British Journal of Pharmacology (BRIT J PHARMACOL )

Publisher: British Pharmacological Society, Blackwell Publishing

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.

  • Impact factor
    5.07
    Show impact factor history
     
    Impact factor
  • 5-year impact
    4.90
  • Cited half-life
    7.70
  • Immediacy index
    1.29
  • Eigenfactor
    0.05
  • Article influence
    1.37
  • Website
    British Journal of Pharmacology website
  • Other titles
    British journal of pharmacology, BJP, Proceedings of the British Pharmacological Society
  • ISSN
    0007-1188
  • OCLC
    1240522
  • Material type
    Periodical, Internet resource
  • Document type
    Journal / Magazine / Newspaper, Internet Resource

Publisher details

Blackwell Publishing

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author cannot archive a post-print version
  • Restrictions
    • Some journals impose embargoes typically of 6 or 12 months, occasionally of 24 months
    • no listing of affected journals available as yet
  • Conditions
    • See Wiley-Blackwell entry for articles after February 2007
    • Publisher version cannot be used
    • On author or institutional or subject-based server
    • Server must be non-commercial
    • Publisher copyright and source must be acknowledged with set statement ("The definitive version is available at www.blackwell-synergy.com ")
    • Articles in some journals can be made Open Access on payment of additional charge
    • 'Blackwell Publishing' is an imprint of 'Wiley-Blackwell'
  • Classification
    ​ yellow

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background and purposeHeteromerization of G protein-coupled receptors is key on the integration of extracellular signals and the subsequent cell response via several mechanisms including heteromer-selective ligand binding, trafficking and/or downstream signaling. Considering the modulatory impact of the lysophosphatidylinositol G protein-coupled receptor 55 (GPR55) on the function of cannabinoid receptor subtype 2 (CB2R) in human neutrophils, a potential heteromerization of CB2R and GPR55 was hypothesized.Experimental approachDirect interaction of human GPR55 and CB2R heterologously expressed in HEK293 cells was assessed by co-immunoprecipitation and bioluminescence resonance energy transfer (BRET) assays. Moreover, the cross-talk on signaling was investigated at downstream levels by label-free real-time methods (Epic dynamic mass redistribution and CellKey impedance assays), ERK1/2-MAP kinase activation and gene reporter assays.Key resultsGPR55 and CB2R colocalize on the surface of human embryonic HEK293 cells, co-precipitate in membrane extracts and form heteromers in living HEK293 cells. Whereas heteromerization leads to a reduction of GPR55-mediated activation of transcription factors (NFAT, NF-κB and CRE), the ERK1/2-MAP kinase activation is potentiated in the presence of CB2R. CB2R-mediated signaling is also affected by co-expression with GPR55. Moreover, label-free assays confirmed a cross-talk between the two receptors.Conclusions and implicationsIn HEK293 cells expressing GPR55 and cannabinoid CB2R receptors, heteromers that are unique signaling units are formed. The signaling by agonists of either receptor is governed i) by the presence or absence of the partner receptors (with the consequent formation of heteromers) and ii) by the activation state of the partner receptor.
    British Journal of Pharmacology 07/2014;
  • British Journal of Pharmacology 03/2014;
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    ABSTRACT: In vitro inhibitory potency (K i)‐based predictions of P‐glycoprotein (P‐gp)‐mediated drug‐drug interactions (DDIs) are hampered by the substantial variability in inhibitory potency. In this study, in vivo‐based [I]/K i values were used to predict the DDI risks of a P‐gp substrate dabigatran etexilate (DABE) using physiologically based pharmacokinetic (PBPK) modelling.
    British Journal of Pharmacology 01/2014; 171(4).
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    ABSTRACT: BACKGROUND AND PURPOSE Annexin A6 (AnxA6) is a calcium-dependent phospholipid binding protein that can be recruited to the plasma membrane to function as a scaffolding protein to regulate signal complex formation, endo- and exocytic pathways as well as distribution of cellular cholesterol. The purpose of this study was to investigate how AnxA6 influences the membrane order in vitro and in vivo. EXPERIMENTAL APPROACH We used Laurdan and di-4-ANEPPDHQ staining in [i] artificial membranes and [ii] live cells to investigate membrane packing and ordered lipid phases, and [iii] a super-resolution imaging approach (photoactivated localization microscopy, PALM) to assess how AnxA6 regulates plasma membrane order domains and protein clustering. KEY RESULTS In artificial membranes, purified AnxA6 induced a significant global increase in membrane order. Confocal microscopy using di-4-ANEPPDHQ in vivo showed that cells expressing high AnxA6 levels display a significant decrease in membrane order. Lck10 and Src15 membrane raft/non-raft markers PALM data revealed that AnxA6 overexpression induces clustering of both raft and nonraft markers. Altered clustering of Lck10 and Src15 in cells expressing AnxA6 was also observed after cholesterol extraction with methyl-β-cyclodextrin or actin cytoskeleton disruption with latrunculin B. CONCLUSIONS AND IMPLICATIONS AnxA6-induced plasma membrane remodelling indicates that elevated AnxA6 expression significantly decreases membrane order through the regulation of cellular cholesterol homeostasis and actin cytoskeleton. This study provides the first in vivo evidence that support current models of annexins as membrane organizers.
    British Journal of Pharmacology 01/2014;
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    ABSTRACT: Background and PurposeImmune challenge of mice with Bacille Calmette–Guérin (BCG) has been reported to cause transient weight loss and a behavioural sickness response. Although BCG‐induced depression involves the kynurenine pathway, weight loss occurs independently of this factor. Because neuropeptide Y (NPY) and peptide YY (PYY) are involved in the regulation of food intake, we hypothesized that they play a role in the BCG‐induced weight loss. Experimental ApproachMale wild‐type, PYY knockout (PYY−/−), NPY knockout (NPY−/−) and NPY−/−;PYY−/− double knockout mice were injected with vehicle or BCG (approximately 108 colony‐forming units per mouse), and their weight, locomotion, exploration and ingestion were recorded for 2 weeks post‐treatment. Key ResultsDeletion of PYY and NPY aggravated the BCG‐induced loss of body weight, which was most pronounced in NPY−/−;PYY−/− mice (maximum loss: 15%). The weight loss in NPY−/−;PYY−/− mice did not normalize during the 2 week observation period. BCG suppressed the circadian pattern of locomotion, exploration and food intake. However, these changes took a different time course than the prolonged weight loss caused by BCG in NPY−/−;PYY−/− mice. The effect of BCG to increase circulating IL‐6 (measured 16 days post‐treatment) remained unaltered by knockout of PYY, NPY or NPY plus PYY. Conclusions and ImplicationsThese data show that NPY and PYY are both required to protect from the action of BCG‐evoked immune challenge to cause prolonged weight loss and disturb energy balance. The findings attest to an important role of NPY and PYY in orchestrating homeostatic reactions to infection and immune stimulation.
    British Journal of Pharmacology 11/2013; 170(5).
  • British Journal of Pharmacology 08/2013;
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    ABSTRACT: Abstract BACKGROUND AND PURPOSE: The histamine H4 receptor has a primary role in inflammatory functions that has made it an attractive target for the treatment of asthma and refractory inflammation. These observations suggested a facilitating action on autoimmune diseases. However, little is known about the role of the H4 receptor in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). EXPERIMENTAL APPROACH: We used EAE induced by myelin oligodendrocyte glycoprotein (MOG35-55 ) in C57BL/6 female mice, as a model of multiple sclerosis. The histamine H4 receptor antagonist 5-chloro-2-[(4-methylpiperazin-1-yl)carbonyl]-1H-indole (JNJ7777120) was injected i.p. daily starting at day 10 post-immunisation (D10 p.i.). Disease severity was monitored by clinical and histopathological evaluation of inflammatory cells infiltrating into the spinal cord, anti-MOG35-55 antibody production, assay of T cell proliferation by [3 H]-thymidine incorporation, mononucleate cells phenotype by flow cytometry, cytokine production by ELISA assay, transcription factors quantification of mRNA expression. KEY RESULTS: Treatment with JNJ7777120 worsened the severity of EAE, increased inflammation and demyelination in the spinal cord of EAE mice, it increased IFN-γ expression in lymph nodes, whereas it suppressed IL-4 and IL-10, and augmented expression of the transcription factors Tbet , FOXP3 and IL-17 mRNA in lymphocytes. JNJ7777120 did neither affect proliferation of anti-MOG35-55 T cells, anti-MOG35-55 antibody production, nor mononucleate cell phenotype. CONCLUSIONS AND IMPLICATIONS: Our data show a detrimental effect of H4 receptor blockade in EAE. Given the interest in the development of H4 receptor antagonists as anti-inflammatory compounds, it is important to understand the role of the H4 receptor in immune diseases to anticipate clinical benefits and also predict possible detrimental effects.
    British Journal of Pharmacology 06/2013;
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    ABSTRACT: BACKGROUND AND PURPOSE: Nutrient sensing in the gut is believed to be accomplished through activation of G-protein coupled receptors expressed on enteroendocrine cells. In particular, L-cells located predominantly in distal regions of the gut secrete GLP-1 and PYY upon stimulation by nutrients and bile acids. The study was designed to address the mechanism of hormone secretion in L-cells stimulated by the bile acid receptor GPBAR1. EXPERIMENTAL APPROACH: A novel, selective, orally bioavailable, and potent GPBAR1 agonist, RO5527239, was synthesized in order to investigate L-cell secretion in vitro and in vivo in mice and monkey. In analogy to bile acids, RO5527239 was conjugated with taurine to reduce oral bioavailability yet retaining its potency. Using RO5527239 and tauro-RO5527239, the acute secretion effects on L-cells were addressed via different routes of administration. KEY RESULTS: GPBAR1 signalling triggers the co-secretion of PYY and GLP-1, and leads to improved glucose tolerance. The strong correlation of plasma drug exposure and plasma PYY levels suggests activation of GPBAR1 from systemically accessible compartments. In contrast to the orally bioavailable agonist RO5527239, we show that tauro-RO5527239 triggers PYY release only when applied intravenously. Compared to mice, a slower and more sustained PYY secretion was observed in monkeys. CONCLUSIONS AND IMPLICATIONS: Selective GPBAR1 activation elicits a strong secretagogue effect on L-cells, which primarily requires systemic exposure. We suggest that GPBAR1 is a key player in the intestinal proximal-distal loop that mediates the early phase of nutrient-evoked L-cell secretion effects.
    British Journal of Pharmacology 03/2013;
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    ABSTRACT: BACKGROUND AND PURPOSE: Phosphodiesterase 4 (PDE4) inhibitors produce potent antidepressant-like and cognition-enhancing effects. However, their clinical utility is limited by the major side effect of emesis, which appears to be PDE4 isoform-specific. Although PDE4D subtype plays the pivotal role in these therapeutic profiles, it is also the primary subtype responsible for emesis. Therefore, the aim of present research was to investigate whether long-form PDE4D variants mediate antidepressant-like and cognition-enhancing effects, but are irrespective with emesis. EXPERIMENTAL APPROACH: In mice microinfused with lentiviral vectors that contained shRNA-mir hairpin structure targeting long-form PDE4Ds into bilateral prefrontal cortices, the tail-suspension and forced-swim tests were used to measure antidepressant-like effects; novel object recognition and Morris water-maze tasks were used to determine cognition-enhancing effects. The emetic potential was assessed by alpha2 adrenergic receptor-mediated anaesthesia, a surrogate measure of emesis. Intracellular cAMP signalling was analysed by time-resolved FRET immunoassay and Western-blot. Dendritic complexity was assessed by Golgi staining. KEY RESULTS: Microinfusions of lentiviral PDE4D-shRNA down-regulated PDE4D4 and PDE4D5, and imitated the antidepressant-like and cognition-enhancing effects of the prototypical PDE4 inhibitor rolipram. The behavioural effects were related to dendritic complexity and mediated by the increased cAMP signalling. In addition, these effects were not enhanced in the presence of rolipram. Finally, while rolipram shortened the duration of combined anaesthesia, RNA interference-mediated PDE4D knock-down in the prefrontal cortex did not. CONCLUSION AND IMPLICATIONS: These data suggest that long-form PDE4Ds, at least PDE4D4 and PDE4D5, may be the promising targets for the development of PDE4 variant-selective inhibitors as the new pharmacotherapies for depressive disorders and neurodegenerative diseases involving memory deficits.
    British Journal of Pharmacology 02/2013; 168(4):1001-1014.
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    ABSTRACT: Background and PurposeSU4312, a potent and selective inhibitor of VEGF receptor‐2 (VEGFR‐2), has been designed to treat cancer. Recent studies have suggested that SU4312 can also be useful in treating neurodegenerative disorders. In this study, we assessed neuroprotection by SU4312 against 1‐methyl‐4‐phenylpyridinium ion (MPP+)‐induced neurotoxicity and further explored the underlying mechanisms. Experimental ApproachMPP+‐treated neurons and 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐treated zebrafish were used to study neuroprotection by SU4312. NOS activity was assayed in vitro to examine direct interactions between SU4312 and NOS isoforms. Key ResultsSU4312 unexpectedly prevented MPP+‐induced neuronal apoptosis in vitro and decreased MPTP‐induced loss of dopaminergic neurons, reduced expression of mRNA for tyrosine hydroxylase and impaired swimming behaviour in zebrafish. In contrast, PTK787/ZK222584, a well‐studied VEGFR‐2 inhibitor, failed to prevent neurotoxicity, suggesting that the neuroprotective actions of SU4312 were independent of its anti‐angiogenic action. Furthermore, SU4312 exhibited non‐competitive inhibition of purified neuronal NOS (nNOS) with an IC50 value of 19.0 μM but showed little or no effects on inducible and endothelial NOS. Molecular docking simulations suggested an interaction between SU4312 and the haem group within the active centre of nNOS. Conclusions and ImplicationSU4312 exhibited neuroprotection against MPP+ at least partly via selective and direct inhibition of nNOS. Because SU4312 could reach the brain in rats, our study also offered a support for further development of SU4312 to treat neurodegenerative disorders, particularly those associated with NO‐mediated neurotoxicity.
    British Journal of Pharmacology 01/2013; 168(5).
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    ABSTRACT: Background and PurposeThe glycoprotein IIb/IIIa receptor is the final common pathway of platelet aggregation, regardless of the agonist, and thus represents an ideal therapeutic target for blocking coronary thrombosis. In this study, the anti‐platelet and antithrombotic actions of Z4A5, a new glycoprotein IIb/IIIa receptor inhibitor, were evaluated in a canine model of acute unstable angina. Experimental ApproachZ4A5 was given i.v. as a bolus followed by 60 min of continuous infusion at doses of 30 μg·kg−1 + 1 μg·kg−1·min−1, 30 μg·kg−1 + 5 μg·kg−1·min−1 or 300 μg·kg−1 + 5 μg·kg−1·min−1. Its antithrombotic effect was evaluated in a model of coronary thrombosis, the injured, stenosed left circumflex coronary artery, in which platelet‐dependent cyclic flow reductions (CFRs) were induced by vascular compression and constriction to simulate clinical acute unstable angina. Platelet aggregation and coagulation parameters were determined in platelet‐rich plasma and platelet poor plasma respectively. Key ResultsThe Z4A5 infusion induced a dose‐dependent reduction in CFR frequency, which returned to baseline levels after the termination of the infusion at low doses. At medium dose that inhibited most part of platelet aggregation, it increased tongue bleeding time marginally with no dramatic changes in haemodynamic and coagulation parameters. Furthermore, the inhibition of ADP‐induced platelet aggregation and prolonged bleeding time observed during Z4A5 infusion reverted to baseline levels after the termination of the infusion. Conclusions and ImplicationsZ4A5 is an effective antithrombotic agent for coronary artery thrombosis with a rapid‐on and rapid‐off pharmacological profile, and could be used as an alternative treatment of coronary artery ischaemic syndromes.
    British Journal of Pharmacology 01/2013; 169(4).
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    ABSTRACT: The award of the 2012 Nobel Prize in Chemistry to Robert Lefkowitz and Brian Kobilka for their work on the structure and function of GPCRs, spanning a period of more than 20 years from the cloning of the human β2‐adrenoceptor to determining the crystal structure of the same protein, has earned both researchers a much deserved place in the pantheon of major scientific discoveries. GPCRs comprise one of the largest families of proteins, controlling many major physiological processes and have been a major focus of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR) since its inception in 1987. We report here recent efforts by the British Pharmacological Society and NC‐IUPHAR to define the endogenous ligands of ‘orphan’ GPCRs and to place authoritative and accessible information about these crucial therapeutic targets online.
    British Journal of Pharmacology 01/2013; 170(4).
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    ABSTRACT: Peroxisome proliferator activated receptors (PPARs) are ligand‐activated transcription factors expressed in trophoblasts, which regulate both cell differentiation and proliferation. In recent years, evidence has linked PPARs to playing an integral role in pregnancy; specifically, PPAR‐β and PPAR‐γ have been shown to play an integral role in placentation, with PPAR‐γ additionally serving to regulate trophoblast differentiation. Recent evidence has shown that PPAR‐γ expression is altered in many complications of pregnancy such as intrauterine growth restriction (IUGR), preterm birth, pre‐clampsia and gestational diabetes. Thus, at present, accumulating evidence from the literature suggests both a pivotal role for PPAR‐γ in the progression of a healthy pregnancy and the possibility that PPAR‐γ may act as a therapeutic target in complicated pregnancies. This review aims to provide a succinct and comprehensive assessment of the role of PPAR‐γ in normal pregnancy and pregnancy complications, and finally its potential as a therapeutic target in the treatment and/or prevention of adverse pregnancy outcomes.
    British Journal of Pharmacology 01/2013; 168(5).
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background and PurposeThe histamine H4 receptor has a primary role in inflammatory functions, making it an attractive target for the treatment of asthma and refractory inflammation. These observations suggested a facilitating action on autoimmune diseases. Here we have assessed the role of H4 receptors in experimental autoimmune encephalomyelitis (EAE) a model of multiple sclerosis (MS). Experimental ApproachWe induced EAE with myelin oligodendrocyte glycoprotein (MOG35–55) in C57BL/6 female mice as a model of MS. The histamine H4 receptor antagonist 5‐chloro‐2‐[(4‐methylpiperazin‐1‐yl)carbonyl]‐1H‐indole (JNJ7777120) was injected i.p. daily starting at day 10 post‐immunization (D10 p.i.). Disease severity was monitored by clinical and histopathological evaluation of inflammatory cells infiltrating into the spinal cord, anti‐MOG35–55 antibody production, assay of T‐cell proliferation by [3H]‐thymidine incorporation, mononucleate cell phenotype by flow cytometry, cytokine production by elisa assay and transcription factor quantification of mRNA expression. Key ResultsTreatment with JNJ7777120 exacerbated EAE, increased inflammation and demyelination in the spinal cord of EAE mice and increased IFN‐γ expression in lymph nodes, whereas it suppressed IL‐4 and IL‐10, and augmented expression of the transcription factors Tbet, FOXP3 and IL‐17 mRNA in lymphocytes. JNJ7777120 did not affect proliferation of anti‐MOG35–55 T‐cells, anti‐MOG35–55 antibody production or mononucleate cell phenotype. Conclusions and ImplicationsH4 receptor blockade was detrimental in EAE. Given the interest in the development of H4 receptor antagonists as anti‐inflammatory compounds, it is important to understand the role of H4 receptors in immune diseases to anticipate clinical benefits and also predict possible detrimental effects. Linked ArticlesThis article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue‐1
    British Journal of Pharmacology 01/2013; 170(1).

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