Compound K attenuated hepatectomy-induced post-operative cognitive dysfunction in aged mice via LXRα activation.

AIMS: Post-operative cognitive dysfunction (POCD) occurs after major surgery in elderly patients and affects the quality of patients' lives. The present study aims to explore the protective effects and possible mechanisms of compound K in old mice with POCD caused by partial hepatectomy. METHODS: Sixteen month-old mice were administered different doses of compound K from the 8th day to 14th day after partial hepatectomy. Cognitive function was subsequently measured with a Morris water-maze (MWM) test. Serum inflammatory cytokine levels were measured by magnetic bead panel; levels of cytokines in the hippocampus were analyzed using immunohistochemistry and immunoblotting. The mRNA levels of target genes were measured using real-time PCR. RESULTS: Compared with the model group, MWM scores were significantly attenuated at days 10 and 14 post-surgery in mice receiving compound K (10, 30 mg/kg) in a dose-dependent manner. Both systemic and local cytokine levels were reduced after treatment of compound K. The alterations in serum lipids were independent of the attenuation of POCD syndrome. An inhibitor of liver X receptor-α (LXRα), GGPP, reversed the effects of compound K. CONCLUSIONS: The results provide evidence for an alleviation of POCD by compound K via local inflammation inhibition in hippocampus tissue; furthermore, the data suggests the mechanism involves the LXRα pathway. The present study supports further evaluation of compound K as a potential effective modulator for POCD.

Sevoflurane Exacerbates Cognitive Impairment Induced by Aß 1-40 in Rats through Initiating Neurotoxicity, Neuroinflammation, and Neuronal Apoptosis in Rat Hippocampus.

OBJECTIVE: This study was aimed at investigating whether sevoflurane inhalation induced cognitive impairment in rats with a possible mechanism involved in the event. METHODS: Thirty-two rats were randomly divided into four groups of normal saline (NS) + O2, NS + sevoflurane (sevo), amyloid-ß peptide (Aß) + O2, and Aß + sevo. The rats in the four groups received bilateral intrahippocampus injections of NS or Aß. The treated hippocampus was harvested after inhaling 30% O2 or 2.5% sevoflurane. Evaluation of cognitive function was performed by Morris water maze (MWZ) and an Aß 1-42 level was determined by ELISA. Protein and mRNA expressions were executed by immunohistochemical (IHC) staining, Western blotting, and qRT-PCR. RESULTS: Compared with the NS-treated group, sevoflurane only caused cognitive impairment and increased the level of Aß 1-42 of the brain in the Aß-treated group. Sevoflurane inhalation but not O2 significantly increased glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule (IBA)1 expression in Aß-treated hippocampus of rats. Expression levels for Bcl-xL, caspase-9, receptor for advanced glycation end products (RAGE) and brain-derived neurotrophic factor (BDNF) were significantly different in quantification of band intensity between the rats that inhaled O2 and sevoflurane in Aß-treated groups (all P < 0.05). Interleukin- (IL-) 1ß, nuclear factor-κB (NF-κB), and inducible nitric oxide synthase (iNOS) mRNA expression increased after the rats inhaled sevoflurane in the Aß-treated group (both P < 0.01). There were no significant differences in the change of GFAP, IBA1, Bcl-xL, caspase-9, RAGE, BDNF, IL-1ß, NF-κB, and iNOS in the NS + O2 and NS + sevo group (all P > 0.05). CONCLUSION: Sevoflurane exacerbates cognitive impairment induced by Aß 1-40 in rats through initiating neurotoxicity, neuroinflammation, and neuronal apoptosis in rat hippocampus.

Activated Α7nachr Improves Postoperative Cognitive Dysfunction and Intestinal Injury Induced by Cardiopulmonary Bypass in Rats: Inhibition of the Proinflammatory Response Through the Th17 Immune Response.

Backgrund/Aims: To investigate the effects of activated α7 nicotinic acetylcholine receptor (α7nAChR) on postoperative cognitive dysfunction (POCD) and intestinal injury induced by cardiopulmonary bypass (CPB) and its relationship with the Th17 response in order to provide a theoretical basis for organ protection and targeted drug therapy during the perioperative period. METHODS: Sprague-Dawley rat models of CPB were established. Rat intestinal and brain injuries were observed after CPB using hematoxylin and eosin staining. Cell apoptosis was determined using terminal deoxynucleotidyl transferase dUTP nick end labeling. Inflammatory factors and markers of brain injury in rat serum were measured using enzyme-linked immunosorbent assay. The expression levels of Bcl-2, Bax, caspase-3, ZO-1, occludin, AQP4, RORγT, and α7nAchR were examined using western blotting. Transcription factor RORγT expression was determined using real-time fluorescent quantitative polymerase chain reaction. Th17 cells in the peripheral blood and spleen were determined using flow cytometry. α7nAchR knockout rats were established. The Th17 response in the peripheral blood and spleen of α7nAchR knockout rats was further verified using flow cytometry. RESULTS: CPB can induce POCD and intestinal injury in rats. α7nAchR activation markedly reduced intestinal injury, POCD, neuronal apoptosis, proinflammatory factor expression, and number of CD4+IL-17+ cells. α7nAchR knockout significantly increased serum D-lactic acid, FABP2, S-100ß, NSE, TNF-α, IL-6, and IL-17 secretion. The number of CD4+IL-17+ cells was also significantly increased. CONCLUSION: α7nAchR activation markedly ameliorates the intestinal injury and POCD induced by CPB. Inhibition of the Th17 immune response can reduce the proinflammatory response, which could provide a new method for clinical perioperative organ protection and targeted drug therapy.

Repeated exposure to sevoflurane impairs the learning and memory of older male rats.

AIMS: Critically ill old patients sometimes require repeated surgical interventions, and thus it is important to determine the influence of repeated exposure to anesthetics on learning and memory. Sevoflurane, a widely used inhalation anesthetic, has few neurological adverse effects and offers a rapid return to consciousness. But the long-term influence of sevoflurane exposure and the effect of repeated sevoflurane exposure on cognition have rarely been reported, and available studies are contradictory. MATERIALS AND METHODS: In the present study, the Morris water maze test was employed to investigate the long-term influence of single (4h) or repeated (2h daily for 5 consecutive days) exposure to 1.5% or 2.5% sevoflurane on the learning ability and memory of old (16-18months old) male rats. Testing was performed from 1day to 4weeks after the last exposure. In the hippocampus, brain derived neurotrophic factor (BDNF), NF-κB mRNA, and apoptosis rate were also examined to determine whether cellular biochemical changes related to cognition and memory occurred after single or repeated exposure to sevoflurane. KEY FINDINGS: Repeated exposure to 2.5% sevoflurane decreased hippocampal levels of BDNF protein, enhanced hippocampal levels of NF-κB mRNA, and increased the apoptosis rate of pyramidal cells. Single exposure to 2.5% sevoflurane, and repeated exposure to either 1.5% or 2.5% sevoflurane significantly compromised learning and memory of old male rats. SIGNIFICANCE: Repeated exposure to sevoflurane impaired the learning and memory of old male rats, an impairment that was accompanied by cognition-related biochemical changes in the hippocampus.

Minocycline attenuates sevoflurane-induced cell injury via activation of Nrf2.

Minocycline has been demonstrated to exert neuroprotective effects in various experimental models. In the present study, we investigated the mechanisms underlying the protective effects of minocycline on cell injury induced by the inhalation of the anesthetic, sevoflurane. In our in vivo experiments using rats, minocycline attenuated sevoflurane-induced neuronal degeneration and apoptosis in the rat hippocampus, and this effect was associated with the minocycline-mediated suppression of oxidative stress in the hippocampus. In in vitro experiments, minocycline inhibited sevoflurane-induced apoptosis and the production of reactive oxygen species (ROS) in H4 human neuroglioma cells. In addition, minocycline suppressed the sevoflurane-induced upregulation of interleukin (IL)-6 and the activation of the nuclear factor-κB (NF-κB) signaling pathway in H4 cells. Furthermore, we found that nuclear factor E2-related factor 2 (Nrf2), an activator of the stress response, was upregulated and activated upon sevoflurane treatment both in the rat hippocampus and in H4 cells. In addition, minocycline further augmented the upregulation and activation of Nrf2 when used in conjunction with sevoflurane. Moreover, the knockdown of Nrf2 in H4 cells by small interfering RNA (siRNA) diminished the cytoprotective effect of minocycline, and attenuated the inhibitory effect of minocycline on ROS production, IL-6 upregulation and the activation of the NF-κB signaling pathway. On the whole, our findings indicate that minocycline may exert protective effects against sevoflurane-induced cell injury via the Nrf2-modulated antioxidant response and the inhibition of the activation of the NF-κB signaling pathway.

Effects of Hydrogen-Rich Saline on Hepatectomy-Induced Postoperative Cognitive Dysfunction in Old Mice.

This study aims to investigate the protective effects and underlying mechanisms of hydrogen-rich saline on the cognitive functions of elder mice with partial hepatectomy-induced postoperative cognitive dysfunction (POCD). Ninety-six old male Kunming mice were randomly divided into 4 groups (n = 24 each): control group (group C), hydrogen-rich saline group (group H), POCD group (group P), and POCD + hydrogen-rich saline group (group PH). Cognitive function was subsequently assessed using Morris water-maze (MWM) test. TNF-α and IL-1ß levels were measured by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, along with NF-κB activity determined by ELISA. The morphology of hippocampal tissues were further observed by HE staining. Learning and memory abilities of mice were significantly impaired at day 10 and day 14 post-surgery, as partial hepatectomy significantly prolonged the escape latency, decreased time at the original platform quadrant and frequency of crossing in group P when compared to group C (p < 0.05). The surgery also increased the contents of TNF-α, IL-1ß, and NF-κB activity at all time points after surgery (p < 0.05). The introduction of hydrogen-rich saline (group PH) partially rescued spatial memory and learning as it shortened escape latency and increased time and crossing frequency of original platform compared to group P (p < 0.05). Moreover, such treatment also decreased TNF-α and IL-1ß levels and NF-κB activity (p < 0.05). In addition, cell necrosis in the hippocampus induced by hepatectomy was also rescued by hydrogen-rich saline. Hydrogen-rich saline can alleviate POCD via inhibiting NF-κB activity in the hippocampus and reducing inflammatory response.

Epidural Analgesia With Bupivacaine and Fentanyl Versus Ropivacaine and Fentanyl for Pain Relief in Labor: A Meta-Analysis.

The aim of this study was to compare the efficacy and safety of the combinational use of bupivacaine and fentanyl versus ropivacaine and fentanyl in epidural analgesia for labor. Multiple electronic databases were searched by using appropriate MeSH terms, and keywords for original research papers published before October 2014. Meta-analyses were based on mean differences between the groups as well as odds ratios. Statistical heterogeneity was tested by I² index. Fifteen randomized controlled trials, recruiting 2097 parturient mothers overall, were selected for the meta-analyses. Concentrations of the preparations used (weight/volume; mean and standard deviations) were bupivacaine 0.1023% ±â€Š0.0375%, ropivacaine 0.1095% ±â€Š0.042%, and fentanyl 0.00021% ±â€Š0.000089%. There were no statistically significant differences between both the combinations in the mean change in Visual Analog Score for pain during labor, incidence of instrumental or cesarean delivery, neonate Apgar score of <7, maternal satisfaction, duration of either first or second stage of labor, oxytocin use for induction, onset of analgesia, and duration of analgesia. Women who received ropivacaine and fentanyl had significantly lower incidence of motor blocks (odds ratio [95% CI] = 0.38 [0.30, 0.48] P < 0.00001, fixed effect and 0.38 [0.27, 0.54] P < 0.0001, random effects I² 30%) when compared with women who received bupivacaine and fentanyl. Incidence of side effects was similar for both the combinations. Analgesia with ropivacaine in combination with fentanyl at 0.1%:0.0002% ratio for labor pain relief is associated with lower incidence of motor blocks in comparison with analgesia with bupivacaine and fentanyl at similar ratio (0.1%: 0.0002%).

Anesthetic Propofol Attenuates Apoptosis, Aß Accumulation, and Inflammation Induced by Sevoflurane Through NF-κB Pathway in Human Neuroglioma Cells.

Anesthetics have been reported to promote Alzheimer's disease neuropathogenesis by inducing amyloid beta (Aß) protein accumulation and apoptosis. The aim of this study was to evaluate the effect of propofol on the apoptosis, Aß accumulation, and inflammation induced by sevoflurane in human neuroglioma cells. Human neuroglioma cells were treated with or without sevoflurane and then co-incubated with or without propofol. Cell apoptosis was evaluated by fluorescence-activated cell sorting analysis (FACS) using AV-PI kits, and data showed that apoptosis induced by sevoflurane was significantly attenuated by propofol treatment. In addition, with the reactive oxygen species (ROS) production measured by FACS after staining with dichloro-dihydrofluorescein diacetate, propofol could significantly reduce the production of ROS as well as the accumulation of Aß induced by sevoflurane assessed by enzyme-linked immuno sorbent assay (ELISA) analysis. On the other hand, the same treatment decreased the inflammation factor production of interleukin-6. Moreover, the level of nuclear factor-kappa B (NF-κB) was tested by Western blot and immunofluorescence assay. We found that the activation of NF-κB pathway was suppressed by propofol. The results suggest that propofol can effectively attenuate the apoptosis, Aß accumulation, and inflammation induced by sevoflurane in human neuroglioma cells through NF-κB signal pathway.

Minocycline alleviates sevoflurane-induced cognitive impairment in aged rats.

Minocycline has been implicated in the treatment for multiple diseases in the nervous system for its neuroprotective properties. However, the mechanism by which minocycline benefits postoperative anesthesia-induced cognitive dysfunction is still unclear. In this study, we introduced minocycline to a rat model of anesthetic-induced learning and memory impairment, to investigate the effects of minocycline on neuroinflammation, beta amyloid (Aß) deposition, and activation of nuclear factor κB (NF-κB) signaling pathway in the hippocampus. Aged rats were treated with sevoflurane to induce cognitive impairment with and without pre-administration of minocycline. The rats were then subjected to Morris water maze tests to evaluate their learning and memory performance. Subsequently, apoptosis in the hippocampal tissue was assessed with TUNEL assays. Furthermore, the levels of apoptosis-related proteins and pro-inflammatory cytokines, Aß responses, and activation of the NF-κB signaling pathway in the hippocampus were examined by Western blot analysis. Our results revealed that minocycline effectively alleviated sevoflurane-induced cognitive impairment in aged rats. Minocycline reduced sevoflurane-induced neuronal apoptosis and inflammation, as well as suppressed sevoflurane-induced Aß accumulation and activation of NF-κB signaling pathway in the hippocampus of aged rats. In conclusion, our findings indicate that minocycline is a potent agent to counteract sevoflurane-induced cognitive impairment and neurotoxicity in the nervous system of aged rats, which is likely to be mediated via NF-κB signaling pathway.

WITHDRAWN: Intrathecal siRNA against Cyr61 attenuates nociception in a rat model of inflammatory pain.

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[Determination of levodropropizine and its pharmacokinetics in human plasma using LC/MS/MS].

AIM: To develop a rapid and sensitive LC/MS/MS method for the analysis of levodropropizine in plasma and study the pharmacokinetics of levodropropizine in healthy Chinese volunteers. METHODS: Levodropropizine and zolmitriptan (internal standard, IS) were extracted from plasma samples and chromatographed on a C18 column and detected using a tandem mass spectrometer with a TurboIon Spray ionization interface. Quantitation was performed using multiple reaction monitoring (MRM) of the transitions of the m/z 237 --> m/z 120 for levodropropizine and m/z 288 --> m/z 58 for the IS. RESULTS: The limit of quantification of the method for levodropropizine was 0.25 microg x L(-1). The assay was linear over the concentration range from 0.25 to 500.0 microg x L(-1) and intra- and inter-day precision over this range were < 11.4% with good accuracy. CONCLUSION: The method is shown to be accurate, and suitable for clinical pharmacokinetic study of levodropropizine.