Intrathecal anesthesia prevents ventricular arrhythmias in rats with myocardial ischemia/reperfusion.

INTRODUCTION: Ventricular arrhythmia is commonly provoked by acute cardiac ischemia through sympathetic exaggeration and is often resistant to antiarrhythmic therapies. Thoracic epidural anesthesia has been reported to terminate fatal ventricular arrhythmia; however, its underlying mechanism is unknown. METHODS: Rats were randomly divided into four groups: sham, sham plus bupivacaine, ischemia/reperfusion (IR), and IR plus bupivacaine groups. Bupivacaine (1 mg/mL, 0.05 mL/100 g body weight) was injected intrathecally into the L5-L6 intervertebral space prior to establishing a myocardial ischemia/reperfusion rat model. Thereafter, cardiac arrhythmia, cardiac function, myocardial injury, and electrical activities of the heart and spinal cord were evaluated. RESULTS: Intrathecal bupivacaine inhibited spinal neural activity, improved heart rate variability, reduced ventricular arrhythmia score, and ameliorated cardiac dysfunction in IR rats. Furthermore, intrathecal bupivacaine attenuated cardiac injury and myocardial apoptosis and regulated cardiomyocyte autophagy and connexin-43 distribution during myocardial IR. CONCLUSION: Our results indicate that intrathecal bupivacaine blunts spinal neural activity to prevent cardiac arrhythmia and dysfunction induced by IR and that this antiarrhythmic activity may be associated with regulation of autonomic balance, myocardial apoptosis and autophagy, and cardiac gap junction function.

Ethanol depresses neurons in the lateral parabrachial nucleus by potentiating pre- and postsynaptic GABAA receptors.

As a psychoactive substance, ethanol is widely used in people's life. However, the neuronal mechanisms underlying its sedative effect remain unclear. In this study, we investigated the effects of ethanol on the lateral parabrachial nucleus (LPB), which is a novel component related to sedation. Coronal brain slices (280 µm thick) containing the LPB were prepared from C57BL/6J mice. The spontaneous firing and membrane potential of LPB neurons, and GABAergic transmission onto these neurons were recorded using whole-cell patch-clamp recordings. Drugs were applied through superfusion. The LPB neurons exhibited a regular spontaneous discharge at a rate of 1.5-3 Hz without burst firing. Brief superfusion of ethanol (30, 60, and 120 mM) concentration-dependently and reversibly suppressed the spontaneous firing of the neurons in LPB. In addition, when synaptic transmission was blocked by tetrodotoxin (TTX) (1 µM), ethanol (120 mM) caused hyperpolarization of the membrane potential. Furthermore, superfusion of ethanol markedly increased the frequency and amplitude of spontaneous and miniature inhibitory postsynaptic currents, which were abolished in the presence of the GABAA receptor (GABAA-R) antagonist picrotoxin (100 µM). In addition, the inhibitory effect of ethanol on the firing rate of LPB neurons was completely abolished by picrotoxin. Ethanol inhibits the excitability of LPB neurons in mouse slices, possibly via potentiating GABAergic transmission onto the neurons at pre- and postsynaptic sites.

Intestinal microbiota analysis and network pharmacology reveal the mechanism by which Lianhua Qingwen capsule improves the immune function of mice infected with influenza A virus.

Objective: Lianhua Qingwen capsule (LHQW) can attenuate lung injury caused by influenza virus infection. However, it is unclear whether the intestinal microbiota plays a role in LHQW activity in ameliorating viral infectious pneumonia. This study aimed to investigate the role of intestinal microbiota in LHQW activity in ameliorating viral infectious pneumonia and its possible mechanisms. Research design and methods: A mouse model of influenza A viral pneumonia was established by intranasal administration in BALB/c mice. Detection of influenza virus in the lungs, pathological examination of the lungs and small intestine, and biochemical detection of inflammatory indices were performed. The effects of LHQW on intestinal microbiota were evaluated by 16S rRNA gene sequencing. The key components and targets of LHQW were screened via network pharmacology and verified through molecular docking, molecular dynamics simulation, and free binding energy calculations. Results: Body weight decreased, inflammatory factor levels were disturbed, and the lung and intestinal mucosal barriers were significantly injured in the infected group. The alpha diversity of the intestinal microbiota decreased, and the abundance of Bacteroidetes, Muribaculaceae_unclassified, and Streptococcus decreased significantly. LHQW treatment reduced the viral load in the lungs, rescued body weight and survival, alleviated lung and intestinal mucosal barrier injury, reversed the reduction in the intestinal microbiota alpha diversity, and significantly increased the abundance of Bacteroidetes and Muribaculaceae. Network pharmacological analysis showed that six active herbal medicinal compounds from LHQW could regulate the intestinal microbiota and inhibit the immune-inflammatory response through the Toll-like receptor (TLR) and nuclear factor-κB (NF-κB) signalling pathways in the lungs. Conclusion: These results suggest that LHQW is effective for treating influenza A virus infectious pneumonia, and the mechanism is associated with the regulation of the TLR4/NF-κB signalling pathway in the lungs by restoring intestinal microbiota and repairing the intestinal wall.

Analysis of the Molecular Mechanism of Punicalagin in the Treatment of Alzheimer's Disease by Computer-Aided Drug Research Technology.

The objective of this work is to explore the effect and potential mechanism of Punicalagin (Pun) in managing Alzheimer's disease (AD) based on computer-aided drug technology. The following methods were used: the intersection genes of Pun and AD were retrieved from the database and subjected to PPI analysis, GO, and KEGG enrichment analyses. Preliminary verification was performed by molecular docking, molecular dynamics (MD) simulation, and combined free energy calculation. The motor coordination and balance ability, anxiety degree, spatial learning, and memory ability of mice were measured by a rotating rod fatigue instrument, elevated cross maze, and Y maze, respectively. The amyloid ß protein (Aß) in the hippocampus was examined by immunohistochemistry, and the phosphorylation of serine at position 404 of the tau protein (Tau-pS404) was examined by western blot in the mouse brain. The PPI network of Pun showed that the intersection genes were closely related and enriched in muscle cell proliferation and the response to lipopolysaccharide. Results of molecular docking, MD simulations, and MM-GBSA demonstrated that Pun was closely bound to the target protein. Pun could improve the cognitive function of AD mice, as well as reduce Aß1-42 deposition and Tau phosphorylation in the brain (P < 0.05, P < 0.01). It can be concluded that Pun holds great promise in improving the cognitive function of AD mice. Mechanistically, Pun potentially acts on ALB, AKT1, SRC, EGFR, CASP3, and IGF-1 targets and mediates proteoglycan, lipid, and atherosclerosis in cancer, so as to reduce the accumulation of neurotoxic proteins in the brain.

Histone acetyltransferase 1 upregulates androgen receptor expression to modulate CRPC cell resistance to enzalutamide.

Castration-resistant prostate cancer (CRPC) is the latest stage of PCa, and there is almost no effective treatment available for the patients with CRPC when next-generation androgen deprivation therapy drugs, such as enzalutamide (ENZ), fail. The androgen receptor (AR) plays key roles in PCa and CRPC progression and drug resistance. Histone acetyltransferase 1 (HAT1) has recently been reported to be highly expressed in some tumors, such as lung carcinoma. However, what relationship between the AR and HAT1, and whether or how HAT1 plays roles in CRPC progression and drug resistance remain elusive. In the present study, we found that HAT1 is highly expressed in PCa cells, and the overexpression of HAT1 is linked with CRPC cell proliferation. Moreover, the HAT1 expression is positively correlated with the expression of AR, including both AR-FL (full-length) and AR-V7 (variant 7), which is mainly mediated by a bromodomain containing protein 4 (BRD4) -mediated pathway. Furthermore, knockdown of HAT1 can re-sensitize the response of CRPC cells to ENZ treatment in cells and mouse models. In addition, ascorbate was observed to decrease AR expression through downregulation of HAT1 expression. Collectively, our findings reveal a novel AR signaling regulation pathway in PCa and CRPC and suggest that HAT1 serves as a critical oncoprotein and an ideal target for the treatment of ENZ resistance in CRPC patients.

Sevoflurane depresses neurons in the medial parabrachial nucleus by potentiating postsynaptic GABAA receptors and background potassium channels.

Despite persistent clinical use for over 170 years, the neuronal mechanisms by which general anesthetics produce hypnosis remain unclear. Previous studies suggest that anesthetics exert hypnotic effects by acting on endogenous arousal circuits. Recently, it has been shown that the medial parabrachial nucleus (MPB) is a novel wake-promoting component in the dorsolateral pons. However, it is not known whether and how the MPB contributes to anesthetic-induced hypnosis. Here, we investigated the action of sevoflurane, a widely used volatile anesthetic agent that best represents the drug class of halogenated ethers, on MPB neurons in mice. Using in vivo fiber photometry, we found that the population activities of MPB neurons were inhibited during sevoflurane-induced loss of consciousness. Using in vitro whole-cell patch-clamp recordings, we revealed that sevoflurane suppressed the firing rate of MPB neurons in concentration-dependent and reversible manners. At a concentration equal to MAC of hypnosis, sevoflurane potentiated synaptic GABAA receptors (GABAA-Rs), and the inhibitory effect of sevoflurane on the firing rate of MPB neurons was completely abolished by picrotoxin, which is a selective GABAA-R antagonist. At a concentration equivalent to MAC of immobility, sevoflurane directly hyperpolarized MPB neurons and induced a significant decrease in membrane input resistance by increasing a basal potassium conductance. Moreover, pharmacological blockade of GABAA-Rs in the MPB prolongs induction and shortens emergence under sevoflurane inhalation at MAC of hypnosis. These results indicate that sevoflurane inhibits MPB neurons through postsynaptic GABAA-Rs and background potassium channels, which contributes to sevoflurane-induced hypnosis.

High cortical delta power correlates with aggravated allodynia by activating anterior cingulate cortex GABAergic neurons in neuropathic pain mice.

Patients with chronic pain often report being sensitive to pain at night before falling asleep, a time when the synchronization of cortical activity is initiated. However, how cortical activity relates to pain sensitivity is still unclear. Because sleep is characterized by enhanced cortical delta power, we hypothesized that enhanced cortical delta power may be an indicator of intensified pain. To test this hypothesis, we used pain thresholds tests, EEG/electromyogram recordings, c-Fos staining, and chemogenetic and pharmacological techniques in mice. We found that sleep deprivation or pharmacologic enhancement of EEG delta power by reserpine and scopolamine dramatically decreased mechanical pain thresholds, but not thermal withdrawal latency, in a partial sciatic nerve ligation model of neuropathic pain mice. On the contrary, suppression of EEG delta power using a wake-promoting agent modafinil significantly attenuated mechanical allodynia. Moreover, when EEG delta power was enhanced, c-Fos expression decreased in most regions of the cortex, except the anterior cingulate cortex (ACC), where c-Fos was increased in the somatostatin- and parvalbumin-positive GABAergic neurons. Chemogenetic activation of GABAergic neurons in ACC enhanced EEG delta power and lowered mechanical pain thresholds simultaneously in naive mice. However, chemogenetic inhibition of ACC GABAergic neurons could not block mechanical allodynia. These results provided compelling evidence that elevated EEG delta power is accompanied with aggravated neuropathic pain, whereas decreased delta power attenuated it, suggesting that enhanced delta power can be a specific marker of rising chronic neuropathic pain and that wake-promoting compounds could be used as analgesics in the clinic.

Combined effects of cigarette smoking, alcohol drinking and eNOS Glu298Asp polymorphism on blood pressure in Chinese male hypertensive subjects.

INTRODUCTION: Genetic factors and lifestyle exposures, as well as their combinations, play important roles in the development of hypertension. We examined whether cigarette smoking, alcohol drinking and the Glu298Asp polymorphism of the endothelial nitric oxide synthase (eNOS) gene generate combined effects on blood pressure (BP) in hypertensive subjects. METHODS: A total of 342 essential hypertensive subjects were recruited from Susong community in Anhui province, China, from July 2017 to January 2018, and the plasma biochemical parameters and the genotype on Glu298Asp polymorphism were determined. RESULTS: There were no gender differences in the distributions of alleles and genotypes in hypertensive subjects. The proportions of cigarette smoking and alcohol drinking in male hypertensive subjects were remarkably higher than those in the females (p<0.001). The systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels of mutant genotypes (Glu/Asp and Asp/Asp) were significantly higher than those of wild genotype (Glu/Glu) (p=0.013 and 0.026, respectively) in male hypertensive subjects. Moreover, the SBP and DBP levels of the mutant genotype were remarkably higher than those of wild genotype in both cigarette smoking and alcohol drinking male hypertensive subjects (p=0.034 and 0.043, respectively). CONCLUSIONS: Cigarette smoking, alcohol drinking and the Glu298Asp polymorphism of the eNOS gene generate combined effects that increase the susceptibility of the mutant genotype to BP in Chinese male hypertensive subjects.

Ethanol Induces Sedation and Hypnosis via Inhibiting Histamine Release in Mice.

Ethanol is one of the most highly abused psychoactive compounds worldwide and induces sedation and hypnosis. The histaminergic system is involved in the regulation of sleep/wake function and is a crucial player in promoting wakefulness. To explore the role and mechanism of the histaminergic system in ethanol-induced sedation and hypnosis, we recorded locomotor activity (LMA) and electroencephalography (EEG)/electromyography (EMG) in mice using an infrared ray passive sensor recording system and an EEG/EMG recording system, respectively, after administration of ethanol. In vivo microdialysis coupled with high performance liquid chromatography and fluorometry technology were used to detect histamine release in the mouse frontal cortex (FrCx). The results revealed that ethanol significantly suppressed LMA of histamine receptor 1 (H1R)-knockout (KO) and wild-type (WT) mice in the range of 1.5-2.5 g/kg, but suppression was remarkably stronger in WT mice than in H1R-KO mice. At 2.0 and 2.5 g/kg, ethanol remarkably increased non-rapid eye movement sleep and decreased wakefulness, respectively. Neurochemistry experimental data indicated that ethanol inhibited histamine release in the FrCx in a dose-dependent manner. These findings suggest that ethanol induces sedation and hypnosis via inhibiting histamine release in mice.

Ephrin-B2 inhibits Aß25-35-induced apoptosis by alleviating endoplasmic reticulum stress and promoting autophagy in HT22 cells.

Previous studies have shown that Erythropoietin-producing hepatocellular carcinoma receptor B2 (EphB2) inhibited Aß-induced neuron apoptosis and improved cognition in AD mice, but the role of which ligand Ephrin B2 (Ephrin-B2, efnB2) is not clear. The aim of this study was to investigate the effect of the efnB2-activated Eph/efn forward signaling pathway on Aß-induced HT22 hippocampal cell apoptosis using recombination mouse Ephrin B2-Fc chimera protein (efnB2-Fc). We found that non-toxic concentrations of efnB2-Fc decreased the release of lactate dehydrogenase (LDH) in HT22 cells and reduced cell apoptosis in a dose-dependent manner. Further studies revealed that efnB2-Fc alleviated Aß-induced ER stress and decreased the expression of ER-stress-related transcriptional factor C/EBP homologous protein (CHOP), binding immunoglobulin protein (Bip) and phosphorylated eukaryotic translation initiation factor 2 subunit α (p-eIF2α) in HT22 cells. These effects of efnB2-Fc were related to the inhibition of Akt/mTOR signal transduction, an increase in the level of microtubule-associated protein 1 light chain 3 Ⅱ (LC3 Ⅱ), and the activation of the autophagy pathway. Our results indicate that the efnB2-mediated forward signaling pathway may activate the autophagy pathway to alleviate the Aß-induced ER stress and apoptosis in the HT22 cell.

Activation of Parabrachial Nucleus Glutamatergic Neurons Accelerates Reanimation from Sevoflurane Anesthesia in Mice.

BACKGROUND: The parabrachial nucleus (PBN), which is a brainstem region containing glutamatergic neurons, is a key arousal nucleus. Injuries to the area often prevent patient reanimation. Some studies suggest that brain regions that control arousal and reanimation are a key part of the anesthesia recovery. Therefore, we hypothesize that the PBN may be involved in regulating emergence from anesthesia. METHODS: We investigated the effects of specific activation or inhibition of PBN glutamatergic neurons on sevoflurane general anesthesia using the chemogenetic "designer receptors exclusively activated by designer drugs" approach. Optogenetic methods combined with polysomnographic recordings were used to explore the effects of transient activation of PBN glutamatergic neuron on sevoflurane anesthesia. Immunohistochemical techniques are employed to reveal the mechanism by which PBN regulated sevoflurane anesthesia. RESULTS: Chemogenetic activation of PBN glutamatergic neurons by intraperitoneal injections of clozapine-N-oxide decreased emergence time (mean ± SD, control vs. clozapine-N-oxide, 55 ± 24 vs. 15 ± 9 s, P = 0.0002) caused by sevoflurane inhalation and prolonged induction time (70 ± 15 vs. 109 ± 38 s, n = 9, P = 0.012) as well as the ED50 of sevoflurane (1.48 vs. 1.60%, P = 0.0002), which was characterized by a rightward shift of the loss of righting reflex cumulative curve. In contrast, chemogenetic inhibition of PBN glutamatergic neurons slightly increased emergence time (56 ± 26 vs. 87 ± 26 s, n = 8, P = 0.034). Moreover, instantaneous activation of PBN glutamatergic neurons expressing channelrhodopsin-2 during steady-state general anesthesia with sevoflurane produced electroencephalogram evidence of cortical arousal. Immunohistochemical experiments showed that activation of PBN induced excitation of cortical and subcortical arousal nuclei during sevoflurane anesthesia. CONCLUSIONS: Activation of PBN glutamatergic neurons is helpful to accelerate the transition from general anesthesia to an arousal state, which may provide a new strategy in shortening the recovery time after sevoflurane anesthesia.

A positive association between the human tissue kallikerin gene A2233C polymorphism and blood pressure response to benazepril.

BACKGROUND: It is generally believed that essential hypertension is influenced by both genetic and environmental factors, as well as their interactions. Tissue kallikrein encoded by the tissue kallikrein gene (KLK1) is a key serine proteinase of kallikrein-kinin system, which is capable of generating potent vasactive peptides, kinins, by selective cleavage of the kininogen substrate. It was reported that the A2233 → C polymorphism in KLK1 gene is associated with essential hypertension. The aim of this study was to examine whether the molecular variations of KLK1 play role in determining the therapeutic response to benazepril, an ACE inhibitor. METHODS: A total of 331 hypertensive individuals were recruited and treated with benazepril for 15 days. A variant impact of KLK1 A2233C was revealed. Chi-square analysis showed that the hypertensive subjects with the mutation genotype (AC + CC) had a higher proportion in systolic blood pressure (SBP, 88.1% vs. 79.0%, χ2 = 4.141, p = 0.042) and diastolic blood pressure (DBP, 91.1% vs. 79.2%, χ2 = 9.336, p = 0.002), respectively, to benazepril medication in good responders than in poor responders. Logistic regression analysis indicated that the hypertensive subjects with AC + CC genotype were more sensitive to the benazepril therapy in SBP (OR=1.97, 95% CI: 1.02-3.80, p = 0.044) and DBP (OR = 1.91, 95% CI: 2.69-5.16, p = 0.003), as compared with those hypertensive subjects with AA genotype. CONCLUSION: Our findings suggest that the A2233C polymorphism of KLK1 may be a marker of evaluation of hypertensive subjects' responses to angiotensin I converting enzyme inhibitors benazepril.

Ethanol inhibits histaminergic neurons in mouse tuberomammillary nucleus slices via potentiating GABAergic transmission onto the neurons at both pre- and postsynaptic sites.

AIM: Ethanol, one of the most frequently used and abused substances in our society, has a profound impact on sedation. However, the neuronal mechanisms underlying its sedative effect remain unclear. In this study, we investigated the effects of ethanol on histaminergic neurons in the tuberomammillary nucleus (TMN), a brain region thought to be critical for wakefulness. METHODS: Coronal brain slices (250 µm thick) containing the TMN were prepared from GAD67-GFP knock-in mice. GAD67-GFP was used to identify histaminergic neurons in the TMN. The spontaneous firing and membrane potential of histaminergic neurons, and GABAergic transmission onto these neurons were recorded using whole-cell patch-clamp recordings. Drugs were applied through superfusion. RESULTS: Histaminergic and GAD67-expressing neurons in the TMN of GAD67-GFP mice were highly co-localized. TMN GFP-positive neurons exhibited a regular spontaneous discharge at a rate of 2-4 Hz without burst firing. Brief superfusion of ethanol (64, 190, and 560 mmol/L) dose-dependently and reversibly suppressed the spontaneous firing of the neurons in the TMN; when synaptic transmission was blocked by tetrodotoxin (1 µmol/L), ethanol caused hyperpolarization of the membrane potential. Furthermore, superfusion of ethanol markedly increased the frequency and amplitude of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs), which were abolished in the presence of the GABAA receptor antagonist bicuculline (20 µmol/L). Finally, ethanol-mediated enhancement of sIPSCs and mIPSCs was significantly attenuated when the slices were pretreated with the GABAB agonist baclofen (30 µmol/L). CONCLUSION: Ethanol inhibits the excitability of histaminergic neurons in mouse TMN slices, possibly via potentiating GABAergic transmission onto the neurons at both pre- and postsynaptic sites.

Specific MAPK inhibitors prevent hyperglycemia-induced renal diseases in type 1 diabetic mouse model.

Mitogen-activated protein kinase (MAPK) and renin-angiotensin system (RAS) play critical roles in the process of renal diseases, but their interaction has not been comprehensively discussed. In the present studies, we investigated the renoprotective effects of MPAK inhibitors on renal diseases in type 1 diabetic mouse model, and clarify the crosstalk among MAPK signaling. Type 1 diabetic mouse model was established in male C57BL/6 J mice, and treated with or without 10 mg/kg MAPK blockers, including ERK inhibitor PD98059, p38 inhibitor SB203850, and JNK inhibitor SP600125 for four weeks. Hyperglycemia induced renal injuries, but treating them with MAPK inhibitors significantly decreased glomerular volume and glycogen in renal tissues. Although slightly changed body weight and fasting blood glucose levels, MAPK inhibitors attenuated blood urea nitrogen, urea protein, and microalbuminuria. Administration also reduced the diabetes-induced RAS activation, including angiotensin II converting enzyme (c) and Ang II, which contributed to its renal protective effects in the diabetic mice. In addition, the anti-RAS of MAPK inhibitor treatment markedly reduced gene expression of tumor necrosis factor-α, interleukin-6, and inducible nitric oxide synthase, fibrotic accumulation, and transforming growth factor-ß1 levels in renal tissues. Furthermore, chemical inhibitors and genetic siRNA results identified the crosstalk among the three MAPK signaling, and proved JNK signaling played a critical role in MAPK-mediated ACE pathway in hyperglycemia state. Collectively, these results support the therapeutic effects of MAPK-specific inhibitors, especially JNK inactivation, on hyperglycemia-induced renal damages.

[Advances in the study of the effect of basal forebrain on sleep-wake regulation].

The basal forebrain(BF) is known to participate in the control of motion, attention, learning and memory, and it also plays a key role in sleep-wake regulation. Although there is a strong heterogeneity among neurons in the BF, the main types are cholinergic, gamma-aminobutyric acid (GABAergic) and glutamatergic neurons. This review provided the research progress in the regulation of sleep-wakefulness behavior by the 3 neurons in the BF. The cholinergic neurons play roles in activation of cortex and promote phase transition between sleep and wakefulness. The cortical projecting GABAergic neurons, which accept the projections from the adjacent cholinergic and glutamatergic neurons, contribute to awakening and the maintenance of normal wakefulness. The GABAergic interneurons may promote sleepiness by inhibiting the wake-active neurons which excite the cortical neurons. The glutamatergic neurons regulate sleep and wakefulness by interacting with neighbor cholinergic and cortical projecting GABAergic neurons or through the direct projection to the cortex as well.

Antinociceptive and hypnotic activities of pregabalin in a neuropathic pain-like model in mice.

To evaluate the antinociceptive and hypnotic effects of pregabalin, we established a neuropathic pain-like model in mice using partial sciatic nerve ligation (PSNL), and examined thermal hyperalgesia, mechanical allodynia, electroencephalogram, rota-rod testing, and c-Fos expression in the anterior cingulate cortex. Gabapentin was used as a reference drug in the study. Pregabalin administered i.g. at 12.5 and 25mg/kg prolonged the duration of thermal latencies by 1.4- and 1.6-fold and increased the mechanical threshold by 2.2- and 3.1-fold 3h after administration, respectively, but did not affect motor coordination in PSNL mice, compared with vehicle control. Pregabalin (12.5 and 25mg/kg) given at 6:30 increased the amount of non-rapid eye movement sleep in a 4-h period by 1.3- and 1.4-fold, respectively, in PSNL mice. However, pregabalin (25mg/kg) given at 20:30 did not alter the sleep pattern in normal mice. Immunohistochemical study showed that PSNL increased c-Fos expression in the neurons of anterior cingulate cortex by 2.1-fold, which could be reversed by pregabalin. These results indicate that pregabalin is an effective treatment for both neuropathic pain and sleep disturbance in PSNL mice.

Comparison the effects of pressurized salt ice packs with water ice packs on patients following total knee arthroplasty.

The aim of this study was to estimate the effects of pressurized salt ice packs (PIP) with water ice packs (WIP) which are used to relieve pain and decrease swelling on patients following total knee arthroplasty (TKA). Sixty-nine patients undergoing primary unilateral TKA were randomly divided into two groups (PIP group and WIP group). We used a visual analog scale (VAS) to score knee pain and the score was recorded. The knee bilateral girth, the slipping times of the ice pack, and the times of wound dressing or bed moist were recorded during cryotherapy. The scores of pain between the two groups were significant difference in 12 h, 24 h, 48 h and 72 h after TKA (P < 0.05). No significant difference was found for the girth measurements of the operative knee on the two levels in 12 h, 24 h and 72 h, respectively. However, there was statistically difference for girth measurements between the two groups in 48 h after TKA (P < 0.05). PIP is a cheap, safe and simple method, which is more effective than WIP on reducing pain and swelling degree of patients. Thus, PIP is recommended in clinical nursing work.

[Peoniflorin activates Nrf2/ARE pathway to alleviate the Abeta(1-42)-induced hippocampal neuron injury in rats].

This study was to investigate the effect of peoniflorin on the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream signal molecules in the hippocampus of Alzheimer's disease (AD) rats for exploring the mechanism of peoniflorin protecting hippocampal neurons. AD model rats were established by bilateral intrahippocampal injection of beta-amyloid(1-42) (Abeta(1-42)) and divided randomly into 3 groups: AD model group, peoniflorin low-dose (15 mg x kg(-1)) group and peoniflorin high-dose (30 mg x kg(-1)) group. The vehicle control rats were given bilateral intrahippocampal injection of solvent with the same volume. After peoniflorin or saline was administered (ip) once daily for 14 days, the hippocampuses of all animals were taken out for measuring the expressions of Nrf2, heme oxygenase-1 (HO-1) and gamma-glutamylcysteine synthethase (gamma-GCS) mRNA by reverse transcription PCR, determining the contents of glutathione (GSH), malondialdehyde (MDA) and carbonyl protein (CP) using colorimetric method, and for assaying the expressions of neuronal apoptosis inhibitory protein (NAIP) and Caspase-3 by immunohistochemical staining method. The results showed that peoniflorin markedly increased the expressions of Nrf2, HO-1 and gamma-GCS mRNA, enhanced the level of GSH and decreased the contents of MDA and CP in the hippocampus, as compared with the model group. Peoniflorin also improved the NAIP expression and reduced the Caspase-3 expression in the hippocampus neurons. In conclusion, peoniflorin protects against the Abeta(1-42)-mediated oxidative stress and hippocampal neuron injury in AD rats by activating the Nrf2/ARE pathway.

[Pharmacokinetics of tramadol hydrochloride in the extracellular fluid of mouse frontal cortex studied by in vivo microdialysis].

The paper aims to explore the studying method for the pharmacokinetics of drugs in target organs, the pharmacokinetic process of tramadol hydrochloride in the extracellular fluid of frontal cortex (FrCx) of mice was investigated. Six male mice (Kunming strain) were anaesthetized (urethane, 1.8 g x kg(-1), ip) and secured on a stereotaxic frame. A microdialysis probe was implanted into the FrCx and perfused with artificial cerebrospinal fluid at a flow rate of 2 microL x min(-1). One hour later, mice were administrated (ip) with tramadol hydrochloride (50 mg x kg(-1)) and dialysates were collected continuously at 12-min intervals (24 microL each) for 6 h. The tramadol concentration in dialysates was determined by HPLC-Ultraviolet detection method, and the concentration-time curve and pharmacokinetic parameters of tramadol were calculated with DAS software. The results showed that the pharmacokinetic process of tramadol in the FrCx extracellular fluid of mice was fitted to a two-compartment open model, and the main pharmacokinetic parameters t1/2alpha, t1/2beta, t(max), C(max) and AUC(0-infinity) were (0.27 +/- 0.05) h, (2.72 +/- 0.24) h, (0.50 +/- 0.10) h, (2 110.37 +/- 291.22) microg x L(-1) and (4 474.51 +/- 441.79) microg x L(-1) x h, respectively. In conclusion, a studying method for pharmacokinetics of drugs in the target organ is established, which is simple and feasible. Tramadol hydrochloride shows a two-compartment model in the extracellular fluid of the mouse FrCx, and the distribution- and elimination half-life are 0.5 h and 2.7 h, respectively.

[Protective effect of paeonol on neurotoxicity induced by Abeta1-42 and underlying mechanisms].

OBJECTIVE: To investigate the protective effect of paeonol on amyloid beta1-42 (Abeta1-42)-induced neurotoxicity and its mechanism. METHOD: Hippocampal neurons of well-grown newborn SD rats and differentiated SH-SY5Y cell lines were cultured with various concentrations of paeonol (1, 5, 10 micromol x L(-1), respectively) for 6 hours and then incubated with Abeta1-42 oligomer (30 micromol x L(-1)) for 24 hours and 48 hours, respectively. The neuron apoptosis was observed by Heochst33258. Annexin V/PI double stain flow cytometry assay was adopted for determining SH-SY5Y cell apoptosis rate. And the expression of BDNF and Bcl-2 mRNA was detected by RT-PCR. RESULT: Compared with the model group, various concentrations of paeonol (1, 5, 10 micromol x L(-1)) significantly reduced the hippocampal neurons karyopycnosis, decreased the rate of SH-SY5Y cell apoptosis to 22.4%, 18.1% and 16.4%, respectively, and improved the expressions of BDNF and Bcl-2 mRNA. CONCLUSION: Paeonol relieves Abeta1-42 oligomer-induced neuron injury by increasing BDNF and Bcl-2 expressions.