113886 articles - 10.09.10
1: J Pharmacol Exp Ther. 2010 Sep 8; [Epub ahead of print]
McCracken ML, Borghese CM, Trudell JR, Harris RA.
1 The University of Texas at Austin;
Alcohols and inhaled anesthetics enhance the function of GABA(A) receptors containing alpha, beta, and gamma subunits. Molecular analysis has focused on the role of the alpha subunits, however there is evidence that the beta subunits may also be important. The goal of our study was to determine whether N265, which is homologous to the site implicated in the alpha subunit (S270), contributes to an alcohol and volatile anesthetic binding site in the GABA(A) receptor beta(2) subunit. We substituted cysteine for N265 and exposed the mutant to the sulfhydryl-specific reagent octyl methanethiosulfonate (OMTS). We used two-electrode voltage clamp electrophysiology in Xenopus oocytes and found that, following OMTS application, GABA-induced currents were irreversibly potentiated in mutant alpha(1)beta(2)(N265C)gamma(2S) receptors (but not alpha(1)beta(2)(I264C)gamma(2S)), presumably due to the covalent linking of octanethiol to the thiol group in the substituted cysteine. Notably, this effect was blocked when OMTS was applied in the presence of octanol. We found that potentiation by butanol, octanol, or isoflurane in the N265C mutant was nearly abolished following the application of OMTS, suggesting that an alcohol and volatile anesthetic binding site at position 265 of the beta(2) subunit was irreversibly occupied by octanethiol and consequently prevented butanol or isoflurane from binding and producing their effects. OMTS did not affect modulation or direct activation by pentobarbital, but there was a partial reduction of allosteric modulation by flunitrazepam and alphaxalone in mutant alpha(1)beta(2)(N265C)gamma(2S) receptors after OMTS was applied. Our findings provide evidence that N265 may contribute to an alcohol and anesthetic binding site.
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PMID: 20826568 [PubMed - as supplied by publisher]2: J Pharmacol Exp Ther. 2010 Sep 8; [Epub ahead of print]
Pini A, Shemesh R, Samuel CS, Bathgate RA, Zauberman A, Hermesh C, Wool A, Bani D, Rotman G.
1 Department of Anatomy, Histology & Forensic Medicine, University of Florence, Italy.;
Pulmonary fibrosis is a progressive and lethal lung disease characterized by accumulation of extracellular matrix and loss of pulmonary function. No cure exists for this pathologic condition, and current treatments often fail to slow its progression or relieve its symptoms. Relaxin was previously shown to induce a matrix degrading phenotype in human lung fibroblasts in vitro and to inhibit pulmonary fibrosis in vivo. A novel peptide which targets the relaxin RXFP1/LGR7 receptor was recently identified using our computational platform designed to predict novel G protein-coupled receptor peptide agonists. In this study, we examined the anti-fibrotic properties of this novel peptide, designated CGEN25009, in human cell based assays and in a murine model of bleomycin-induced pulmonary fibrosis. Similarly to relaxin, CGEN25009 was found to have an inhibitory effect on TGF-beta1-induced collagen deposition in human dermal fibroblasts, while enhancing MMP-2 expression. The peptide's biological activity was also similar to relaxin in generating cellular stimulation of cAMP, cGMP and NO in the THP-1 human cell line. In vivo, 2-week administration of CGEN25009 in a preventive or therapeutic mode, i.e. concurrently with or 7 days after bleomycin treatment, respectively, caused a significant reduction of lung inflammation and injury, and ameliorated adverse airway remodeling and peri-bronchial fibrosis. The results of this study indicate that CGEN25009 displays anti-fibrotic and anti-inflammatory properties and may offer a new therapeutic option for the treatment of pulmonary fibrosis.
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PMID: 20826567 [PubMed - as supplied by publisher]3: J Pharmacol Exp Ther. 2010 Sep 8; [Epub ahead of print]
Ding Y, Gao ZG, Jacobson KA, Suffredini A.
1 National Institutes of Health, Clinical Center, Critical Care Medicine Department;
The purinergic nucleotide adenosine 5'-triphosphate (ATP) is released from stressed cells and is implicated in vascular inflammation. Glucocorticoids are essential to stress responses and are used therapeutically yet little information describes the effects of glucocorticoids on ATP-induced inflammation. In a human microvascular endothelial cell line (HMEC-1), extracellular ATP induced IL-6 secretion in a dose- and time- dependent manner. When cells were pretreated with dexamethasone, a prototypic glucocorticoid, ATP-induced IL-6 production was enhanced in a time- and dose- dependent manner. Mifepristone, a glucocorticoid receptor antagonist blocked these effects. ATP-induced IL-6 release was significantly inhibited by a phospholipase C inhibitor (U73122) (63.2 +/- 3 %, p < 0.001) and abolished by a p38 mitogen activated protein kinase inhibitor (SB203580) (88 +/- 1 %, p <0.001). Cells treated with dexamethasone induced mRNA expression of the purinergic P2Y(2) receptor (P2Y2R) 1.8 +/-; 0.1 fold and when stimulated with ATP, enhanced Ca2+ release and augmented IL-6 mRNA expression. Silencing of the P2Y(2)R by its siRNA decreased ATP-induced IL-6 production by 81 +/- 1 % (p <0.001). Dexamethasone enhanced the transcription rate of P2Y(2)R mRNA and induced a dose-related increase in the activity of the P2Y(2)R promoter. Further, dexamethasone enhanced ATP induction of adhesion molecule transcription and augmented the release of IL-8. Dexamethasone leads to an unanticipated enhancement of endothelial inflammatory mediator production by extracellular ATP via a P2Y(2)R dependent mechanism. These data define a novel positive feedback loop of glucocorticoids and ATP-induced endothelial inflammation.
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PMID: 20826566 [PubMed - as supplied by publisher]4: J Pharmacol Exp Ther. 2010 Sep 8; [Epub ahead of print]
Rene P, Le Gouill C, Pogozheva ID, Lee G, Mosberg HI, Farooqi IS, Valenzano KJ, Bouvier M.
1 University of Montreal;
Heterozygous null mutations in the melanocortin-4 receptor (MC4R) cause early-onset obesity in humans, indicating that metabolic homeostasis is sensitive to quantitative variation in MC4R function. Most of the obesity-causing MC4R mutations, functionally characterized to date, lead to intracellular retention of receptors by the cell's quality control system. Thus, recovering cell surface expression of mutant MC4Rs could have a beneficial therapeutic value. We tested a pharmacological chaperone approach to restore cell surface expression and function of ten different mutant forms of hMC4R found in obese patients. Five cell permeable MC4R-selective ligands were tested and displayed pharmacological chaperone activities, restoring cell surface targeting and function of the receptors with distinct efficacy profiles for the different mutations. Such mutation-specific efficacies suggested a structure-activity relationship between compounds and mutant receptor conformations that may open a path toward personalized therapy. In addition, one of the five pharmacological chaperones restored function to most of the mutant receptors tested. Combined with its ability to reach the central nervous system and its selectivity for the MC4R, this pharmacological chaperone may represent a candidate for the development of a targeted therapy suitable for a large subset of patients with MC4R-deficient obesity.
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PMID: 20826565 [PubMed - as supplied by publisher]5: Mol Pharmacol. 2010 Jul 22; [Epub ahead of print]
Zhao P, Sharir H, Kapur A, Cowan A, Geller EB, Adler MW, Seltzman HH, Reggio PH, Heynen-Genel S, Sauer M, Chung TD, Bai Y, Chen W, Caron MG, Barak LS, Abood ME.
1 Temple University School of Medicine;
The orphan receptor GPR35 has known agonists, kynurenic acid, zaprinast, 5-nitro-2-(3-phenylproproplyamino) benzoic acid (NPPB), and lysophosphatidic acids. Their relatively low affinities for GPR35 and prominent off target effects at other pathways, however, diminish their utility for understanding GPR35 signalling and for identifying potential therapeutic uses of GPR35. In a screen of the Prestwick Library of drug and drug-like compounds, we have found that pamoic acid is a potent GPR35 agonist. Pamoic acid is considered by the Food and Drug Administration as an inactive compound that enables long-acting formulations of numerous drugs, such as the antihelminthics, oxantel pamoate and pyrantel pamoate; the psychoactive compounds Vistaril (hydroxyzine pamoate) and Tofranil-PM (imipramine pamoate), and the peptide hormones Trelstar (triptorelin pamoate) and OncoLar (octreotide pamoate). We have found that pamoic acid induces a Gi/o-linked, GPR35-mediated increase in the phosphorylation of ERK1/2, beta-arrestin2 recruitment to GPR35, and GPR35 internalization. In mice it attenuates visceral pain perception indicating an antinociceptive effect possibly through GPR35 receptors. We have also identified in collaboration with the Sanford-Burnham Institute Molecular Libraries Probe Production Center new classes of GPR35 antagonist compounds, including the nanomolar potency antagonist CID2745687. Pamoic acid and potent antagonists like CID2745687 present novel opportunities for expanding the chemical space of GPR35, elucidating GPR35 pharmacology, and stimulating GPR35 associated drug development. Our results indicate that the unexpected biological functions of pamoic acid may yield potential new uses for a common drug constituent.
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PMID: 20826425 [PubMed - as supplied by publisher]6: Pharmacol Biochem Behav. 2010 Sep 3; [Epub ahead of print]
Khalilzadeh E, Tamaddonfard E, Farshid AA, Erfanparast A.
Division of Physiology, Department of Basic Sciences, Faculty of Veterinary Medicine, P.O. Box 1177, Urmia University, Urmia 57135, Iran.
The present study was aimed to investigate the effects of microinjection of histamine, chlorpheniramine (a histamine H(1) receptor antagonist), ranitidine (a histamine H(2) receptor antagonist) and thioperamide (a histamine H(3) receptor antagonist) into the dentate gyrus on the formalin-induced pain. A biphasic pattern (first phase: 0-5min and second phase: 15-60min) in nociceptive responses was induced after subcutaneous injection of formalin (50mul, 2.5%) into the ventral surface of right hind paw. Microinjection of histamine (1 and 2mug) into the dentate gyrus decreased the intensity of nociceptive responses. Intra-dentate gyrus microinjection of chlorpheniramine and ranitidine at the same doses of 1 and 4mug had no effects, whereas thioperamide at a dose of 4mug suppressed both phases of formalin-induced pain. Pretreatments with chlorpheniramine and ranitidine at the same dose of 4mug prevented histamine (2mug)-induced antinociception, while thioperamide (4mug) increased histamine (2mug)-induced antinociception. These results indicated that activation of brain neuronal histamine at the levels of dentate gyrus produced antinociception. The post-synaptic H(1), H(2) receptors and pre-synaptic H(3) receptors of histamine may be involved in the histamine-induced antinociception at the level of the dentate gyrus. Copyright (c) 2010. Published by Elsevier Inc.
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PMID: 20826178 [PubMed - as supplied by publisher]7: Eur J Pharmacol. 2010 Sep 3; [Epub ahead of print]
Qin HY, Luo JL, Qi SD, Xu HX, Sung JJ, Bian ZX.
School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.
This study aimed to clarify the relationship between TRPV1 activation-induced visceral pain and the serotonin pathway in the colon of rats. The effects of para-chlorophenylalanine (pCPA) on visceral pain threshold pressure were assessed in capsaicin -induced visceral pain of rats. The expression of TRPV1 in the colon was examined by immunohistochemistry and Western blot analysis, and TRPV1 excitability in dorsal root ganglion (DRG) neurons was examined by whole-cell patch-champ recording in pCPA-treated rats. Calcineurin and Ca(2+) -calmodulin-dependent kinase II (CaMKII), the important proteins in maintaining TRPV1 function in the colon, were also tested by Western blot analysis and immunofluorescence staining. Results showed that pCPA significantly increased the capsaicin-induced visceral pain threshold by 2.3-fold, and the enhanced visceral pain threshold corresponded with decreased 5-HT content (58 % depleted) and enterochromaffin cell number (80 % reduced). The reduced excitability of TRPV1 in DRG neurons, instead of changed TRPV1 expression, is responsible for the enhanced visceral pain threshold in 5-HT depleted rats, and the mechanism may be related to the decreased expression of pCaMKII. These results indicate that visceral hypersensitivity induced by TRPV1 activation is modulated through 5-HT pathways and the attenuated function of TRPV1 and decreased protein expression of pCaMKII may play an important role in capsaicin-induced TRPV1 desensitization under 5-HT-depleted condition. The important role of TRPV1 and 5-HT in generating and maintaining visceral hypersensitivity may provide insights for the treatment of visceral hypersensitivity. Copyright (c) 2010. Published by Elsevier B.V.
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PMID: 20826151 [PubMed - as supplied by publisher]8: Eur J Pharmacol. 2010 Sep 3; [Epub ahead of print]
Chen WH, Yang D, Wang WY, Zhang J, Wang YP.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China; Graduate School of the Chinese Academy of Sciences,China.
Changrolin (2, 6-bis[pyrrolidin-1-ylmethyl]-4-[quinazolin-4-ylamino] phenol) is an anti-arrhythmic drug derived from beta-dichroine, an active component of the Chinese medicinal herb, Dichroa febrifuga Lour. To elucidate the mechanism underlying the anti-arrhythmic effect of changrolin, we used the whole-cell patch-clamp technique to characterize the electrophysiological actions of changrolin in isolated rat cardiomyocytes. In this study, changrolin inhibited delayed rectified K(+) currents (I(K)) in a concentration-dependent manner with inhibiting the current by 11.9%+/-4.7%, 27.8%+/-3.4%, 31.5% +/- 3.6% and 40.8% +/- 3.7% at 10, 30, 100 and 300muM, respectively (n=7-8). Changrolin was less effective against transient outward K(+) currents (I(to)), and only showed significantly inhibitory effect at the highest concentration (300muM). Changrolin also induced a concentration-dependent inhibition of sodium currents (I(Na)) with an IC(50) of 10.19muM (Hill coefficient=-1.727, n=6-7). In addition, changrolin exerted a holding potential-dependent block on Na(+) channels, produced a hyperpolarizing shift in the steady-state inactivation curve, as well as exhibited a marked frequency-dependent component to the blockade of Na(+) channels. Finally, calcium currents (I(Ca)) was decreased by changrolin in a concentration-dependent manner with an estimated IC(50) of 74.73muM (Hill coefficient=-0.9082, n=6). In conclusion, changrolin blocks Na(+) and Ca(2+) channels, and also blocks K(+) channels (I(to) and I(K)) to some extent. Notably, changrolin preferentially blocks the inactivated state of Na(+) channels. These effects lead to a modification of electromechanical function and likely contribute to the termination of arrhythmia. Copyright (c) 2010. Published by Elsevier B.V.
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PMID: 20826150 [PubMed - as supplied by publisher]9: Eur J Pharmacol. 2010 Sep 3; [Epub ahead of print]
Lau GT, Huang H, Leung LK.
Department of Biochemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
Butein is a flavonoid isolated from the bark of Rhus verniciflua Stokes and the flowers of Butea monosperma, and is known to be a potential therapeutic drug for treating inflammation and cancer. Cyclooxygenase (COX) converts arachidonic acid to prostanoids, and increased expression of its isoform COX-2 has been observed in breast cancer tissues. It has been suggested that COX inhibitors can be used as chemopreventive agents against breast carcinogenesis. This study examined the potential suppressive effect of the flavonoid on phorbol 12-myristate 13-acetate (PMA)-induced COX-2 expression in the non-tumorigenic MCF-10A and cancerous MCF-7 breast cells. Immunoblot and mRNA analyses revealed that butein at or below 10muM significantly inhibited PMA-induced COX-2 expression in these breast cells. The blocking of the PKC signaling pathway appeared to be the underlying mechanism. butein treatment reduced the amount of phospho-mitogen activated protein kinase (MAPK) ERK-1/2, and the total activity of PKC. Activated ERKs might trigger the transcriptional activation of COX-2. Reporter gene assays as well as electrophoretic mobility shift assays (EMSA) illustrated that butein inhibited transcription of this gene. This study showed that butein down-regulated PMA-induced COX-2 expression in both cancerous and non-cancerous breast cells, and such findings could provide the basis for pharmaceutical development of butein. Copyright (c) 2010. Published by Elsevier B.V.
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PMID: 20826149 [PubMed - as supplied by publisher]10: Eur J Pharmacol. 2010 Sep 3; [Epub ahead of print]
Laino CH, Fonseca C, Sterin-Speziale N, Slobodianik N, Reines A.
Instituto de Investigaciones en Ciencias de la Salud Humana (IICSHUM), Departamento de Ciencias Exactas, Fisicas y Naturales, Universidad Nacional de La Rioja, Argentina.
Despite the advances in psychopharmacology, the treatment of depressive disorders is still not satisfactory. Side effects and resistance to antidepressant drugs are the greatest complications during treatment. Based on recent evidence, omega-3 fatty acids may influence vulnerability and outcome in depressive disorders. The aim of this study was to further characterize the omega-3 antidepressant-like effect in rats in terms of its behavioral features in the depression model forced swimming test either alone or in combination with antidepressants fluoxetine or mirtazapine. Ultimately, we prompted to determine the lowest dose at which omega-3 fatty acids and antidepressant drugs may still represent a pharmacological advantage when employed in combined treatments. Chronic diet supplementation with omega-3 fatty acids produced concentration-dependent antidepressant-like effects in the forced swimming test displaying a behavioral profile similar to fluoxetine but different from mirtazapine. Fluoxetine or mirtazapine at antidepressant doses (10 and 20mg/kg/day, respectively) rendered additive effects in combination with omega-3 fatty acid supplementation (720mg/kg/day). Beneficial effects of combined treatment were also observed at sub-effective doses (1mg/kg/day) of fluoxetine or mirtazapine, since in combination with omega-3 fatty acids (720mg/kg/day), antidepressants potentiated omega-3 antidepressant-like effects. The antidepressant-like effects occurred in the absence of changes in brain phospholipid classes. The therapeutic approach of combining omega-3 fatty acids with low ineffective doses of antidepressants might represent benefits in the treatment of depression, especially in patients with depression resistant to conventional treatments and even may contribute to patient compliance by decreasing the magnitude of some antidepressant dose-dependent side effects. Copyright (c) 2010. Published by Elsevier B.V.
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PMID: 20826148 [PubMed - as supplied by publisher]11: Eur J Pharmacol. 2010 Sep 3; [Epub ahead of print]
Miltyk W, Surazynski A, Dondzilo J, Palka J.
Department of Pharmaceutical Analysis, Medical University in Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland.
Degenerative joint diseases are related to the excessive degradation of collagen and proteoglycans in cartilage. One of potent inflammatory mediators of cartilage metabolism is interleukin-1 (IL-1) that has been implicated in the pathogenesis of degenerative joint diseases. Peripheral benzodiazepine receptor ligands have anti-inflammatory activity in rheumatoid arthritis. The present study shows that 4'-chlorodiazepam (Ro-54864), an agonist of peripheral benzodiazepine receptors, counteract inhibition of collagen and DNA biosynthesis, induced by IL-1. Pk-1195, an antagonist of peripheral benzodiazepine receptors did not restore inhibitory effects of IL-1. The mechanism of collagen biosynthesis and cell division regulation involve insulin-like growth factor - I receptor signaling. We found that IL-1 inhibited expression of IGF-IR, while Ro-54864 stimulated the expression of this receptor. Increase in the expression of this receptor was accompanied by increase in mTOR expression and AKT phosphorylation while it had no effect on Ras-Raf-mitogen activated protein kinase (MAPK) pathway. Although IL-1 caused activation of apoptosis in chondrocytes, an addition of Ro-54864 to the cells inhibited the process as detected by annexin V cell staining followed by flow cytometry. The mechanism of this process may be related to protective effect of signal induced by IGF-I receptor. The data suggest that the mechanism of the protective effects of Ro-54864 on IL-1 -induced effects in chondrocytes undergoes through mTOR and AKT signaling. It suggest that peripheral benzodiazepine receptor agonist may be considered as a potential pharmacotherapeutical agents in the treatment of inflammatory diseases. Copyright (c) 2010. Published by Elsevier B.V.
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PMID: 20826147 [PubMed - as supplied by publisher]12: Eur J Pharmacol. 2010 Sep 3; [Epub ahead of print]
Mohamad AS, Akhtar MN, Zakaria ZA, Perimal EK, Khalid S, Mohd PA, Khalid MH, Israf DA, Lajis NH, Sulaiman MR.
Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.
The present study examined the potential antinociceptive activity of flavokawin B (6'-hydroxy-2',4'-dimethoxychalcone), a synthetic chalcone using chemical- and thermal-induced nociception models in mice. It was demonstrated that flavokawin B (FKB; 0.3, 1, 3 and 10mg/kg) administered via both oral (p.o.) and intraperitoneal (i.p.) routes produced significant and dose-dependent inhibition in the abdominal constrictions induced by acetic acid, with the i.p. route produced antinociception of approximately 7-fold more potent than the p.o. route. It was also demonstrated that FKB produced significant inhibition in the two phases of the formalin-induced paw licking test. In addition, the same treatment of flavokawin B (FKB) exhibited significant inhibition of the neurogenic nociceptive induced by intraplantar injections of glutamate and capsaicin. Likewise, this compound also induced a significant increase in the response latency period to thermal stimuli in the hot plate test and its antinociceptive effect was not related to muscle relaxant or sedative action. Moreover, the antinociception effect of the FKB in the formalin-induced paw licking test and the hot plate test was not affected by pretreatment of non-selective opioid receptor antagonist, naloxone. The present results indicate that FKB produced pronounced antinociception effect against both chemical and thermal models of pain in mice that exhibited both peripheral and central analgesic activity. Copyright (c) 2010. Published by Elsevier B.V.
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PMID: 20826146 [PubMed - as supplied by publisher]13: Eur J Pharmacol. 2010 Sep 3; [Epub ahead of print]
Zhang W, Fievez L, Zhang F, Cheu E, Antoine N, Delguste C, Zhang Y, Rong W, Bureau F, Advenier C, Gustin P.
Department of Physiology, School of Medicine, Shanghai Jiaotong University, China.
The anti-inflammatory properties of inhaled formoterol and ipratropium bromide, alone or in combination, were investigated in a rat model of chronic pulmonary inflammation with airspace enlargement induced by cadmium inhalation. At the end of the protocol, cadmium-induced increase of airway resistance was prevented by formoterol (4mg/30ml) or ipratropium (0.20mg/20ml). Formoterol elicited a significant decrease in total cell and neutrophil counts in bronchoalveolar lavage fluid as well as on the activity of gelatinase B (MMP-9), an enzyme strongly expressed in alveolar macrophages and epithelial cells. Additionally, a significant attenuation of the lung lesions characterized by inflammatory cell infiltration within the alveoli and the interstitium and a decrease in mean linear intercept was observed. Although ipratropium alone had no effects on the cadmium-induced pulmonary inflammation and emphysema, its combination with an inefficient concentration of formoterol (1mg/30ml) showed a synergistic inhibitory effect on neutrophil and total cell counts as well as on the mean linear intercept associated with a synergistic inhibition on the MMP-9 activity. Gelatinase A (MMP-2) activity was not influenced by drug pretreatments. Neither macrophage metalloelastase (MMP-12) activity nor levels of cytokines IL-1beta, TNF-alpha and GM-CSF in bronchoalveolar lavage fluid were modified in rats chronically exposed to cadmium. No desensitization of beta2-adrenoceptors or cholinergic receptors on airway smooth muscles and inflammatory cells during the protocol was observed. In conclusion, formoterol alone or combined with ipratropium bromide partially protect the lungs against the chronic inflammation and airspace enlargement by reducing neutrophilic infiltration possibly via the inhibition of MMP-9 activity. Copyright (c) 2010. Published by Elsevier B.V.
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PMID: 20826145 [PubMed - as supplied by publisher]14: Eur J Pharmacol. 2010 Sep 3; [Epub ahead of print]
Zhang WJ, Feng J, Zhou R, Ye LY, Liu HL, Peng L, Lou JN, Li CH.
Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, P.R. China.
To investigate the in vitro effect of tanshinone IIA on leukocyte-associated hypoxia-reoxygenation injury of human brain blood barrier (BBB), we established the BBB model by culturing purified primary human brain microvascular endothelial cells (HBMVEC) to confluence on cell culture insert. BBB was identified by tight junction, transendothelial electrical resistance (TEER) and the permeability of BBB to horseradish peroxidase (HRP). The effect of tanshinone IIA on the permeability of BBB was tested at 2h after hypoxia and 1h after reoxygenation with or without the supernatants of activated leukocytes. The effect of tanshinone IIA on leukocytes activation was analyzed by detection of MMP-9, cytokines and reactive oxygen species. The results showed that BBB formed by confluent HBMVECs had no cellular gap. Immunofluorescent staining for ZO-1 confirmed that the cells were connected by tight junction. Moreover, the BBB model had a higher TEER and a lower permeability for HRP than confluent HUVECs. The permeability of BBB for HRP was enhanced by hypoxia-reoxygenation and further greatly enhanced by adding the supernatants of activated leukocytes before reoxygenation. But such an effect was reversed by addition of tanshinone IIA before hypoxia. Moreover, tanshinone IIA could decrease the levels of MMP-9, TNF-alpha, IL-1alpha, IL-2, IFN-gamma and reactive oxygen species in leukocytes. In conclusion, tanshinone IIA can protect BBB against leukocyte-associated hypoxia-reoxygenation injury by attenuating the activation of leukocytes and inhibiting the injury effects of leukocytic products. Tanshinone IIA may be a novel therapeutic agent for cerebral ischemia-reperfusion injury. Copyright (c) 2010. Published by Elsevier B.V.
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PMID: 20826144 [PubMed - as supplied by publisher]15: Eur J Pharmacol. 2010 Sep 3; [Epub ahead of print]
Nakamura J.
Protein kinase CbetaI (PKCbetaI) mediates insulin signaling and attenuates beta1-adrenoceptor-stimulated lipolysis. In this work, the effect of the PKC activator phorbol 12-myristate 13-acetate (PMA) on the antilipolytic action of insulin was determined by analyzing lipolysis induced by a beta3-adrenoceptor agonist CL 316243. PMA inhibited the insulin antilipolytic action. The pan-PKC inhibitors GF 109203X and chelerythrine inhibited the PMA effect, but the PKCalpha/beta inhibitors Go 6976 and CGP 53353 did not. Exposure of cells to PMA downregulated PKCs alpha, betaI, and delta within 3h and PKCepsilon within 12h. The effect of PMA on insulin action greatly diminished when PKCepsilon was downregulated. Inhibitors of phosphatidylinositol 3-kinase (PI3-K), Akt, and phosphodiesterase 3B (PDE3B) diminished the PMA effect. PMA inhibited insulin-stimulated phosphorylation of Tyr in insulin receptor beta subunit and Ser/Thr in Akt. These data suggest that PMA inhibits the antilipolytic signal mediated by the insulin receptor, PI3-K, Akt, and PDE3B. The most probable target of PMA is PKCepsilon. Copyright (c) 2010. Published by Elsevier B.V.
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PMID: 20826143 [PubMed - as supplied by publisher]16: Eur J Pharmacol. 2010 Sep 3; [Epub ahead of print]
Zhao LH, Ding YX, Zhang L, Li L.
Department of Pharmacology, Xuanwu Hospital of Capital Medical University, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing 100053, P. R. China; Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, P. R. China.
Cornel iridoid glycoside (CIG) is a main component extracted from a traditional Chinese herb Cornus officinalis. Our previous study found that CIG improved neurological function in cerebral ischemic rats. The aim of this study was to investigate the therapeutic benefit of CIG in rats with fimbria-fornix transection (FFT) and explore the underlying molecular mechanisms. CIG (20, 60 and 180mg/kg) or vehicle was intragastrically administered once daily to rats, starting immediately after the surgery and lasting for 4 weeks. Morris water maze and step-through tests showed that the memory deficits seen in FFT rats were significantly improved by CIG treatment. Immunohistochemical analysis showed that CIG treatment attenuated the loss of neurons in hippocampus. To elucidate the memory-improving mechanism of CIG, the neurotrophic factors, synaptic proteins and Bcl-2 family proteins in hippocampus were measured by Western blot analysis. FFT reduced hippocampal protein levels of nerve growth factor (NGF), tyrosine receptor kinase A (Trk A) , brain-derived neurotrophic factor (BDNF), synaptophysin (SYP) and B-cell lymphoma-2 (Bcl-2), but not levels of tyrosine receptor kinase B (Trk B) and growth-associated protein 43 (GAP-43). FFT also elevated cytochorome C (Cyt c) and bcl-2-Associated X Protein (Bax). Administration of CIG to FFT rats significantly elevated the expression of NGF, TrkA, BDNF, SYP, GAP-43 and Bcl-2, and decreased the expression of Cyt c and Bax. These results indicated that CIG effectively counteracted cognitive impairments caused by fimbria-fornix lesions, and the mechanisms might be related to promoting neuronal survival and providing a beneficial environment for brain repair. Copyright (c) 2010. Published by Elsevier B.V.
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20826142&dopt=ExternalLink
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PMID: 20826142 [PubMed - as supplied by publisher]17: Eur J Pharmacol. 2010 Sep 3; [Epub ahead of print]
Rondon ES, Vieira AS, Valadao CA, Parada CA.
Department of Veterinary Medicine, Faculty of Veterinary Medicine and Animal Sciences (FAMEZ), Mato Grosso do Sul Federal University - UFMS; Av. Senador Filinto Muller, 2443; Zip Code 79070-460, Campo Grande, Mato Grosso do Sul - Brazil.
Intrathecal or epidural administration of NMDA (N-methyl-D-aspartate) receptors antagonists, in special ketamine and ifenprodil are used to control moderate to severe hyperalgesia in humans. Activation of NMDA receptor usually requires binding of two agonists, glutamate and glycine, in different receptor subunits. Ketamine is a NMDA receptor antagonist and acts at phencyclidine site in NR1 subunit while ifenprodil is a selective NR2B subunit antagonist of NMDA receptor. The aim of this study was to investigate the pharmacological interactions between ketamine or its isomers and ifenprodil, when intrathecally co-administrated, to reduce prostaglandin E(2)-induced hyperalgesia in rat's hind paw. The intrathecal administration of ketamine, its isomers R(-) or S(+), or ifenprodil induced anti-hyperalgesic effects in a dose-related manner. Ifenprodil, in a dose that did not induce significant effect when administrated alone, significantly improved the anti-hyperalgesic effect of ketamine or its isomers. The other way round, ketamine or S(+) ketamine, but not R(-) ketamine, in a dose that did not induce significant effect when administrated alone, improved the anti-hyperalgesic effect of ifenprodil. However, by comparing ED(50)s (half maximal effective doses), ifenprodil-induced potentiation of ketamine was significantly greater than ketamine-induced potentiation of ifenprodil. The findings of this present study suggest that intrathecal administration of very small doses of ifenprodil, just before and ketamine significantly improves its anti-hyperalgesic effect and this association could be useful to control inflammatory pain with less undesirable effects. Copyright (c) 2010. Published by Elsevier B.V.
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20826141&dopt=ExternalLink
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PMID: 20826141 [PubMed - as supplied by publisher]18: Eur J Pharmacol. 2010 Sep 3; [Epub ahead of print]
Luszczki JJ, Cioczek JD, Kocharov SL, Andres-Mach M, Kominek M, Zolkowska D.
Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, PL 20-090 Lublin, Poland; Isobolographic Analysis Laboratory, Institute of Agricultural Medicine, Jaczewskiego 2, PL 20-950 Lublin, Poland.
The aim of the study was to determine the influence of N-(ortho-carboxyanilinomethyl)-p-isopropoxyphenylsuccinimide [o-CAMIPPS], N-(meta-carboxyanilinomethyl)-p-isopropoxyphenylsuccinimide [m-CAMIPPS], and N-(para-carboxyanilinomethyl)-p-isopropoxyphenylsuccinimide [p-CAMIPPS] on the protective activity of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) in the mouse maximal electroshock seizure model. The results indicate that all tested succinimide derivatives administered intraperitoneally at doses of 75 and 150mg/kg significantly elevated the threshold for electroconvulsions in mice. Succinimide derivatives at a dose of 37.5mg/kg had no effect on the threshold for electroconvulsions in mice. Furthermore, o-CAMIPPS (37.5mg/kg) significantly reduced the anticonvulsant activity of carbamazepine, but not that of phenobarbital, phenytoin and valproate in the maximal electroshock-induced seizures in mice. Anticonvulsant efficacy of carbamazepine, phenobarbital, phenytoin and valproate in the maximal electroshock-induced seizures in mice was not changed after administration of m-CAMIPPS or p-CAMIPPS. Pharmacokinetic experiment revealed that o-CAMIPPS significantly increased total brain concentrations of carbamazepine in mice. In conclusion, the reduced anticonvulsant action of carbamazepine by o-CAMIPPS in the maximal electroshock-induced seizures, despite the increased total brain carbamazepine concentrations after combined administration of carbamazepine with o-CAMIPPS, may suggest the antagonistic interaction between drugs. The combinations of m-CAMIPPS or p-CAMIPPS with carbamazepine, phenobarbital, phenytoin and valproate were neutral from a preclinical viewpoint. Copyright (c) 2010. Published by Elsevier B.V.
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20826140&dopt=ExternalLink
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PMID: 20826140 [PubMed - as supplied by publisher]19: Eur J Pharmacol. 2010 Sep 3; [Epub ahead of print]
Yamabe N, Noh JS, Park CH, Kang KS, Shibahara N, Tanaka T, Yokozawa T.
Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Previously, we have reported that Corni Fructus possessed hypoglycemic and hypocholesterolemic effects in streptozotocin-induced type 1 diabetic rats and diet-induced hypercholesterolemic rats. Herein, we have focused on the effect and mechanism of loganin, a major iridoid glycoside of Corni Fructus, on the type 2 diabetic db/db mice. Loganin was orally administered to db/db mice at a dose of 20 or 100mg/kg body weight daily for 8weeks. The biochemical factors and expressions of protein and mRNA related to lipid metabolism, inflammation, advanced glycation endproducts, and its receptor were measured. In loganin-treated db/db mice, hyperglycemia and dyslipidemia were ameliorated in both the serum and hepatic tissue; however, in the kidney, only triglyceride was reduced. The enhanced oxidative stress was alleviated by loganin through a decrease in thiobarbituric acid-reactive substances (liver and kidney) and reactive oxygen species (serum, liver, and kidney), as well as augmentation of the oxidized to reduced glutathione ratio (liver and kidney). The marked lipid-regulatory effect of loganin was exerted in the liver of type 2 diabetic mice via suppressing mRNA expressions related to lipid synthesis and adjusting the abnormal expression of peroxisome proliferator-activated receptor alpha and sterol regulatory element-binding protein in the nucleus. Furthermore, loganin inhibited advanced glycation endproducts formation and the expression of its receptor, and nuclear factor-kappa B-induced inflammation in the hepatic tissue of db/db mice. Loganin exhibits protective effects against hepatic injury and other diabetic complications associated with abnormal metabolic states and inflammation caused by oxidative stress and advanced glycation endproducts formation. Copyright (c) 2010. Published by Elsevier B.V.
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20826139&dopt=ExternalLink
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PMID: 20826139 [PubMed - as supplied by publisher]20: Eur J Pharmacol. 2010 Sep 3; [Epub ahead of print]
Nakamura H, Ding WG, Sanada M, Maeda K, Kawai H, Maegawa H, Matsuura H.
Division of Neurology, Department of Internal Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan; Department of Physiology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
Repolarization of cardiac action potentials is regulated by several types of K(+) currents. The present study examined the presence and functional significance of rapid delayed rectifier (I(Kr)) in left and right atrial myocytes of mouse heart, using whole-cell patch-clamp method. The functional role of ultrarapid delayed rectifier (I(Kur)) in the repolarization was also examined by blocking with 4-aminopyridine (50muM). The presence of I(Kr) was detected in left and right atrial myocytes as an E-4031 (5muM)-sensitive current that exhibited relatively rapid activation during depolarization and half activation voltage of -17.5 and -17.4mV for left and right atrial myocytes, respectively. The current density of I(Kr) was similar between left and right atria. The prolongation of action potential measured at 50% repolarization evoked by 4-aminopyridine was significantly larger in left than in right atrium, which appears to be consistent with the larger amplitude of I(Kur) in left atrium. On the other hand, the prolongation of action potential measured at 90% repolarization caused by E-4031 was significantly larger in right than in left atrium. The longer action potential of right atrium, which may result at least partly from smaller amplitude of I(Kur), is likely to enhance the functional significance of I(Kr) in repolarization process of right atrium, despite of similar magnitude of I(Kr) in left and right atria. Our data thus identifies I(Kr) in mouse atria and indicates the presence of functional interaction between I(Kr) and I(Kur) that potentially contributes to repolarization heterogeneity in left and right atria of mouse heart. Copyright (c) 2010. Published by Elsevier B.V.
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20826138&dopt=ExternalLink
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PMID: 20826138 [PubMed - as supplied by publisher]