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
    • Author cannot archive a post-print version
  • Restrictions
    • 12 months embargo
  • Conditions
    • Some journals have separate policies, please check with each journal directly
    • 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: Allosteric modulation of the mGlu2 receptor is a potential strategy for treatment of various neurological and psychiatric disorders. Here we describe the in vitro characterization of the mGlu2 PAM JNJ-46281222 and its radiolabelled counterpart [(3) H]JNJ-46281222. Using this novel tool, we also describe the allosteric effect of orthosteric glutamate binding and the presence of a bound G protein on PAM binding and use computational approaches to further investigate the binding mode. Experimental approach: We have used radioligand binding studies, functional assays, site-directed mutagenesis, homology modelling and molecular dynamics to study the binding of JNJ-46281222. Key results: JNJ-46281222 is an mGlu2 -selective, highly potent PAM with nanomolar affinity (KD = 1.7 nM). Binding of [(3) H]JNJ-46281222 was increased by the presence of glutamate and greatly reduced by the presence of GTP, indicating the preference for a G protein bound state of the receptor for PAM binding. Its allosteric binding site was visualized and analysed by a computational docking and molecular dynamics study. The simulations revealed amino acid movements in regions expected to be important for activation. The binding mode was supported by [(3) H]JNJ-46281222 binding experiments on mutant receptors. Conclusion and implications: Our results obtained with JNJ-46281222 in unlabelled and tritiated form further contribute to our understanding of mGlu2 allosteric modulation. The computational simulations and mutagenesis provide a plausible binding mode with indications of how the ligand permits allosteric activation. This study is therefore of interest for mGlu2 and class C receptor drug discovery.
    British Journal of Pharmacology 11/2015; DOI:10.1111/bph.13390
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    ABSTRACT: Background and purpose: Ventricular arrhythmias induced by hERG blockers are a consequence of both ventricular repolarisation alterations as a substrate associated with presence of high frequency (HF) oscillations as a primary trigger factor, the autonomic nervous system playing a modulator role. The present study was undertaken to investigate the role of β1 adrenoceptors on the HF relationship between magnitude of heart rate and QT interval changes within discrete 10 second intervals, sorted in 5 bpm heart rate increments and to study its implication for torsadogenic hERG blockers. Experimental approach: The HF relationship was studied under conditions of autonomic blockade with atenolol (β1 adrenoceptors blocker) in the absence or presence of five hERG blockers in beagle dogs. In total, effects of 14 hERG blockers on the HF relationship were reported. Key results: All tested torsadogenic hERG blockers caused a vertical shift of the HF relationship while hERG blockers associated with a low risk of Torsades de Pointes did not cause any vertical shift. Effects on the HF relationship were fully prevented by atenolol for four torsadogenic agents (quinidine, thioridazine, risperidone and terfenadine) and only partially reduced in the case of dofetilide, leading to characterisation of two profiles of torsadogenic agents. Conclusions and implications: The HF relationship allowed demonstration of signs of transient sympathetic activation during HF oscillations mediated by β1 adrenoceptors in the presence of torsadogenic hERG blockers. We suggest the HF relationship as new biomarker for Torsades de pointes liability assessment with potential implications both in preclinical studies and the clinic.
    British Journal of Pharmacology 11/2015; DOI:10.1111/bph.13391
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    ABSTRACT: Background and purpose: Glucose-dependent insulinotropic polypeptide (GIP) impacts lipid, bone, and glucose homeostasis. The GIP receptor belongs to G protein-coupled receptor family B1 and signals through GαS. High affinity ligands for in vivo use are needed to elucidate GIP's physiological functions and pharmacological potential. GIP(1-30)NH2 is a naturally occurring truncation of GIP(1-42). Here we characterize eight N-terminal trrncations of human GIP(1-30)NH2 : GIP(2- to 9-30)NH2 . Experimental approach: COS-7 cells were transiently transfected with the human GIP receptor and assessed for cAMP accumulation upon ligand stimulation or competition binding with (125) I-GIP(1-42), (125) I-GIP(1-30)NH2 , (125) I-GIP(2-30)NH2 , or (125) I-GIP(3-30)NH2 as radioligands. Key results: GIP(1-30)NH2 displaced (125) I-GIP(1-42) equally to GIP(1-42) (Ki 0.75 nM), whereas the eight variants displayed lower affinities (Ki 2.3-347 nM) with highest affinities of GIP(3-30)NH2 and (5-30)NH2 . Agonism was only observed for GIP(1-30)NH2 with an Emax on 100% of GIP(1-42) and GIP(2-30)NH2 (Emax 20%). GIP(2- to 9-30)NH2 displayed antagonism (IC50 12-450 nM) and right-shifts of the GIP(1-42)-response curve. Schild plot analyses identified GIP(3-30)NH2 and GIP(5-30)NH2 as competitive antagonists (Ki 15 nM). Importantly, GIP(3-30) antagonized with a 26-fold higher potency than GIP(3-42). Binding studies with agonist ((125) I-GIP(1-30)NH2 ), partial agonist ((125) I-GIP(2-30)NH2 ) and competitive antagonist ((125) I-GIP(3-30)NH2 ) revealed distinct receptor conformations for these three ligand classes. Conclusions and implications: The N-terminus is crucial for GIP agonist functionality. Removal of the C-terminus of the naturally occurring DPP4-product GIP(3-42) creates another naturally occurring, but superior antagonist GIP(3-30)NH2 , that together with GIP(5-30)NH2 were high-affinity competitive antagonist and thus may be suitable tool compounds for basic GIP research and future pharmacological interventions.
    British Journal of Pharmacology 11/2015; DOI:10.1111/bph.13384
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    ABSTRACT: Background and purpose: Transient Receptor Potential Canonical 5 (TRPC5) proteins assemble to create calcium-permeable non-selective cationic channels. We sought novel modulators of these channels through studies of natural products. Experimental approach: Intracellular calcium measurements and patch-clamp recordings were made from cell lines. Compounds were generated by synthetic chemistry. Key results: Through a screen of natural products in Traditional Chinese Medicines the flavonol galangin was identified as an inhibitor of lanthanide-evoked calcium entry in TRPC5 over-expressing HEK 293 cells (IC50 0.45 μM). Galangin also inhibited lanthanide-evoked TRPC5-mediated current in whole-cell and outside-out patch recordings. In differentiated 3 T3-L1 cells it inhibited constitutive and lanthanide-evoked calcium entry through endogenous TRPC5-containing channels. The related natural flavonols, kaempferol and quercetin, were less potent inhibitors of TRPC5. Myricetin and luteolin lacked effect and apigenin was a stimulator. Based on structure-activity relationship studies with natural and synthetic flavonols, we designed 3,5,7-trihydroxy-2-(2-bromophenyl)-4H-chromen-4-one (AM12) which inhibited lanthanide-evoked TRPC5 activity with an IC50 of 0.28 μM. AM12 also inhibited TRPC5 activity evoked by the agonist (-)-Englerin A and was effective in excised outside-out membrane patches, suggesting a relatively direct effect. It inhibited TRPC4 channels similarly but its inhibitory effect on TRPC1-TRPC5 heteromeric channels was weaker. Conclusions and implications: The data suggest that galangin (a natural product from the ginger family) is a TRPC5 inhibitor and that other natural and synthetic flavonoids contain antagonist or agonist capabilities at TRPC5 and closely related channels depending on the substitution patterns of both the chromone core and the phenyl ring.
    British Journal of Pharmacology 11/2015; DOI:10.1111/bph.13387
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    ABSTRACT: A major obstacle to islet cell transplantation is the early loss of transplanted islets resulted from the instant blood-mediated inflammation reaction (IBMIR). The activation of complement pathways plays a central role in IBMIR. The aim of this study was to test the inhibitory effect of "painting" human islets with APT070, a membrane-localizing C3 convertase inhibitor, on inflammation evoked by exposure to human serum in vitro and by transplantation in vivo in a humanized diabetic mouse model. In vitro human islets pre-incubated with APT070 were exposed to allogeneic whole blood. In vivo, similarly treated islets were transplanted underneath the kidney capsule of streptozotocin-induced diabetic NOD-scid IL2rγ(-/-) mice that has been reconstituted with human CD34(+) stem cells. Complement activation and islet hormone content were assayed using enzyme-linked immunosorbent assays. Supernatants and sera were assayed for cytokines using cytometric beads array. Morphology of the islets incubated with human serum in vitro and in graft-bearing kidney were evaluated using immunofluorescence staining. Our results showed that in vitro pre-incubation with APT070 decreased C-peptide release and iC3b production, with diminished deposition of C4d and C5b-9 in islets embedded in blood clots. In vivo, the APT070-treated islets maintained intact structure and showed less infiltration of inflammatory cells than untreated islets. The pretreatments also significantly reduced pro-inflammatory cytokines in supernatants and sera. These data indicate that pre-treatment of islets with APT070 might reduce intra-islet inflammation with accompanying preservation of insulin secretion by beta cells, and that APT070 could be as a potential therapeutical tool in islet transplantation.
    British Journal of Pharmacology 11/2015; DOI:10.1111/bph.13388
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    ABSTRACT: Background and purpose: Sepsis is a systemic inflammatory response syndrome accompanied by excessive production of inflammatory cytokines and cardiovascular dysfunction. Importantly, macrophage-derived pro-inflammatory response plays a key role in septic cardiovascular impairment. This study aimed to investigate the effects of trimetazidine (TMZ) on macrophage pro-inflammatory response in endotoxin-induced myocardial dysfunction. Experimental approach: Mice pretreated with TMZ were challenged with lipopolysaccharide (LPS) by intraperitoneal injection and cardiac function was evaluated. Levels of macrophage infiltration, macrophage inflammatory response and cardiomyocyte apoptosis were examined using immunohistochemical staining, ELISA, RT-PCR, Western blot, TUNEL and flow cytometry assay. Key results: Results showed that TMZ pretreatment prevented LPS-induced myocardial dysfunction and apoptosis. Consistently, TMZ lowered levels of proinflammatory cytokines in serum and heart tissue and myocardial macrophage infiltration. Bone marrow transplantation indicated that TMZ alleviated LPS-induced myocardial dysfunction via decreasing macrophage infiltration. TMZ reduced proinflammatory cytokines expression in LPS-stimulated cardiac and peritoneal macrophages. Co-culture of TMZ pretreated macrophages with cardiomyocytes and conditioned media from TMZ pretreated macrophages both decreased LPS-induced cardiomyocyte apoptosis. The anti-apoptosis effects of TMZ resulted from the reduction of proinflammatory cytokines, which achieved partially by normalizing the Sirt1/AMPK/Nrf2/HO-1 and Sirt1/PPARα pathway in macrophages. Meanwhile, secretions of cytokines were also regulated by ROS, which were attenuated by TMZ via activation of Sirt1, AMPK and PPARα. Conclusions and implication: In conclusion, TMZ protected against LPS-induced myocardial dysfunction and apoptosis, associated with inhibition of macrophage pro-inflammatory response. Our studies suggest that TMZ might represent a novel therapeutic agent to prevent and treat sepsis induced myocardial dysfunction.
    British Journal of Pharmacology 11/2015; DOI:10.1111/bph.13386
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    ABSTRACT: Background and purpose: Cathepsin K (CatK) is a major drug target for the treatment of osteoporosis. Potent active site-directed inhibitors have been developed and showed variable success in clinical trials. These inhibitors block the entire activity of CatK and thus may interfere with other pathways. The present study investigates the anti-resorptive effect of an exosite inhibitor that selectively inhibits only the therapeutically relevant collagenase activity of CatK. Experimental approach: Human osteoclasts and fibroblasts were used to analyse the effect of the exosite inhibitor, ortho-dihydrotanshinone (DHT1), and the active site inhibitor, odanacatib (ODN), on bone resorption and TGF-ß1 degradation. Cell cultures, western blot, light and scanning electron microscopy as well as energy dispersive x-ray spectroscopy, molecular modeling and enzymatic assays were used to evaluate the inhibitors. Key results: DHT1 selectively inhibits the collagenase activity of CatK, without affecting the viability of osteoclasts. Both inhibitors abolished the formation of resorption trenches, with respective IC50 values of 60.1±0.4 nM (DHT1) and 14.2±4.4 nM (ODN). Maximal reductions of other resorption parameters by DHT1 and ODN were comparable: respectively 41% and 33% for total resorption surface, 46% and 48% for resorption depths, and 83% and 61% for CTx release. DHT1 did not affect the turnover of fibrosis-associated TGF-ß1 in fibroblasts, whereas 500 nM ODN was inhibitory. Conclusions and implications: Our study shows that an exosite inhibitor of CatK can specifically block bone resorption without interfering with other pathways.
    British Journal of Pharmacology 11/2015; DOI:10.1111/bph.13383
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    ABSTRACT: Background and purpose: Ca(2+) -activated chloride channels (CaCCs) play varied physiological roles and constitute potential therapeutic targets for conditions such as asthma and hypertension. TMEM16A encodes a CaCC. CaCC pharmacology is restricted to compounds with relatively low potency and poorly defined selectivity. Anthracene-9-carboxylic acid (A9C), an inhibitor of various chloride channel types, exhibits complex effects on native CaCCs and cloned TMEM16A channels providing both activation and inhibition. The mechanisms underlying these effects are not fully defined. Experimental approach: Patch-clamp electrophysiology in conjunction with concentration jump experiments were employed to define the mode of interaction of A9C with TMEM16A channels. Key results: In the presence of high intracellular Ca(2+) , A9C inhibited TMEM16A currents in a voltage-dependent manner by entering the channel from the outside. A9C activation, revealed in the presence of submaximal intracellular Ca(2+) concentrations, was also voltage dependent. The electric distance of A9C inhibiting and activating binding site was ~0.6 in each case. Inhibition occurred according to an open-channel block mechanism. Activation was due to a dramatic leftward shift in the steady-state activation curve and slowed deactivation kinetics. Extracellular A9C competed with extracellular Cl(-) , suggesting that A9C binds deep in the channel's pore to exert both inhibiting and activating effects. Conclusions and implications: A9C is an open TMEM16A channel blocker and gating modifier. These effects require A9C binding to a region within the pore that is accessible from the extracellular side of the membrane. These data will aid the future drug design of compounds that selectively activate or inhibit TMEM16A channels.
    British Journal of Pharmacology 11/2015; DOI:10.1111/bph.13381
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    ABSTRACT: Background and purpose: Angiotensin II (AngII) induces vascular smooth muscle cell (VSMC) migration and growth, which is responsible for vascular remodeling in some cardiovascular diseases. It has been demonstrated to activate a Cl(-) current, but the underlying mechanism is not clear. Experimental approach: Whole-cell patch clamp, co-immunoprecipitation (co-IP), site-specific mutagenesis, angiotensin II-induced hypertensive mice model were used. Key results: In VSMC, AngII induced a ClC-3-dependent Cl(-) current that was abolished in ClC-3 null mice. The activation mechanism of this AngII-induced Cl(-) current was related to the interaction between ClC-3 and Rho-kinase 2 (ROCK2), as shown by N-terminal or C-terminal truncation of ClC-3, ROCK2 siRNA and Co-IP experiments. We then tried to establish whether or not the phosphorylation site of ClC-3 at threonine 532 is critical for AngII-induced Cl(-) current and VSMC migration through ROCK. The ClC-3 T532D mutant (mutation of threonine 532 to aspartate), mimicking the phosphorylation state of ClC-3, significantly potentiated AngII-induced Cl(-) current and VSMC migration; while ClC-3 T532A (mutation of threonine 532 to alanine) had the opposite effects. Furthermore, we found a marked decrease in AngII-induced VSMC migration in ClC-3 null mice that was insensitive to Y27632, an inhibitor of ROCK2. In addition, AngII-induced cerebrovascular remodeling was ameliorated in ClC-3 null mice, possibly by ROCK2 pathway. Conclusions and implications: ClC-3 protein phosphorylation at threonine 532 by ROCK2 is required for AngII-induced Cl(-) current and VSMC migration that are involved in AngII-induced hypertensive vascular remodeling.
    British Journal of Pharmacology 11/2015; DOI:10.1111/bph.13385
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    ABSTRACT: In 2003 the first report was published that presented proof of principle for a novel class of fluorescence-resonance-energy-transfer (FRET) biosensors for use in living cells. This novel sensor class was built on the base of G-protein-coupled receptors (GPCRs), which represent an integral transmembrane receptor family passing the membrane seven times and are thus also called the 7TM receptor family. As an estimated number of 30% of all marketed drugs exert their effects by modulating GPCR function, these initial reports promised the gain of novel insights into receptor function. Such FRET sensors have slowly, but progressively, made their way into the standard tool-box for GPCR-research as several groups are now reporting on the generation and use of these sensors. By now, FRET sensors have been reported for 18 different GPCRs and more are expected to be added. These particular receptor sensors have been used to investigate receptor dynamics in living cells, to evaluate ligand binding and ligand efficacy in real-time, to study voltage and mechanosensitivity of GPCRs, or to study the influence of receptor polymorphisms on receptor function in real-time. In this review we will describe the different design principles of these GPCR-based sensors and will summarize their current biological applications in living cells.
    British Journal of Pharmacology 11/2015; DOI:10.1111/bph.13382
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    ABSTRACT: Background and purpose: Endothelin (ET-1) is increased in patients with sickle cell disease (SCD) and may contribute to the development of sickle cell nephropathy. The current study was designed to determine whether ET-1 acting via the ETA receptor contributes to renal injury in a mouse model of SCD. Experimental approach: Adult, humanized HbSS sickle mice had increased ET-1 mRNA expression in both the cortex and glomeruli compared to heterozygous HbAS controls. In the renal cortex, ETA receptor mRNA expression was also elevated in sickle mice although ETB receptor mRNA expression was unchanged. Ligand binding assays confirmed that sickle mice had increased ETA receptors in the renal vascular tissue when compared to control mice. Key results: In response to protein kinase C stimulation, reactive oxygen species (ROS) production by isolated glomeruli from HbSS sickle mice was increased compared to HbSA controls, an effect that was prevented by 1 week in vivo treatment with the selective ETA antagonist, ABT-627. Protein and nephrin excretion were both elevated in sickle mice, effects that were also significantly attenuated by ABT-627. Finally, ETA antagonism caused a significant reduction in mRNA expression of NADPH oxidase subunits, which may to contribute to nephropathy in sickle cell disease. Conclusions and implications: These data support a novel role for ET-1 in the progression of sickle nephropathy, specifically via the ETA receptor and suggest a potential role for ETA antagonism in a treatment strategy.
    British Journal of Pharmacology 11/2015; DOI:10.1111/bph.13380
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    ABSTRACT: Background and purpose: Emerging evidence suggests that abnormal transport of amyloid-β (Aβ) across the blood-brain barrier (BBB) is involved in diabetes-associated cognitive decline. We investigated whether PPARγ agonists restore Aβ transport across the BBB and hippocampal plasticity in db/db mice. Experimental approach: Efflux or influx of Aβ across the BBB was determined by stereotaxic intra-cerebral or intra-arterial infusion of (125) I-Aβ1-40 , respectively. Receptor for advanced glycation end products (RAGE) or low-density lipoprotein receptor related protein 1 (LRP1) participating in Aβ influx or efflux, PPARγ and NF-κB p65 at the BBB, as well as hippocampal Aβ, caspase-3, Bax and Bcl-2 were assayed by Western blot, immunohistochemistry or RT-PCR. In vivo hippocampal long term potentiation (LTP) recording, Morris water maze (MWM) task and Y-maze test were also performed. Key results: Treatment with PPARγ agonists rosiglitazone (0.8 mg/kg) or pioglitazone (9.0 mg/kg) for 6 weeks significantly increased Aβ efflux and decreased Aβ influx across the BBB in db/db mice, concomitant with decreased hippocampal Aβ1-40 or Aβ1-42 , ameliorated neuronal apoptosis evidenced by inactivated caspase-3 and increased ratio of Bcl-2/Bax, and increased hippocampal plasticity characterized by enhancing in vivo LTP and better performance on behavioural tests. Further study found that PPARγ agonists promoted LRP1 gene expression by activation of PPARγ and suppressed RAGE gene expression by inactivation of NF-κB signaling at the BBB of db/db mice. Conclusions and implications: PPARγ agonists modify abnormal Aβ transport across the BBB accompanied by amelioration of β-amyloidosis and improvement of hippocampal plasticity under diabetic context.
    British Journal of Pharmacology 10/2015; DOI:10.1111/bph.13378
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    ABSTRACT: Bankground and purpose: Doxorubicin (Dox) is a powerful antineoplastic agent for treating a wide range of cancers. However, doxorubicin cardiotoxicity of the heart has largely limited its clinical use. It is known that all-trans retinoic acid (ATRA) plays important roles in many cardiac biological processes, however, the protective effects of ATRA on doxorubicin cardiotoxicity remain unknown. Here, we studied the effect of ATRA on doxorubicin cardiotoxicity and underlying mechanisms. Experimental approaches: Cellular viability assays, western blotting and mitochondrial respiration analyses were employed to evaluate the cellular response to ATRA in H9c2 cells and primary cardiomyocytes. Quantitative PCR (Polymerase Chain Reaction) and gene knockdown were performed to investigate the underlying molecular mechanisms of ATRA's effects on doxorubicin cardiotoxicity. Key results: ATRA significantly inhibited doxorubicin-induced apoptosis in H9c2 cells and primary cardiomyocytes. ATRA was more effective against doxorubicin cardiotoxicity than resveratrol and dexrazoxane. ATRA also suppressed reactive oxygen species (ROS) generation, and restored the expression level of mRNA and proteins in phase II detoxifying enzyme system: Nrf2 (nuclear factor-E2-related factor 2), MnSOD (manganese superoxide dismutase), HO-1 (heme oxygenase1) as well as mitochondrial function (mitochondrial membrane integrity, mitochondrial DNA copy numbers, mitochondrial respiration capacity, biogenesis and dynamics). Both Erk1/2 (extracellular signal-regulated kinase1/2) inhibitor (U0126) and Erk2 siRNA, but not Erk1 siRNA, abolished the protective effect of ATRA against doxorubicin-induced toxicity in H9c2 cells. Remarkably, ATRA did not compromise the anticancer efficacy of doxorubicin in gastric carcinoma cells. Conclusion and implication: ATRA protected cardiomyocytes against doxorubicin-induced toxicity by activating the Erk2 pathway without compromising the anticancer efficacy of doxorubicin. Therefore, ATRA may be a promising candidate as a cardioprotective agent against doxorubicin cardiotoxicity.
    British Journal of Pharmacology 10/2015; DOI:10.1111/bph.13377
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    ABSTRACT: Background and purpose: Delta opioid receptor (DORs) agonists are being developed as potential treatments for depression and alcohol use disorders. This is particularly interesting as depression is frequently co-morbid with alcohol use disorders. Yet we have previously shown that DOR agonists range widely in their ability to modulate alcohol intake, finding that certain DOR agonists actually increase alcohol consumption in mice. We propose that variances in beta-arrestin2 recruitment contribute to the differential behavioral profile of DOR agonists. Experimental approach: We used three diarylmethylpiperazine based non-peptidic DOR selective agonists (SNC80, SNC162, ARM390) and three structurally diverse DOR agonists (TAN-67, KNT127 and NIH11082). We tested these agonists in cAMP and β-arrestin 2 recruitment assays and a behavioral assay of alcohol intake in male C57BL/6 mice. We used β-arrestin 2 knockout mice and a model of depression-like behavior to further study the role of β-arrestin 2 in DOR pharmacology. Key results: All six tested DOR agonists are full agonist in the cAMP assay but display distinct β-arrestin 2 recruitment efficacy. The efficacy of DOR agonists to recruit β-arrestin 2 positively correlates with their ability to increase alcohol intake (r = 0.93 p < 0.01). The effects of the very efficacious recruiter SNC80 on alcohol intake, alcohol place preference and depression-like behavior are β-arrestin 2 dependent. Conclusions and implications: Our finding that DOR agonists that strongly recruit beta-arrestin2 can increase alcohol intake carry important ramifications for drug development of DOR agonists for treatment of alcohol use disorders and depressive disorders.
    British Journal of Pharmacology 10/2015; DOI:10.1111/bph.13374
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    ABSTRACT: Background and purpose: Upon stimulation, neutrophils release their nuclear contents called neutrophil extracellular traps (NETs) containing unfolded chromatin and lysosomal enzymes. NETs have been demonstrated to play a critical role in host defense, although the role of prostaglandin E2 (PGE2 ), a bioactive substance generated in inflammatory tissues, in the NET formation remains unclear. Experimental approach: The effects of prostaglandin E2 (PGE2 ), agonists and antagonists of its receptors, and moderators of the cyclic AMP (cAMP)-protein kinase A pathway on formation of the neutrophil-extracellular traps (NETs) were examined in vitro with isolated neutrophils and in vivo with a newly established mouse model. Key results: PGE2 inhibited phorbol 12-myristate 13-acetate (PMA)-induced NET formation in vitro through EP2 and EP4 Gαs-coupled receptors. Incubation with a cell-permeable cyclic AMP (cAMP) analogue, db2 cAMP, or several types of inhibitors of a cAMP-degrading enzyme, phosphodiesterase, also suppressed NET formation. In the assay established here, where agarose gel was subcutaneously implanted in mice and NET formation was detected on the surface of the gel, NET areas were inhibited in agarose gels containing rolipram, a PDE4 inhibitor and butaprost, an EP2 agonist. Conclusion and implication: PGE2 inhibits NET formation through the production of cAMP. The findings would contribute to development of novel treatments for NETosis-related diseases.
    British Journal of Pharmacology 10/2015; DOI:10.1111/bph.13373
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    ABSTRACT: Background and purpose: Orphan nuclear receptor Nur77 is implicated in the survival and apoptosis of cancer cells. The purpose of this study is to determine whether and how Nur77 serves to mediate the effect of the inflammatory cytokine tumor necrosis factor-alpha (TNFα) in cancer cells and to identify and characterize new agents targeting Nur77 for cancer therapy. Experimental approach: The effects of TNFα on the expression and function of Nur77 were studied using in vitro and in vivo models. Nur77 expression was evaluated in tumor tissues from breast cancer patients. The anti-cancer effects of honokiol and its mechanism of action were assessed by in vitro, cell-based and animal studies. Key results: TNFα rapidly and potently induced the expression of Nur77 in breast cancer cells through activation of the IκB kinase (IKK) and Jun N-terminal kinase (JNK). Knocking down Nur77 resulted in TNFα-dependent apoptosis, while ectopic Nur77 expression in MCF-7 cells promoted their growth in animals. Levels of Nur77 were higher in tumor tissues than the corresponding tumor surrounding tissues in about 50% breast cancer patients studied. Our in vitro and animal studies also identified honokiol as an effective sensitizer of TNFα-induced apoptosis by inhibiting TNFα-induced Nur77 mRNA expression, which could be attributed to its interference of TNF receptor-1 (TNFR1) interaction with receptor-interacting protein-1 (RIP1). Conclusions and implicatons: TNFα-induced Nur77 serves as a survival factor to attenuate the death effect of TNFα in cancer cells. With its proven human safety profile, honokiol represents a promising agent that warrants further clinical development.
    British Journal of Pharmacology 10/2015; DOI:10.1111/bph.13375
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    ABSTRACT: Background and purpose: In vivo and in vitro studies have demonstrated a protective effect of cannabidiol (CBD) in reducing infarct size in stroke models, and against epithelial barrier damage in numerous disease models. We aimed to investigate whether CBD also affects blood-brain barrier (BBB) permeability following ischaemia. Experimental approach: Human brain microvascular endothelial cell (HBMEC) and human astrocyte (HA) co-cultures modelled the BBB. Ischaemia was modelled by oxygen-glucose deprivation (OGD) and permeability was measured by transepithelial electrical resistance. Key results: CBD (10 μM) prevented the increase in permeability caused by 4 h OGD. CBD was most effective when administered pre-OGD, but protective effects were observed up to 2 h into reperfusion. This effect was inhibited by a peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, and partially reduced by a serotonin (5-HT1A ) antagonist (but was unaffected by antagonists of CB1 , CB2 , TRPV1 or adenosine A2A ). CBD also reduced cell damage (lactate dehydrogenase) and markers of cellular adhesion (VCAM-1). In HBMEC monocultures, CBD decreased vascular cell adhesion protein 1 (VCAM-1) and increased vascular endothelial growth factor (VEGF), which was inhibited by PPARγ antagonism. Conclusions and implications: These data suggest that activity at the BBB could represent an as yet unrecognised mechanism of CBD-induced neuroprotection in ischaemic stroke, mediated by PPARγ and 5-HT1A . This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 10/2015; DOI:10.1111/bph.13368
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    ABSTRACT: Background and purpose: The rise in intracelluar Ca(2+) stimulates the expression of the transcription factor c-Fos. Depending on the mode of entry of Ca(2+) into the cytosol, distinct signal transducers and transcription factors are required. Here, we have analyzed the signaling pathway connecting a Ca(2+) influx via activation of transient receptor potential melastatin-3 (TRPM3) channels with enhanced c-Fos expression. Experimental approach: Transcription of c-Fos promoter/reporter genes that were integrated into the chromatin via lentiviral gene transfer was analyzed in HEK293 cells overexpressing TRPM3. The transcriptional activation potential of c-Fos was measured using a GAL4-c-Fos fusion protein. Key results: The signaling pathway connecting TRPM3 stimulation with enhanced c-Fos expression requires the activation of MAP kinases. On the transcriptional level, three Ca(2+) -responsive elements, the cAMP response element, and the binding sites for the serum response factor and AP-1, are essential for the TRPM3-mediated stimulation of the c-Fos promoter. Ternary complex factors are additionally involved in connecting TRPM3 stimulation with the upregulation of c-Fos expression. Stimulation of TRPM3 channels also increases the transcriptional activation potential of c-Fos. Conclusions and implications: Signaling molecules involved in connecting TRPM3 with the c-Fos gene are MAP kinases, and the transcription factors CREB, SRF, AP-1, and ternary complex factors. As c-Fos constitutes, together with other basic region leucine zipper transcription factors, the AP-1 transcription factor complex, the results of this study explain TRPM3-induced activation of AP-1 and connects TRPM3 with the biological functions regulated by AP-1.
    British Journal of Pharmacology 10/2015; DOI:10.1111/bph.13372