British Journal of Pharmacology Impact Factor & Information

Publisher: British Pharmacological Society, Wiley

Journal description

All aspects of experimental pharmacology including: Cellular and molecular pharmacology Biochemical pharmacology Neuroscience All aspects of general pharmacology Special Reports for rapid publication of important new results of special pharmacological significance The British Journal of Pharmacology is the leading 'original papers' publication in the field of general pharmacology.

Current impact factor: 4.84

Impact Factor Rankings

2015 Impact Factor Available summer 2016
2014 Impact Factor 4.842
2013 Impact Factor 4.99
2012 Impact Factor 5.067
2011 Impact Factor 4.409
2010 Impact Factor 4.925
2009 Impact Factor 5.204
2008 Impact Factor 4.902
2007 Impact Factor 3.767
2006 Impact Factor 3.825
2005 Impact Factor 3.41
2004 Impact Factor 3.325
2003 Impact Factor 3.611
2002 Impact Factor 3.45
2001 Impact Factor 3.502
2000 Impact Factor 3.689
1999 Impact Factor 3.722
1998 Impact Factor 3.704
1997 Impact Factor 3.619
1996 Impact Factor 4.075
1995 Impact Factor 4.739
1994 Impact Factor 4.695
1993 Impact Factor 5.27
1992 Impact Factor 5.094

Impact factor over time

Impact factor

Additional details

5-year impact 4.96
Cited half-life 7.50
Immediacy index 1.51
Eigenfactor 0.05
Article influence 1.32
Website British Journal of Pharmacology website
Other titles British journal of pharmacology (Online), BJP
ISSN 1476-5381
OCLC 39502220
Material type Document, Periodical, Internet resource
Document type Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details


  • Pre-print
    • Author can archive a pre-print version
  • Post-print
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  • Restrictions
    • 12 months embargo
  • Conditions
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    • On author's personal website, institutional repositories, arXiv, AgEcon, PhilPapers, PubMed Central, RePEc or Social Science Research Network
    • Author's pre-print may not be updated with Publisher's Version/PDF
    • Author's pre-print must acknowledge acceptance for publication
    • Non-Commercial
    • Publisher's version/PDF cannot be used
    • Publisher source must be acknowledged with citation
    • Must link to publisher version with set statement (see policy)
    • If OnlineOpen is available, BBSRC, EPSRC, MRC, NERC and STFC authors, may self-archive after 12 months
    • If OnlineOpen is available, AHRC and ESRC authors, may self-archive after 24 months
    • Publisher last contacted on 07/08/2014
    • This policy is an exception to the default policies of 'Wiley'
  • Classification
    ​ yellow

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background and purpose: 5-Aminolevulinic acid (5-ALA) has been widely used in photodynamic therapy and immunofluorescence of tumors. In the present study, the intestinal permeability and oral pharmacokinetics of 5-ALA were evaluated to probe the significance of the proton-coupled oligopeptide transporter 1 (PEPT1) in the oral absorption and systemic exposure of this substrate. Experimental approach: In situ single-pass intestinal perfusions and in vivo oral pharmacokinetic studies were performed in wildtype and Pept1 knockout mice. Perfusion studies were performed as a function of concentration-dependence, specificity, and permeability of 5-ALA in different intestinal segments. Pharmacokinetic studies were performed after 0.2 and 2.0 μmoL/g doses of 5-ALA. Key results: We found that the permeability of 5-ALA was substantial in duodenal, jejunal and ileal regions of wildtype mice, but the residual permeability of 5-ALA in Pept1 knockout small intestine was only about 10% of that observed in wildtype animals. Moreover, the permeability of 5-ALA in jejunum was specific for PEPT1 with no apparent contribution of other transporters, including the proton-coupled amino acid transporter 1 (PAT1). After oral dosing, the systemic exposure of 5-ALA was reduced by about 2-fold during PEPT1 ablation, and the pharmacokinetics was dose-proportional after the 0.2 and 2.0 µmol/g doses. PEPT1 had a minor effect on the disposition and peripheral tissue distribution of 5-ALA. Conclusion and implications: Collectively, our findings suggested a major role of PEPT1 in the intestinal permeability and oral absorption of 5-ALA. In contrast, PAT1 appeared to play a limited role, at best. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 10/2015; DOI:10.1111/bph.13356
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    ABSTRACT: Background and purpose: Quetiapine has a range of clinical activity distinct from other atypical antipsychotic drugs, demonstrating efficacy as monotherapy in bipolar depression, major depressive disorder and generalized anxiety disorder. The neuropharmacological mechanisms underlying this clinical profile are not completely understood; however, the major active metabolite, norquetiapine, has been shown to have a distinct in vitro pharmacological profile consistent with a broad therapeutic range and may contribute to the clinical profile of quetiapine. Experimental approach: We evaluated quetiapine and norquetiapine, using in vitro binding and functional assays of targets known to be associated with antidepressant and anxiolytic drug actions, and compared these activities to a representative range of established antipsychotics and antidepressants. To determine how the in vitro pharmacological properties translate into in vivo activity, we used preclinical animal models with translational relevance to established antidepressant-like and anxiolytic-like drug action. Key results: Norquetiapine had equivalent activity to established antidepressants at norepinephrine transporter (NET), while quetiapine was inactive. Norquetiapine was active in the mouse forced swimming and rat learned helplessness tests. In in vivo receptor occupancy studies, norquetiapine had significant occupancy at NET at behaviourally relevant doses. Both quetiapine and norquetiapine were agonists at 5-HT1A receptors, and the anxiolytic-like activity of norquetiapine in rat punished responding was blocked by the 5-HT1A antagonist, WAY100635. Conclusions and implications: Quetiapine and norquetiapine have multiple in vitro pharmacological actions and results from preclinical studies suggest that activity at NET and 5-HT1A receptors contributes to the antidepressant and anxiolytic effects in patients treated with quetiapine. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 10/2015; DOI:10.1111/bph.13346
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    ABSTRACT: Cardiac hypertrophy is a mechanism to compensate increased cardiac work load, i.e. after myocardial infarction or upon pressure overload. However, on the long run cardiac hypertrophy is a prevailing risk factor for the development of heart failure. During pathological remodeling processes leading to heart failure, decompensated hypertrophy, cardiomyocytes death via apoptosis or necroptosis, and fibrosis as well as progressive cardiomyocytes dysfunction appear. Interestingly, the induction of hypertrophy, cell death or fibrosis is mediated by similar signaling pathways. Therefore, tiny changes in the signaling cascade are able to switch physiological cardiac remodeling to heart failure progression. We will here illustrate examples for such molecular switches changing compensated hypertrophy into heart failure progression. Thereby, we will focus on the substantial importance of intermingled signaling cascades of the TGFβ superfamily. In this context, potential therapeutic targets for pharmacological interventions attenuating heart failure progression will be discussed. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 10/2015; DOI:10.1111/bph.13344
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    ABSTRACT: Adenosine has been proposed to exert anti-hypertrophic effects. However, the precise regulation and the role of the different adenosine receptor subtypes in the heart and their effects on hypertrophic signalling are largely unknown. We aimed to characterize expression and function of the A1 receptor in response to hypertrophic stimulation in vitro and in vivo. Pro-hypertrophic/A1 receptor stimulation of neonatal rat cardiomyocytes and male C57/Bl6 mice, subcutaneous drug administration, RT-PCR, 3[H]-leucine-incorporation assay, immunostaining, tissue staining, western-blot, gravimetric analyses and echocardiography were applied in this study. In isolated neonatal rat cardiomyocytes, phenylephrine up-regulated the A1 receptor in a concentration-dependent manner, while angiotensinII and insulin-like growth factor I had no such effect. The selective A1 receptor agonist N6-cyclopentyladenosine counteracted the phenylephrine (10 μM), but not the angiotensinII (1 μM) or insulin-like growth factor I (20 ng ml−1) mediated hypertrophic phenotype (cardiomyocyte size, sarcomeric organization, total protein synthesis, c-fos expression; p<0.01). In C57/BL6 mice, continuous N6-cyclopentyladenosine infusion (2 mg kg−1 day−1; 21 days) blunted phenylephrine (120 mg kg−1 day−1; 21 days) induced hypertrophy (heart weight, cardiomyocyte size, foetal genes), fibrosis, matrix metalloproteinase 2 up-regulation and generation of oxidative stress – all hallmarks of maladaptive remodelling. Concurrently, phenylephrine administration increased A1 receptor expression. Our data allude to a negative feedback mechanism attenuating pathological hypertrophy following α1-adrenoceptor stimulation and thereby suggest the A1 receptor as a potential target for therapeutic strategies to prevent transition from compensated myocardial hypertrophy to decompensated heart failure due to chronic cardiac pressure-overload. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 09/2015; DOI:10.1111/bph.13339
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    ABSTRACT: Background and purpose: While cannabinoids have been proposed as a potential treatment for neuropathic pain, they have limitations. Cannabinoid receptor agonists have good efficacy in animal models of neuropathic pain, they have a poor therapeutic window. Conversely, selective fatty acid amide hydrolase (FAAH) inhibitors which enhance the endocannabinoid system have a better therapeutic window, but lesser efficacy. We examined whether JZL195, a dual inhibitor of FAAH and monacylglycerol lipase (MAGL) could overcome these limitations. Experimental approach: C57BL/6 mice underwent the chronic constriction injury (CCI) model of neuropathic pain. Mechanical and cold allodynia, plus cannabinoid side-effects were assessed in response to systemic drug application. Key results: JZL195 and the cannabinoid receptor agonist WIN55212 produced dose dependent reductions in CCI-induced mechanical and cold allodynia, plus side-effects including motor incoordination, catalepsy and sedation. JZL195 reduced allodynia with an ED50 at least four times less than that at which it produced side-effects. By contrast, WIN55212 reduced allodynia and produce side-effects with similar ED50s. The maximal anti-allodynic effect of JZL195 was greater than that produced by selective FAAH, or MAGL inhibitors. The JZL195 induced anti-allodynia was maintained during repeated treatment. Conclusions and implications: These findings suggest that JZL195 has greater anti-allodynic efficacy than selective FAAH, or MAGL inhibitors, plus a greater therapeutic window than a cannabinoid receptor agonist. Thus, dual FAAH/MAGL inhibition may have greater potential in alleviating neuropathic pain, compared to selective FAAH and MAGL inhibitors, or cannabinoid receptor agonists. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 09/2015; DOI:10.1111/bph.13337
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    ABSTRACT: Background and purpose: Drug-target residence time is an important, yet often overlooked, parameter in drug discovery. Multiple studies have proposed an increased residence time to be beneficial for improved drug efficacy and/or longer duration of action. Currently there are many drugs on the market targeting the gonadotropin-releasing hormone (GnRH) receptor for the treatment of hormone-dependent diseases. Surprisingly, the kinetic receptor binding parameters of these analogues have not yet been reported. Therefore, this project focused on determining the receptor binding kinetics of twelve GnRH peptide agonists, including many marketed drugs. Experimental approach: A novel radioligand binding competition association assay was developed and optimized for the human GnRH receptor with the use of a radiolabeled peptide agonist, (125) I-triptorelin. In addition to radioligand binding studies, a homogenous time-resolved fluorescence (TR-FRET) Tag-lite™ method was developed as an alternative assay for the same purpose. Key results: Two novel competition association assays were successfully developed and applied to determine the kinetic receptor binding characteristics of twelve high affinity GnRH peptide agonists. Results obtained from both methods were highly correlated. Interestingly, the binding kinetics of the peptide agonists were more divergent than their affinities with residence times ranging from 5.6 min (goserelin) to 125 min (deslorelin). Conclusions and implications: Our research provides new insights by incorporating kinetic, next to equilibrium, binding parameters in current research and development that can potentially improve future drug discovery targeting the GnRH receptor. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 09/2015; DOI:10.1111/bph.13342
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    ABSTRACT: Background and purpose: The vast majority of neuromyelitis optica (NMO) is characterized by the existence of an autoantibody called NMO-IgG, which recognizes the extracellular domains of aquaporin-4 (AQP4). Binding of NMO-IgG to AQP4 expressed in end-feet of astrocytes causes complement-dependent disruption of astrocytes followed by demyelination. A therapeutic option for NMO is the prevention of the binding of NMO-IgG to AQP4 with high avidity nonpathogenic chimeric monoclonal antibodies. Experimental approach: cDNAs encoding variable regions of heavy and light chains of monoclonal antibodies against the extracellular domains of human AQP4 were cloned from hybridoma total RNA and fused to those encoding constant regions of human IgG1 and Igκ, respectively. Then mammalian expression vectors were constructed to establish stable cell-lines secreting mature chimeric antibodies. Key results: Original monoclonal antibodies showed high avidity binding to human AQP4 as determined by ELISA. Live imaging using Alexa-Fluor-555-labeled antibodies revealed that D15107 more rapidly bound to cells expressing human AQP4 than others and strongly enhanced endocytosis of AQP4, while D12092 also bound rapidly to human AQP4 but enhanced endocytosis to a lesser degree. Chimeric D15107 prevented complement-dependent cytotoxicity induced by NMO-IgG from patient sera in vitro. Conclusions and implications: We established nonpathogenic high avidity chimeric antibodies against the extracellular domains of human AQP4, which provide a novel therapeutic option for preventing the progress and recurrence of NMO/NMO spectrum disorders. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 09/2015; DOI:10.1111/bph.13340
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    ABSTRACT: Background and purpose: Herein we characterize 3-cyclopropyl-1-(4-(6-((1,1-dioxidothiomorpholino)methyl)-5-fluoropyridin-2-yl)benzyl)imidazolidine-2,4-dione hydrochloride (LEI-101), as a novel, peripherally restricted cannabinoid 2 receptor (CB2 R) agonist, using both in vitro and in vivo assays/models, including a clinically relevant murine model of nephropathy. Experimental approach: We investigated the effects of LEI-101 on CB2 R binding and functional activity. We assessed its in vitro and in vivo selectivity. Efficacy of LEI-101 was determined in a mouse model of cisplatin-induced nephrotoxicity. Key results: LEI-101 behaved as a partial CB2 R agonist in β-arrestin and GTPγS assays and was ~100-fold selective in CB2 R/CB1 R-binding assays. It did not display any activity on endocannabinoid hydrolases and nor did it react with serine hydrolases in an activity-based protein profiling assay. In mice, LEI-101 had excellent oral bioavailability reaching high concentrations in the kidney and liver with minimal penetration to the brain. LEI-101 up to a dose of 60 mg/kg (p.o.) did not exert any CNS-mediated effects in the mice tetrad assay. LEI-101 (p.o. or i.p.) at 3 or 10 mg/kg dose-dependently prevented kidney dysfunction and/or morphological damage induced by cisplatin in mice. These protective effects were associated with improved renal histopathological injury, attenuated oxidative stress and inflammation in the kidney, and were absent in CB2 R knockout mice. Conclusion and implications: These results indicate that LEI-101 is a selective, largely peripherally restricted, orally available CB2 R agonist with therapeutic potential in diseases that are associated with inflammation and/or oxidative stress, including kidney disease. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 09/2015; DOI:10.1111/bph.13338
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    ABSTRACT: Background and purpose: Acetaminophen (APAP) is the most widely used over-the-counter non-steroidal analgesic. Overdose of APAP is the leading cause of hospital admission for acute liver failure. 5-Lipoxygenase (5-LO) catalyzes arachidonic acid to form leukotrienes, which lead to inflammation and oxidative stress. In this study, we examined whether ablation or pharmacological inhibition of 5-LO could protect mice against APAP-induced hepatic toxicity. Experimental approach: Both genetic and pharmacological mouse models were used to study the role of 5-LO in APAP-induced liver toxicity. Serum and tissue biochemistry, H&E staining and real-time PCR were used to assess liver toxicity. Key results: Ablation or pharmacological inhibition of 5-LO in mice markedly ameliorated APAP-induced hepatic injury, as revealed by decreased serum alanine transaminase and aspartate aminotransferase levels and hepatic centrilobular necrosis. The hepatoprotective effect of 5-LO inhibition was associated with induction of antitoxic phase II conjugating enzymes Sult2a1, suppression of protoxic phase I cytochrome P450 3A11 and reduction of hepatic transporter MRP3. In 5-LO-/- mice, level of glutathione was increased and oxidative stress decreased. In addition, peroxisome proliferator-activated receptor α, a nuclear receptor that confers resistance to APAP toxicity, was activated in 5-LO-/- mice. Conclusions and implications: 5-LO may play a critical role in APAP-induced hepatic toxicity by regulating APAP metabolism and oxidative stress. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 09/2015; DOI:10.1111/bph.13336
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    ABSTRACT: Background and purpose: The ventral portion of the medial prefrontal cortex (vMPFC) comprises the infralimbic(IL), prelimbic(PL) and dorsopenducular(DP) cortices. The IL and PL regions facilitate the baroreceptor reflex arc. Such facilitatory role on the baroreflex is suggested to be played by the vMPFC glutamatergic transmission, through N-methyl-D-aspartate glutamate receptors (NMDA receptors). The glutamatergic transmission can be modulated by other neurotransmitters, such as the endocannabinoids, which are agonists of the transient receptor potencial vanilloid type 1(TRPV1 receptors). The TRPV1 channels facilitate the glutamatergic transmission in the brain. Thus, our hypothesis is that the vMPFC TRPV1 receptors enhance the cardiac baroreflex response. Experimental approach: Male Wistar rats, had stainless steel guide cannulae bilaterally implanted into the vMPFC. Afterwards, a catheter was inserted into the femoral artery, for MAP and HR recording, and into the femoral vein for baroreflex activation. Key results: The TRPV1 receptors antagonism by capsazepine or 6-iodo-nordihydrocapsaicin (6-IODO) microinjection into the vMPFC reduced the cardiac baroreflex activity in unanesthetized rats. Capsaicin microinjected into the vMPFC increased the cardiac baroreflex activity in unanesthetized rats. The antagonism of the TRPV1 receptors with an ineffective dose of 6-IODO abolished the increasing in the cardiac baroreflex response induced by capsaicin. The higher doses of capsaicin administered into the vMPFC after the ineffective dose of 6-IODO displaced the dose-response curve of the baroreflex parameters to the right, with no alteration in the maximum effect of capsaicin. Conclusions and implications: The present work shows that the vMPFC TRPV1 receptors increase the cardiac baroreceptor reflex response. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 09/2015; DOI:10.1111/bph.13327
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    ABSTRACT: Background and purpose: It has been proposed that medicinal strains of cannabis and therapeutic preparations would be safer with a more balanced concentration ratio of Δ9-tetrahydrocannabinol (THC) to cannabidiol (CBD), as CBD reduces the adverse psychotropic effects of THC. However, our understanding of CBD and THC interactions is limited and the brain circuitry mediating interactions between CBD and THC are unknown. The aim of this study is to investigate whether CBD modulates THC-induced functional effects and c-Fos expression in a 1:1 dose ratio that approximates therapeutic strains of cannabis and nabiximols. Experimental approach: Male C57BL/6 mice were treated with vehicle, CBD, THC, or a combination of CBD and THC (10 i.p. for both cannabinoids) to examine effects on locomotor activity, anxiety-related behaviour, body temperature, and brain c-Fos expression (a marker of neuronal activation). Key results: CBD potentiated THC-induced locomotor suppression but reduced the hypothermic and anxiogenic effects of THC. CBD alone had no effect on these measures. THC increased brain activation as measured by c-Fos expression in 11 of the 35 brain regions studied; CBD co-administration suppressed THC-induced c-Fos expression in 6 of these brains regions. This effect was most pronounced in the medial preoptic nucleus and lateral PAG. CBD alone treatment diminished c-Fos expression only in the central nucleus of the amygdala compared to vehicle. Conclusions and implications: These data re-affirm that CBD modulates the pharmacological actions of THC and provide information regarding brain regions involved in the interaction between CBD and THC.
    British Journal of Pharmacology 09/2015; DOI:10.1111/bph.13333
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    ABSTRACT: Background and purpose: Specific high potent receptor antagonists are valuable tools when evaluating animal and human physiology. Within the glucose-dependent insulinotropic polypeptide (GIP) system, considerable attention has been given to the presumed GIP receptor antagonist (Pro3)GIP and its effect in murine studies. We conducted a pharmacological analysis of this ligand including interspecies differences between the rodent and human GIP system. Experimental approach: Transiently transfected COS-7 cells were assessed for cAMP accumulation upon ligand stimulation and assayed in competition binding using (125) I-human GIP. Using isolated perfused rodent pancreata both from wild type and GIPR-deficient animals, insulin-, glucagon-, and somatostatin-releasing properties in response to species-specific GIP and (Pro3)GIP analogues were evaluated. Key results: Human (Pro3)GIP is an efficacious agonist on the human GIPR with similar efficacy (Emax ) in cAMP production as human GIP, while both rat and mouse(Pro3)GIP were partial agonists on their corresponding receptors. Rodent GIPs are more potent and efficacious at their receptors than human GIP. In perfused pancreata at 7 mM glucose, both rodent (Pro3)GIP analogues induced modest insulin, glucagon and somatostatin secretion corresponding to the partial agonism observed in cAMP production. Conclusions and Implications When evaluating compound properties it is important to consider interspecies differences both at the receptor and ligand level. Thus, in rodent models human GIP is a comparatively weak partial agonist. Human (Pro3)GIP is not an effective antagonist, so there is still a need for an effective antagonist for the elucidation of GIP's physiology.
    British Journal of Pharmacology 09/2015; DOI:10.1111/bph.13323
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    ABSTRACT: Background and purpose: β2/3-subunit-selective modulation of γ-aminobutyric acid (GABA) type A (GABAA ) receptors by valerenic acid (VA) is determined by the presence of transmembrane residue β2/3 N265. Currently, it is unknown whether β2/3 N265 is part of VA's binding pocket or is involved in the transduction pathway of VA's action. Aim of the study was to clarify the localization of VA's binding pocket on GABAA receptors. Experimental approach: Docking and a structure-based 3D-pharmacophore were employed to identify candidate amino acid residues that are likely to interact with VA. Selected amino acid residues were mutated and VA-induced modulation of the resulting GABAA receptors expressed in Xenopus oocytes was analyzed. Key results: A binding pocket for VA at the β(+) /α(-) -interface encompassing amino acid β3N265 was predicted. Mutational analysis of suggested amino acid residues revealed a complete loss of VA's activity on β3M286W channels as well as significantly decreased efficacy and potency of VA on β3N265S and β3F289S receptors. In addition, reduced efficacy of VA-induced IGABA enhancement was also observed for α1M235W, β3R269A and β3M286A constructs. Conclusions and implications: Our data suggest that amino acid residues β3N265, β3F289 and β3M286 and β3R269 in the β3-subunit, at or near the etomidate/propofol binding site(s), form part of a VA binding pocket. The identification of the binding pocket for VA is essential for elucidating its pharmacological effects and might also help to develop new selective GABAA receptor ligands.
    British Journal of Pharmacology 09/2015; DOI:10.1111/bph.13329
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    ABSTRACT: BACKGROUND AND PURPOSEAbnormal Ca2+ metabolism has been involved in the pathogenesis of vascular dysfunction associated to oxidative stress. We sought to investigate here the actions of hydrogen peroxide (H2O2) on store-operated Ca2+ (SOC) entry in coronary arteries and to assess whether it is impaired in arteries from a rat model of metabolic syndrome.EXPERIMENTAL APPROACHSimultaneous measurements of intracellular Ca2+ [Ca2+]i and contractile responses were performed in coronary arteries from Wistar and obese Zucker rats (OZR) mounted in microvascular myographs and the effects of H2O2 were assessed.KEY RESULTSH2O2 evoked a rise in intracellular [Ca2+]i accompanied by simultaneous vasoconstriction that were markedly reduced in a Ca2+-free medium. Upon Ca2+ readdition, a nifedipine-resistant sustained Ca2+ entry not coupled to contraction was obtained in endothelium-denuded coronary arteries. The effect of H2O2 on this voltage-independent Ca2+ influx was concentration-dependent and high micromolar H2O2 concentrations were inhibitory and reduced SOC entry evoked by inhibition of the sarcoplasmic reticulum (SR) ATPase (SERCA). H2O2-induced rises in Fura signal were mimicked by Ba2+ and reduced by heparin, gadolinium (Gd3+) and by the selective inhibitor of the Orai1-mediated Ca2+ entry Pyr6. In coronary arteries from obese Zucker rats (OZR), intracellular Ca2+ mobilization and SOC entry activated by acute exposure to H2O2 were augmented and associated to local oxidative stress.CONCLUSION AND IMPLICATIONSH2O2 has dual concentration-dependent stimulatory/inhibitory effects on store-operated IP3R- and Orai1-mediated Ca2+ entry not coupled to vasoconstriction in coronary VSM. SOC entry activated by H2O2 is enhanced and associated with vascular oxidative stress in coronary arteries in metabolic syndrome. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 09/2015; DOI:10.1111/bph.13322
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    ABSTRACT: Valproic acid (VPA), a widely used epilepsy and bipolar disorder treatment, provides acute protection against haemorrhagic shock-induced mortality in a range of in vivo models through an unknown mechanism. In the liver, this effect occurs with a concomitant protection against a decrease in GSK3β-Ser(9) phosphorylation. Here, we develop an in vitro model to investigate this protective effect of VPA and define a molecular mechanism. The human hepatocarcinoma cell line (Huh7) was exposed to conditions occurring during haemorrhagic shock (hypoxia, hypercapnia, and hypothermia) to investigate the changes in GSK3β-Ser(9) phosphorylation for a four hour period following treatment with VPA, related congeners, peroxisome proliferator-activated receptor (PPAR) agonists, antagonists, and siRNA. Huh7 cells undergoing combined hypoxia, hypercapnia, and hypothermia reproduce the reduced GSK3β-Ser(9) phosphorylation shown in vivo during haemorrhagic shock and this change was blocked by VPA. The protective effect occurred through upstream PTEN and Akt signalling, and prevented downstream β-catenin degradation while increasing histone 2/3 acetylation. This effect was reproduced by several valproic acid-related compounds with known PPARγ agonist activity, independent of histone deacetylase (HDAC) inhibitory activity. Specific pharmacological inhibition (by T0070907) or by knockdown of PPARγ blocked the effect of VPA in protection against these signalling changes and apoptosis, and specific activation of PPARγ using Ciglitazone reproduced changes shown by VPA during protection against haemorrhagic shock-like conditions. Changes in GSK3β-Ser(9) phosphorylation in in vivo haemorrhagic shock models can be modelled in vitro, and this has identified a role for PPARγ activation in the protective role of VPA. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 09/2015; DOI:10.1111/bph.13320
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    ABSTRACT: Background and purpose: Sphingosine-1-phosphate (S1P), an important inflammatory mediator, has been shown to regulate cyclooxygenase-2 (COX-2) production and promote various cellular responses such as cell migration. Mevastatin (MVS), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, effectively inhibits inflammatory responses. However, the mechanisms underlying S1P-evoked COX-2-dependent cell migration which is modulated by MVS in human tracheal smooth muscle cells (HTSMCs) remain unclear. Experimental approach: The COX-2 expression was determined by Western blotting, real time-PCR, and promoter analyses. The signaling molecules were investigated by pretreatment with respective pharmacological inhibitors or transfection with siRNAs. The interaction between COX-2 promoter and transcription factors was determined by chromatin immunoprecipitation (ChIP) assay. Finally, the effect of MVS on HTSMC migration and leukocyte count in BAL fluid and COX-2 expression induced by S1P was determined by cell migration assay, cell counting, and Western blot. Key results: We observed that S1P stimulated mTOR activation through the Nox2/ROS and PI3K/Akt pathways, which can further stimulate FoxO1 phosphorylation and translocation to the cytosol. We also found that S1P induced CREB activation and translocation via an mTOR-independent signaling pathway. Finally, we showed that pretreatment with MVS markedly reduced S1P-induced cell migration and COX-2/PGE2 production via a PPARγ-dependent signaling. Conclusions and implications: MVS attenuates the S1P-induced COX-2 expression and cell migration via the regulation of FoxO1 and CREB phosphorylation and translocation by PPARγ in HTSMCs. MVS could be beneficial for prevention of airway inflammation in the future. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 09/2015; DOI:10.1111/bph.13326
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    ABSTRACT: BACKGROUND AND PURPOSERegulators of G protein signaling (RGS) are strong determinants of metabotropic receptor activity, reducing the lifespan of the GTP-bound state of G proteins. Accumulating evidence suggests that the reduced potency of analgesic agents in neuropathic pain may be due to alterations in RGS. We investigated the effects of intrathecal CCG 63802, a specific RGS4 inhibitor, on neuropathic pain and signaling through the cannabinoid receptor type 1 (CB1) after nerve lesion.KEY RESULTSMale Sprague Dawley rats treated with CCG 63802 two times daily for the first week after nerve injury showed attenuated thermal hyperalgesia during the treatment period. The spinal level of anandamide was up-regulated in nerve lesioned animals irrespective of the treatment. Although the expression of CB1 was unaffected, HU210-induced CB1 signaling was impaired by the nerve lesion and rescued by intrathecal CCG 63802 treatment. A functional link between CB1 and RGS4 was unequivocally shown in transfected HEK cells combining CB1 expression with conditional expression of RGS4. Inhibition of cAMP production, a down-stream effect of CB1 signaling, was blunted upon RGS4 overexpression. RGS4 expression also attenuated the CB1-controlled activation of extracellular-signal-regulated kinase.CONCLUSIONS AND IMPLICATIONSSpinal inhibition of RGS4 restores endogenous analgesic signaling to effectively mitigate neuropathic pain. This report suggests that signaling through the CB1 may be involved in this beneficial effect. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 09/2015; DOI:10.1111/bph.13324
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    ABSTRACT: Background and purpose: In drug research using the rat Langendorff preparation, it is possible to study left ventricular (LV) contractility using an intraventricular balloon (IVB), and arrhythmogenesis during coronary ligation-induced regional ischaemia. Assessing both concurrently would halve animal requirements. We aimed to test the validity of this approach. Experimental approach: The electrocardiogram (ECG) and LV function (IVB) were recorded during regional ischaemia of different extents, in a randomized and blinded study. Key results: IVB-induced proarrhythmia was anticipated, yet in hearts with an ischaemic zone (IZ) made deliberately small, an inflated IVB reduced ischaemia-induced VF incidence as a trend. Repeating studies in hearts with large IZs revealed the effect to be significant. There were no changes in QT or other variables that might explain the effect. Insertion of an IVB that was minimally inflated had no effect on any variable versus 'no IVB' controls. The antiarrhythmic effect of verapamil (a positive control drug) was unaffected by IVB inflation. Removal of an inflated (but not a non-inflated) IVB caused a release of lactate commensurate with reperfusion of an endocardial/subendocardial layer of IVB-induced ischaemia. This was confirmed by intracellular (31) phosphorus ((31) Pi ) nuclear magnetic resonance (NMR) spectroscopy. Conclusions and implications: IVB inflation does not inhibit VF suppression by a standard drug, but it has profound antiarrhythmic effects of its own, likely due to inflation-induced localized ischaemia. This means rhythm and contractility cannot be assessed concurrently by this approach, with implications for drug discovery and safety assessment.
    British Journal of Pharmacology 09/2015; DOI:10.1111/bph.13332
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    ABSTRACT: BACKGROUND AND PURPOSEPlatelets are potent regulators of neutrophil accumulation in septic lung damage. In the present study, we hypothesised that platelet-derived CXCL4 might support pulmonary neutrophilia in a murine model of abdominal sepsis.EXPERIMENTAL APPROACHPolymicrobial sepsis was triggered by coecal ligation and puncture (CLP) in C57BL/6 mice. Platelet secretion of CXCL4 was studied by using confocal microscopy. Plasma and lung levels of CXCL4, CXCL1 and CXCL2 were determined by use of ELISA. Flow cytometry was used to examine surface expression of Mac-1 on neutrophils.KEY RESULTSCLP increased CXCL4 levels in plasma and depletion of platelets markedly reduced plasma levels of CXCL4 in septic animals. Administration of the Rac1 inhibitor NSC23766 decreased the CLP-induced enhancement of CXCL4 levels in plasma by 77%. In addition, inhibition of Rac1 abolished proteinase-activated receptor-4 agonist-induced secretion of CXCL4 from isolated platelets. Inhibition of CXCL4 reduced CLP-evoked neutrophil recruitment, oedema formation and tissue damage in the lung. However, immunoneutralisation of CXCL4 had no effect on CLP-induced expression of Mac-1 on neutrophils. Targeting CXCL4 significantly attenuated plasma and lung levels of CXCL1 and CXCL2 in septic mice. CXCL4 had no effect on neutrophil chemotaxis in vitro, indicating an indirect effect of CXCL4 on pulmonary neutrophilia. Intratracheal administration of CXCL4 enhanced infiltration of neutrophils and formation of CXCL2 in the lung. Treatment with the CXCR2 antagonist SB225002 markedly reduced CXCL4-provoked neutrophil accumulation in the lung. CXCL4 caused clear-cut secretion of CXCL2 from isolated alveolar macrophages.CONCLUSIONS AND IMPLICATIONSThese results indicate that Rac1 controls platelet secretion of CXCL4 and that CXCL4 is a potent stimulator of neutrophil accumulation in septic lung damage via generation of CXCL2 in alveolar macrophages. We conclude that platelet-derived CXCL4 plays an important role in lung inflammation and tissue damage in polymicrobial sepsis. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 09/2015; DOI:10.1111/bph.13325