of TM led to mild ER stress without cell or organism lethality. We showed that mild ER stress preconditioning reduced microglia activation and neuronal death as well as improved LPS-induced memory impairment in rats. In addition, pre-exposure to nonlethal doses of TM in microglia showed significant protection against LPS-induced proinflammatory cytokine production and M1/2b polarization. However, sodium 4-PBA, a compound that ameliorates ER stress, ablated this protective effect in vivo and in vitro. CONCLUSIONS: Based on our findings, we conclude that the mild ER stress not only limits the accumulation of misfolded proteins but also protects tissues from harmful endotoxemia insults. Therefore, ER stress preconditioning has potential therapeutic value for the treatment of neurodegenerative diseases.

Blocking ATP-sensitive potassium channel alleviates morphine tolerance by inhibiting HSP70-TLR4-NLRP3-mediated neuroinflammation.

BACKGROUND: Long-term use of morphine induces analgesic tolerance, which limits its clinical efficacy. Evidence indicated morphine-evoked neuroinflammation mediated by toll-like receptor 4 (TLR4) - NOD-like receptor protein 3 (NLRP3) inflammasome was important for morphine tolerance. In our study, we investigated whether other existing alternative pathways caused morphine-induced activation of TLR4 in microglia. We focused on heat shock protein 70 (HSP70), a damage-associated molecular pattern (DAMP), which was released from various cells upon stimulations under the control of KATP channel and bound with TLR4-inducing inflammation. Glibenclamide, a classic KATP channel blocker, can improve neuroinflammation by inhibiting the activation of NLRP3 inflammasome. Our present study investigated the effect and possible mechanism of glibenclamide in improving morphine tolerance via its specific inhibition on the release of HSP70 and activation of NLRP3 inflammasome induced by morphine. METHODS: CD-1 mice were used for tail-flick test to evaluate morphine tolerance. The microglial cell line BV-2 and neural cell line SH-SY5Y were used to investigate the pharmacological effects and the mechanism of glibenclamide on morphine-induced neuroinflammation. The activation of microglia was accessed by immunofluorescence staining. Neuroinflammation-related cytokines were measured by western blot and real-time PCR. The level of HSP70 and related signaling pathway were evaluated by western blot and immunofluorescence staining. RESULTS: Morphine induced the release of HSP70 from neurons. The released HSP70 activated microglia and triggered TLR4-mediated inflammatory response, leading to the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) p65 and the activation of NLRP3 inflammasome. Moreover, anti-HSP70 neutralizing antibody partly attenuated chronic morphine tolerance. The secretion of HSP70 was under the control of MOR/AKT/KATP/ERK signal pathway. Glibenclamide as a classic KATP channel blocker markedly inhibited the release of HSP70 induced by morphine and suppressed HSP70-TLR4-NLRP3 inflammasome-mediated neuroinflammation, which consequently attenuated morphine tolerance. CONCLUSIONS: Our study indicated that morphine-induced extracellular HSP70 was an alternative way for the activation of TLR4-NLRP3 in analgesic tolerance. The release of HSP70 was regulated by MOR/AKT/KATP/ERK pathway. Our study suggested a promising target, KATP channel and a new leading compound, glibenclamide, for treating morphine tolerance.

Procyanidins alleviates morphine tolerance by inhibiting activation of NLRP3 inflammasome in microglia.

BACKGROUND: The development of antinociceptive tolerance following repetitive administration of opioid analgesics significantly hinders their clinical use. Evidence has accumulated indicating that microglia within the spinal cord plays a critical role in morphine tolerance. The inhibitor of microglia is effective to attenuate the tolerance; however, the mechanism is not fully understood. Our present study investigated the effects and possible mechanism of a natural product procyanidins in improving morphine tolerance via its specific inhibition on NOD-like receptor protein3 (NLRP3) inflammasome in microglia. METHODS: CD-1 mice were used for tail-flick test to evaluate the degree of pain. The microglial cell line BV-2 was used to investigate the effects and the mechanism of procyanidins. Reactive oxygen species (ROS) produced from BV-2 cells was evaluated by flow cytometry. Cell signaling was measured by western blot assay and immunofluorescence assay. RESULTS: Co-administration of procyanidins with morphine potentiated its antinociception effect and attenuated the development of acute and chronic morphine tolerance. Procyanidins also inhibited morphine-induced increase of interleukin-1ß and activation of NOD-like receptor protein3 (NLRP3) inflammasome. Furthermore, procyanidins decreased the phosphorylation of p38 mitogen-activated protein kinase, inhibited the translocation of nuclear factor-κB (NF-κB), and suppressed the level of reactive oxygen species in microglia. CONCLUSIONS: Procyanidins suppresses morphine-induced activation of NLRP3 inflammasome and inflammatory responses in microglia, and thus resulting in significant attenuation of morphine antinociceptive tolerance.

S100A8 contributes to postoperative cognitive dysfunction in mice undergoing tibial fracture surgery by activating the TLR4/MyD88 pathway.

Neuro-inflammation plays a key role in the occurrence and development of postoperative cognitive dysfunction (POCD). Although S100A8 and Toll-like receptor 4 (TLR4) have been increasingly recognized to contribute to neuro-inflammation, little is known about the interaction between S100A8 and TLR4/MyD88 signaling in the process of systemic inflammation that leads to neuro-inflammation. Firstly, we demonstrated that C57BL/6 wide-type mice exhibit cognitive deficit 24h after the tibial fracture surgery. Subsequently, increased S100A8 and S100A9 expression was found in the peripheral blood mononuclear cells (PBMCs), spleen, and hippocampus of C57BL/6 wide-type mice within 48h after the surgery. Pre-operative administration of S100A8 antibody significantly inhibited hippocampal microgliosis and improved cognitive function 24h after the surgery. Secondly, we also observed TLR4/MyD88 activation in the PBMCs, spleen, and hippocampus after the surgery. Compared with those in their corresponding wide-type mice, TLR4(-/-) and MyD88(-/-) mice showed lower immunoreactive area of microglia in the hippocampal CA3 region after operation. TLR4 deficiency also led to reduction of CD45(hi)CD11b(+) cells in the brain and better performance in both Y maze and open field test after surgery, suggesting a new regulatory mechanism of TLR4-dependent POCD. At last, the co-location of S100A8 and TLR4 expression in spleen after operation suggested a close relationship between them. On the one hand, S100A8 could induce TLR4 activation of CD11b(+) cells in the blood and hippocampus via intraperitoneal or intracerebroventricular injection. On the other hand, TLR4 deficiency conversely alleviated S100A8 protein-induced hippocampal microgliosis. Furthermore, the increased expression of S100A8 protein in the hippocampus induced by surgery sharply decreased in both TLR4 and MyD88 genetically deficient mice. Taken together, these data suggest that S100A8 exerts pro-inflammatory effect on the occurrence and development of neuro-inflammation and POCD by activating TLR4/MyD88 signaling in the early pathological process of the postoperative stage.

Propofol attenuation of hydrogen peroxide-induced injury in human umbilical vein endothelial cells involves aldose reductase.

Propofol is a widely used intravenous anesthetic agent with antioxidant/antiapoptotic properties. Aldose reductase (AR) has been implicated in oxidative stress and apoptosis in endothelial cells. AR inhibition may protect cells from cardiovascular injury. Although the cytoprotective effect of propofol against hydrogen peroxide (H2O2)-induced injury has been widely studied, there is no information about the effects of propofol on AR. We therefore investigated the effect of propofol on H2O2-mediated injury and on aldose reductase expression. We found that propofol protected HUVECs against H2O2-induced damage and apoptosis and ameliorated AR expression induced by H2O2. Propofol also inhibited H2O2-induced p38 MAPK, JNK and Akt phosphorylation. Epalrestat (an AR inhibitor) or ablation of AR siRNA had a similar effect to propofol. The results suggest that propofol may be a preemptive anesthetic in patients with cardiovascular disease and inhibition of AR might be a new cytoprotective pathway for propofol.

Effects of postoperative analgesia with the combination of tramadol and lornoxicam on serum inflammatory cytokines in patients with gastric cancer.

OBJECTIVE: To compare the effects of postoperative patient-controlled intravenous analgesia (PCIA) with morphine, tramadol, or tramadol combined with lornoxicam on serum inflammatory cytokine production. METHODS: 60 patients with an American Society of Anesthesiologists (ASA) physical status of I or II, undergoing radical correction of gastric cancer, were equally randomized to receive PCIA with morphine (M group), tramadol (T group), or tramadol combined with lornoxicam (L group). The visual analog scale (VAS) and Bruggemann comfort scale (BCS) scores were used to evaluate the postoperative analgesic efficacy. Serum levels of the interleukins (IL) IL-2, IL-6, and IL-10, and soluble IL-2 receptor (sIL-2R) were measured before anesthesia, 90 min after incision, and 24, 48, and 72 h after surgery. RESULTS: No significant difference was found in the VAS, BCS, or baseline serum IL-2, IL-6, IL-10, or sIL-2R between the groups. At 90 min after incision, only the IL-6 levels increased (p < 0.05). At 24 h after surgery, the IL-2 levels decreased, with the M group having the lowest levels, while IL-6, IL-10, and sIL-2R levels increased, with the M group having the highest level and the L group having the lowest level (p < 0.05). At 48 h after surgery, the cytokine levels were starting to return to the baselines but still had statistical significance (p < 0.05). At 72 h after surgery, only the IL-6 levels had returned to their baseline. CONCLUSION: PCIA using tramadol combined with lornoxicam has less influence on inflammatory cytokines than morphine or tramadol alone in patients undergoing gastric cancer surgery.

[Effects of preloading epidural space with epinephrine (1:200 000) on the incidence of vascular injuries through the insertion of an epidural catheter during cesarean section].

OBJECTIVE: To evaluate the effects of preloading epidural space with epinephrine (1:200 000) on the incidence of vascular injuries through the insertion of an epidural catheter during cesarean section. METHODS: Between May 2011 and December 2011, upon obtaining institutional ethics approval and informed consent from the Human Ethics Committee of Nanjing Medical University, 100 laboring women with singleton cephalic presentation at term, ASA (American Society of Anesthesiologists) class I-II, undergoing caesarean section under continuous epidural analgesia were randomly divided into E and N groups according to a random digit table (n = 50 each). After an identification of epidural space, 5 ml of normal saline with epinephrine (1:200 000) was injected into epidural space in group E and 5 ml of normal saline in group N through an epidural needle. The syringe plunger was pressed firmly for 20 seconds to ensure a sufficient diffusion. For both groups, the levels of mean arterial pressure and heart rates were recorded prior to anesthesia (T1), 2 min after switching into a supine horizontal position after successful puncture (T2), the time of fetal delivery (T3) and when surgery was over (T4). The cases with bloody fluid in epidural puncture needle during puncture or epidural catheter during catheter placement, fresh blood in epidural catheter and bloody fluid in caudal end of epidural catheter during extubation were recorded. RESULTS: All hemodynamic changes were within the normal ranges. There were no obvious inter-group differences (P > 0.05). No significant difference existed in the cases with bloody fluid in epidural needle during catheter insertion (10% vs 12%) or epidural catheter during catheter placement (4% vs 6%), fresh blood in epidural catheter (0% vs 0%) or bloody fluid in caudal end of epidural catheter during extubation (26% vs 30%) between the groups (P > 0.05). CONCLUSION: Preloading epidural space with epinephrine (1:200 000) may not lower the incidence of vascular injuries through the insertion of an epidural catheter during cesarean section.

Laparotomy-Induced Peripheral Inflammation Activates NR2B Receptors on the Brain Mast Cells and Results in Neuroinflammation in a Vagus Nerve-Dependent Manner.

Background: The pathophysiological mechanisms underlying postoperative cognitive dysfunction (POCD) remain unclear over the years. Neuroinflammation caused by surgery has been recognized as an important element in the development of POCD. Many studies also suggest that the vagus nerve plays an important role in transmitting peripheral injury signals to the central nervous system (CNS) and the resultant neuroinflammation. Previously, we have demonstrated that brain mast cells (BMCs), as the "first responders", play a vital role in neuroinflammation and POCD. However, how the vagus nerve communicates with BMCs in POCD has not yet been clarified. Methods: In the current study, we highlighted the role of the vagus nerve as a conduction highway in surgery-induced neuroinflammation for the first time. In our model, we tested if mice underwent unilateral cervical vagotomy (VGX) had less neuroinflammation compared to the shams after laparotomy (LP) at an early stage. To further investigate the roles of mast cells and glutamate in the process, we employed KitW-sh mice and primary bone marrow-derived MCs to verify the glutamate-NR2B axis on MCs once again. Results: Our results demonstrated that there were higher levels of glutamate and BMCs activation as early as 4 h after LP. Meanwhile, vagotomy could partially block the increases and reduce neuroinflammation caused by peripheral inflammation during the acute phase. Excitingly, inhibition of NR2B receptor and knockout of mast cells can attenuateneuroinflammation induced by glutamate. Conclusion: Taken together, our findings indicate that the vagus is a high-speed pathway in the transmission of peripheral inflammation to the CNS. Activation of BMCs triggered a neuroinflammatory cascade. Inhibition of NR2B receptor on BMCs can reduce glutamate-induced BMCs activation, neuroinflammation, and memory impairment, suggesting a novel treatment strategy for POCD.

[Comparison of effects in puerpera and fetus with ephedrine and phenylephrine during a cesarean delivery].

OBJECTIVE: To compare the different effects in fetus and puerpera with an equivalent dose of ephedrine (E) and phenylephrine (Ph) for maintaining maternal blood pressure near baseline during spinal anesthesia for a cesarean delivery. METHODS: Ninety mature parturient women with single-embryo scheduled for an elective cesarean delivery under spinal anesthesia at our hospital during January-June 2010 were randomly divided into 3 groups (E, E + Ph and Ph, n = 30 each). Group E received an infusion of ephedrine (ephedrine 4 g/L), Group E + Ph ephedrine plus phenylephrine (ephedrine 2 g/L + phenylephrine 25 mg/L) and Group Ph phenylephrine (phenylephrine 50 mg/L). The blood pressure was maintained near baseline by adjusting the infusion rate during anesthesia. The maternal blood pressure, heart rate and fetal heart rate were measured at the time points of 1, 3, 5 and 10 min, skin incision and uterine incision after injecting anesthetic into subarachnoid space. Immediately after delivery, maternal arterial, umbilical arterial and umbilical venous blood samples were withdrawn for the measurements of blood gases and plasma concentrations of lactate and glucose. RESULTS: The fetal heart rate of groups E and E + Ph significantly increased after infusion [5 min: (150 ± 10) times/min vs (142 ± 13) times/min, (146 ± 10) times/min vs (142 ± 9) times/min, both P < 0.05] while those of group Ph had no significant changes [5 min: (143 ± 9) times/min vs(143 ± 6) times/min, P > 0.05]. The incidence of fetal tachycardia in groups E and E + Ph was greater than that in group Ph. In group E, umbilical arterial and umbilical venous pH and base excess were lower than those in groups E + Ph and Ph [umbilical arterial: 7.20 ± 0.10 vs 7.27 ± 0.05, 7.28 ± 0.03, (-3.1 ± 3.1) mmol/L vs (-0.9 ± 1.7) mmol/L, (-0.3 ± 1.7) mmol/L, umbilical venous:7.29 ± 0.09 vs 7.34 ± 0.03, 7.34 ± 0.03, (-3.3 ± 2.9) mmol/L vs (-2.0 ± 1.7) mmol/L, (-0.9 ± 1.5) mmol/L, all P < 0.05]. Umbilical arterial PCO2 and plasma concentrations of lactate and glucose in group E were greater than those in group Ph (all P < 0.05). Umbilical arterial and umbilical venous plasma concentrations of lactate and glucose were greater in group E + Ph than those in group Ph (all P < 0.05). But base excess was lower (P < 0.05). CONCLUSION: Phenylephrine may be more ideal for treating the hypotension of spinal anesthesia for a cesarean delivery. It corrects hypotension following spinal anesthesia, improves fetal oxygen supply and demand balance but induces no metabolic excitation in fetus as compared with ephedrine.

Neuroimmune connections between corticotropin-releasing hormone and mast cells: novel strategies for the treatment of neurodegenerative diseases.

Corticotropin-releasing hormone is a critical component of the hypothalamic-pituitary-adrenal axis, which plays a major role in the body's immune response to stress. Mast cells are both sensors and effectors in the interaction between the nervous and immune systems. As first responders to stress, mast cells can initiate, amplify and prolong neuroimmune responses upon activation. Corticotropin-releasing hormone plays a pivotal role in triggering stress responses and related diseases by acting on its receptors in mast cells. Corticotropin-releasing hormone can stimulate mast cell activation, influence the activation of immune cells by peripheral nerves and modulate neuroimmune interactions. The latest evidence shows that the release of corticotropin-releasing hormone induces the degranulation of mast cells under stress conditions, leading to disruption of the blood-brain barrier, which plays an important role in neurological diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism spectrum disorder and amyotrophic lateral sclerosis. Recent studies suggest that stress increases intestinal permeability and disrupts the blood-brain barrier through corticotropin-releasing hormone-mediated activation of mast cells, providing new insight into the complex interplay between the brain and gastrointestinal tract. The neuroimmune target of mast cells is the site at which the corticotropin-releasing hormone directly participates in the inflammatory responses of nerve terminals. In this review, we focus on the neuroimmune connections between corticotropin-releasing hormone and mast cells, with the aim of providing novel potential therapeutic targets for inflammatory, autoimmune and nervous system diseases.

Effects of preemptive intravenous lornoxicam on the analgesic efficacy of epidural morphine and expression of chemokines in women undergoing hysterectomy.

BACKGROUND: It is believed that preemptive IV lornoxicam treatment can reduce the consumption of other analgesics, improve analgesic efficacy, and ameliorate immune function during patient-controlled IV analgesia. However, the effects of preemptive IV lornoxicam treatment on the analgesic efficacy of patient-controlled epidural analgesia (PCEA) with morphine and on chemokine expression remain unknown. OBJECTIVE: The aim of this prospective, randomized, controlled study was to observe the effects of preemptive IV lornoxicam treatment on the analgesic efficacy of PCEA with morphine and on the expression of monocyte chemotactic protein-1 (MCP-1) and stromal cell-derived factor-1α (SDF-1α) in women undergoing hysterectomy. METHODS: Patients undergoing elective hysterectomy with combined spinal and epidural anesthesia were randomized to 1 of 3 groups to receive IV lornoxicam 8 mg before anesthesia (group 1), lornoxicam 16-mg injection before anesthesia (group 2), or isotonic saline (control) before anesthesia. PCEA was used to treat postoperative pain, and a visual analog scale (VAS) and the Bruggemann Comfort Scale (BCS) were used to evaluate analgesic efficacy. Morphine consumption was recorded. To measure plasma concentrations of MCP-1 and SDF-1α via enzyme-linked immunosorbent assay, venous blood samples were obtained from patients at 4 separate times: before anesthesia (baseline); 0 (immediately after anesthesia administration); and 24 and 48 hours after surgery. RESULTS: Forty-five patients (mean [SD] age, 41 [5] years; mean [SD] weight, 54 [6] kg) undergoing elective hysterectomy were included in the study. There were no significant differences in VAS scores, BCS scores, or morphine consumption between the 3 groups. Compared with baseline values, MCP-1 and SDF-1α concentrations were increased significantly immediately after surgery in all 3 groups (all, P < 0.01) and returned to near-baseline values at 24 hours postsurgery in groups 1 and 2, and by 48 hours postsurgery in the control group. MCP-1 and SDF-1α concentrations in groups 1 and 2 were significantly lower than those in the control group immediately (all, P < 0.01) and 24 hours postsurgery (all, P < 0.05). CONCLUSION: Preemptive IV lornoxicam treatment was associated with attenuation of the plasma concentrations of MCP-1 and SDF-1α immediately after and 24 hours after hysterectomy and was associated with more rapid resolution to near-baseline concentrations of both cytokines in these patients compared with controls; however, it was not associated with significantly reducing epidural morphine consumption.

[Protective effects of ketamine on allergen-induced airway inflammatory injure and high airway reactivity in asthma: experiment with rats].

OBJECTIVE: To observe the effects of ketamine on bronchial hyperresponsiveness and airway inflammation in equal asthma. METHODS: 56 Brown-Norway rats were randomly assigned to seven groups: negative control group (Group A), asthma model group (Group B) and inhalation groups with nebulized ketamine at different concentrations (Group C, D, E) and intraperitoneal injection groups with ketamine at different doses (Group F, G). The rats were sensitized by injection of ovalbumin (OVA) together with aluminum hydroxide and Bordetella pertussis as adjuvants, then challenged by repeated intermittent (thrice weekly) exposure to aerosolized OVA for two weeks. Before challenge, the sensitized rats were exposed to an aerosol of phosphate buffered saline (PBS) or ketamine at the concentrations of 12.5 mg/ml, 25 mg/ml and 50 mg/ml respectively in Groups B, C, D and E. The sensitized rats were intraperitoneally injected with ketamine at the doses of 50 microg/kg or 100 microg/kg respectively in Group F and G. The sensitized rats in Group A received phosphate buffered solution (PBS) by inhalation. The airway reactivity to acetylcholine (ACH) was assessed in vivo 24 hr after the last OVA challenge, then the lungs were removed for measurement of the mRNA and protein expression of iNOS and production of NO and lung sections for histopathologic examination. RESULTS: (1) In the OVA-sensitized and challenged rats, the dose-response curve of the expiratory resistance (Re) shifted to the upper-left +/- ward compared with that of PBS control rats. In addition, the provocation doses required to increase the Re by 100%, 200% and 400% for OVA-sensitized and challenged rats in Group B were significantly lower than those of the PBS control rats (14.65 +/- 1.19 vs 32.28 +/- 1.43, 15.17 +/- 1.19 vs 38.91 +/- 1.39, and 16.28 +/- 1.18 vs 56.53 +/- 1.38, all P < 0.01). The OVA-sensitized rats treated with ketamine before OVA challenge demonstrated a significant decrease in AHR by a rightward shift of the dose-response curves to ACH and significant higher provocation doses compared with that of the OVA control rats (P < 0.05). (2) Marked inflammatory changes in the airways of Group B were present, while obviously lessen inflammatory cell infiltration in peribronchial and perialveolar tissues and improved lung edema were observed in the groups treated with ketamine. (3) Quantitation by densitometry showed that the relative density of iNOS mRNA bands normalized to beta-actin was significantly higher in the OVA control than the PBS control (1.0 +/- 0.07 vs 0.48 +/- 0.07, P < 0.01). Treatment with ketamine significantly decreased the expression of iNOS mRNA in Group C (0.65 +/- 0.07), Group D (0.58 +/- 0.09), Group E (0.56 +/- 1.00), and Group F (0.66 +/- 0.06) when compared with Group B (all P < 0.05). (4) The relative iNOS protein levels (ratios of iNOS/beta-actin) determined by densitometry analysis showed a 4-fold increase in Group A compared with those in the negative group (0.54 +/- 0.08 vs 0.13 +/- 0.08, P < 0.05). When compared with those of the OVA control, the levels of relative iNOS protein expression showed a significant decrease in the lungs from the rats treated with ketamine inhalation at the doses of 12.5 mg/ml (0.20 +/- 0.03) and 25 mg/ml (0.18 +/- 0.03) and with ketamine and intraperitoneally the at dose of 50 microg/kg (0.21 +/- 0.04) (P < 0.05). (5) NO production in pulmonary tissues was significantly higher in the OVA-treated rats compared to the PBS controls (0.39 +/- 0.04 micromol/g protein vs 0.13 +/- 0.01 micromol/g protein, P < 0.01), but this OVA-triggered NO production was significantly decreased by treatment with 12.5 and 25 mg/ml inhaled ketamine (0.19 +/- 0.03 micromol/g and 0.17 +/- 0.03 micromol/g, both P < 0.05) and 50 microg/kg i.p.-injected ketamine (0.16 +/- 0.04 micromol/g, P < 0.05) when compared with the OVA-treated rats. CONCLUSION: Both inhalation and systemic administration of ketamine attenuate inflammatory the lung injury and airway hyperreactivity of the OVA-induced asthma model. The protective effects of ketamine is achieved by inhibiting OVA-provoked over-expression of mRNA and protein of iNOS and reducing the production of NO in pulmonary tissues.

Protective effects of Garcinol against neuropathic pain - Evidence from in vivo and in vitro studies.

Neuroinflammatory processes have a vital role in the pathogenesis of neuropathic pain. Garcinol, harvested from Garcinia indica, is known to exert potent anti-inflammatory properties. Recent studies have indicated that Garcinol may inhibit activation of nuclear factor-κB (NF-κB) by inhibiting NF-κB/p65 acetylation. These findings prompted us to evaluate the protective effects of Garcinol in the lumbar fifth spinal nerve ligation (SNL)-induced rat model of neuropathic pain and Lipopolysaccharide(LPS)-stimulated primary cultured microglia. In the present study, we found that intrathecal administration of Garcinol significantly attenuated SNL-induced nociceptive behaviors. Garcinol suppressed microglial activation as well as the expression of interleukin (IL)-1ß, IL-6, inducible nitric oxide synthase (iNOS)/nitric oxide (NO), and cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) in the spinal cord of SNL rats. It also reduced the nuclear translocation of NF-κB by decreasing acetyl-p65 protein expression. Similarly, in the in vitro study, Garcinol decreased the production of NO/iNOS, PGE2/COX-2, and proinflammatory cytokines in LPS-exposed microglia. Likewise, Garcinol inhibited the NF-κB signaling pathway by downregulating acetyl-p65 levels in LPS-challenged microglia. Our findings suggest that Garcinol may have protective effects against neuropathic pain that are associated with the inhibition of neuroinflammation in microglia. Therefore, Garcinol could be a promising agent in the treatment of neuropathic pain.

[The protective effects of dexmedetomidine on perioperative myocardial injury in patients with hypertensive myocardial hypertrophy].

OBJECTIVE: The purpose of this study was to evaluate the effects of dexmedetomidine (DEX) on patients with hypertensive myocardial hypertrophy. METHODS: Fifty four patients with hypertensive myocardial hypertrophy were enrolled in the study and were randomly divided into two groups (n=27). Patients in groupD were pretreated with DEX (1 µg/kg) before induction and then maintain with 0.5 µg/(kg·h) DEX. Patients in group C were pretreated with saline at the same time. All patients were connected with holter recorder 2 h before anesthesia and were continuously recorded for 24 h. Blood sample were collected to measure ischemia modified albumin(IMA) and serum cardiac troponin I (cTnI) at the time of T0 (before induction), T1(1 h after surgery), T2(4 h after surgery), T3(12 h after surgery) and T4(24 h after surgery). The surgery time, blood loss and side effect of two groups were recorded at the same time. RESULTS: The serum IMA level in group D was lower than that of group C at the time of T1, T2 and T3 (P<0.05). The serum cTnI in group C was higher than that of group D at the time of T1, T2, T3 and T4 (P<0.05). Changes of ST and complicated ventricular arrhythmias ingroup D were lower than those of group C (P<0.05). CONCLUSIONS: DEX could reduce the incidence of myocardial damage, changes of ST and complicated ventricular arrhythmias in patients with hypertensive myocardial hypertrophy.

Effects of epidural anesthesia and postoperative epidural analgesia on immune function in esophageal carcinoma patients undergoing thoracic surgery.

Thoracic epidural anesthesia (TEA) has been demonstrated to significantly reduce stress and immune dysfunction in trauma patients. In esophageal carcinoma patients undergoing thoracic surgery, TEA combined with general anesthesia during surgery and subsequent postoperative patient-controlled epidural analgesia (PCEA) may improve plasma cortisol (Cor), interleukin (IL)-6 and IL-17 levels and helper T-cell differentiation. A total of 60 esophageal carcinoma patients undergoing thoracic surgery were randomly allocated into groups I, II, III and I (n=15 per group). During surgery, groups I and II received total intravenous general anesthesia (TIVA), whereas groups III and IV received combined TEA and TIVA. Postoperatively, groups I and III received postoperative patient-controlled intravenous analgesia (PCIA), while groups II and IV received PCEA. The Cor, IL-6, IFN-γ, IL-4 and IL-17 levels were measured in peripheral blood samples collected prior to anesthesia (T0), at 2 h after incision (T1), at 4 h postoperatively (T2), at 24 h postoperatively (T3) and at 48 h postoperatively (T4). The plasma Cor, IL-17 and IL-6 levels increased significantly at the beginning of the operation in groups I, II and III, while in group IV there were no significant differences during the entire period, concurrent with enhanced Th0 to Th2 shift, contributing to a Th2-dominant Th1/Th2 ratio. General anesthesia with TEA more efficiently inhibited the onset of the Th2-dominant status and decreased the plasma levels of Cor and IL-6 compared to general anesthesia alone and PCEA inhibited the Th2-dominant status more efficiently compared to PCIA. Therefore, general anesthesia combined with TEA and sole administration of PCEA were demonstrated to inhibit the stress response and minimize immune dysfunction, generating most pronounced results upon combination TEA/PCEA treatment.