| 1. |
- Bengtsson, Jörgen, et al.
(author)
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The influence of age on the distribution of morphine and morphine-3-glucuronide across the blood-brain barrier in sheep
- 2009
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In: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 157:6, s. 1085-1096
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Journal article (peer-reviewed)abstract
- Background and purpose The effect of age on the distribution of morphine and morphine-3-glucuronide (M3G) across the blood-brain barrier (BBB) was studied in a sheep model utilizing intracerebral microdialysis. The effect of neonatal asphyxia on brain drug distribution was also studied. Experimental approach Microdialysis probes were inserted into the cortex, striatum and blood of 11 lambs (127 gestation days) and six ewes. Morphine, 1 mg.kg(-1), was intravenously administered as a 10 min constant infusion. Microdialysis and blood samples were collected for up to 360 min and analysed using liquid chromatography-tandem mass spectrometry. The half-life, clearance, volume of distribution, unbound drug brain : blood distribution ratio (K(p,uu)) and unbound drug volume of distribution in brain (V(u,brain)) were estimated. Key results Morphine K(p,uu) was 1.19 and 1.89 for the sheep and premature lambs, respectively, indicating that active influx into the brain decreases with age. Induced asphyxia did not affect transport of morphine or M3G across the BBB. Morphine V(u,brain) measurements were higher in sheep than in premature lambs. The M3G K(p,uu) values were 0.27 and 0.17 in sheep and premature lambs, indicating a net efflux from the brain in both groups. Conclusions and implications The morphine K(p,uu) was above unity, indicating active transport into the brain; influx was significantly higher in premature lambs than in adult sheep. These results in sheep differ from those in humans, rats, mice and pigs where a net efflux of morphine from the brain is observed.
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| 2. |
- Dold, Stefan, et al.
(author)
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Simvastatin protects against cholestasis-induced liver injury.
- 2009
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In: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 156, s. 466-474
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Journal article (peer-reviewed)abstract
- Background: Bile duct obstruction is associated with hepatic accumulation of leukocytes and liver injury. The aim of this study was to evaluate the effect of simvastatin on cholestasis-induced liver inflammation and tissue damage. Experimental approach: C57BL/6 mice were treated with simvastatin (0.02 and 0.2 mg.kg(-1)) and vehicle before and after undergoing bile duct ligation (BDL) for 12 h. Leukocyte recruitment and microvascular perfusion in the liver were analysed using intravital fluorescence microscopy. CXC chemokines in the liver were determined by enzyme-linked immunosorbent assay. Liver damage was monitored by measuring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Hepatic levels of myeloperoxidase (MPO) were also determined. Key results: Administration of 0.2 mg.kg(-1) simvastatin decreased ALT and AST by 87% and 83%, respectively, in BDL mice. This dose of simvastatin reduced hepatic formation of CXC chemokines by 37-82% and restored sinusoidal perfusion in cholestatic animals. Moreover, BDL-induced leukocyte adhesion in sinusoids and postsinusoidal venules, as well as MPO levels in the liver, was significantly reduced by simvastatin. Notably, administration of 0.2 mg.kg(-1) simvastatin 2 h after BDL induction also decreased cholestatic liver injury and inflammation. Conclusions and implications: These findings show that simvastatin protects against BDL-induced liver injury. The hepatoprotective effect of simvastatin is mediated, at least in part, by reduced formation of CXC chemokines and leukocyte recruitment. Thus, our novel data suggest that the use of statins may be an effective strategy to protect against the hepatic injury associated with obstructive jaundice.
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| 3. |
- Düringer, Caroline, et al.
(author)
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Agonist-specific patterns of beta(2)-adrenoceptor responses in human airway cells during prolonged exposure.
- 2009
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In: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 158, s. 169-179
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Journal article (peer-reviewed)abstract
- Background and purpose: beta(2)-Adrenoceptor agonists (beta(2)-agonists) are important bronchodilators used in the treatment of asthma and chronic obstructive pulmonary disease. At the molecular level, beta(2)-adrenergic agonist stimulation induces desensitization of the beta(2)-adrenoceptor. In this study, we have examined the relationships between initial effect and subsequent reduction of responsiveness to restimulation for a panel of beta(2)-agonists in cellular and in vitro tissue models. Experimental approach: beta(2)-Adrenoceptor-induced responses and subsequent loss of receptor responsiveness were studied in primary human airway smooth muscle cells and bronchial epithelial cells by measuring cAMP production. Receptor responsiveness was compared at equi-effective concentrations, either after continuous incubation for 24 h or after a 1 h pulse exposure followed by a 23 h washout. Key findings were confirmed in guinea pig tracheal preparations in vitro. Key results: There were differences in the reduction of receptor responsiveness in human airway cells and in vitro guinea pig trachea by a panel of beta(2)-agonists. When restimulation occurred immediately after continuous incubation, loss of responsiveness correlated with initial effect for all agonists. After the 1 h pulse exposure, differences between agonists emerged, for example isoprenaline and formoterol induced the least reduction of responsiveness. High lipophilicity was, to some extent, predictive of loss of responsiveness, but other factors appeared to be involved in determining the relationships between effect and subsequent loss of responsiveness for individual agonists. Conclusions and implications: There were clear differences in the ability of different beta(2) agonists to induce loss of receptor responsiveness at equi-effective concentrations.
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| 4. |
- Muhammad, Asad, et al.
(author)
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P-selectin glycoprotein-ligand-1 regulates pulmonary recruitment of neutrophils in a platelet-independent manner in abdominal sepsis
- 2009
-
In: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 156:2, s. 307-315
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Journal article (peer-reviewed)abstract
- Neutrophil-mediated lung injury is an insidious feature in sepsis although the mechanisms regulating pulmonary recruitment of neutrophils remain elusive. Here, we investigated the role of P-selectin glycoprotein-ligand-1 (PSGL-1) in sepsis-induced neutrophil recruitment and tissue injury in the lung. Bronchoalveolar infiltration of neutrophils, levels of myeloperoxidase, oedema formation and CXC chemokines were determined 24 h after caecal ligation and puncture (CLP) in mice. Animals were pretreated with a control antibody, monoclonal antibodies directed against PSGL-1 and P-selectin as well as a platelet-depleting antibody directed against GP1b alpha. CLP caused pulmonary damage characterized by oedema formation, neutrophil infiltration and increased levels of CXC chemokines in the lung. Immunoneutralization of PSGL-1 or P-selectin reduced CLP-induced neutrophil recruitment in the bronchoalveolar space by more than 56% and lung myeloperoxidase activity by 62%. Notably, the inhibitory effect of the anti-PSGL-1 antibody on sepsis-induced neutrophil infiltration was also observed in platelet-depleted mice. Moreover, inhibition of PSGL-1 and P-selectin abolished CLP-induced oedema formation and tissue damage in the lung. CLP-induced formation of CXC chemokines was not changed in mice pretreated with the anti-PSGL-1 and anti-P-selectin antibodies. These data demonstrate that PSGL-1 plays a key role in pulmonary infiltration of neutrophils as well as lung oedema associated with abdominal sepsis. Moreover, our findings suggest that PSGL-1-dependent neutrophil recruitment is independent of circulating platelets. Thus, these novel findings indicate that PSGL-1 may be a useful target to protect against sepsis-induced accumulation of neutrophils and tissue damage in the lung.
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| 5. |
- Sadegh, Mardjaneh Karbalaei, et al.
(author)
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Biomechanical properties and innervation of the female caveolin-1-deficient detrusor.
- 2011
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In: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; Dec, s. 1156-1170
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Journal article (peer-reviewed)abstract
- Background and purpose: Caveolin-1-deficiency is associated with substantial urogenital alterations. Here, a mechanical, histological and biochemical characterization of female detrusors from wild-type (WT) and caveolin-1-deficient (KO) mice was made to increase the understanding of detrusor changes caused by lack of caveolae. Experimental approach: Length-tension relationships were generated, and we recorded responses to electrical field stimulation (EFS), the muscarinic receptor agonist carbachol, and the purinoceptor agonist ATP. Tyrosine nitration and the contents of caveolin-1, cavin-1, muscarinic M(3) receptors, phospholipase C(β1) (PLC(β1) ), muscle-specific kinase (MuSK), and L-type Ca(2+) -channels were determined by immunoblotting. Innervation was assessed by immunohistochemistry. Key results: Bladder to body weight ratio was not changed, nor was there any change in the optimum circumference for force development. Depolarization- and ATP-induced stress was reduced, as was carbachol-induced stress between 0.1 and 3 µM, but the supramaximal relative (% K(+) ) response to carbachol was increased, as was M(3) expression. The scopolamine-sensitive component of the EFS-response was impaired, and yet bladder nerves contained little caveolin-1. The density of cholinergic nerves was unchanged, whereas CART- and CGRP-positive nerves were reduced. Immunoblotting revealed loss of MuSK. Conclusions and implications: Ablation of caveolae in the female detrusor leads to generalised impairment of contractility, ruling out prostate hypertrophy as a contributing factor. Cholinergic neuroeffector transmission is impaired without conspicuous changes in the density of cholinergic nerves or morphology of their terminals, but correlating with reduced expression of MuSK.
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| 6. |
- Awla, Darbaz, et al.
(author)
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Lymphocyte function antigen-1 regulates neutrophil recruitment and tissue damage in acute pancreatitis.
- 2011
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In: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 163, s. 413-423
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Journal article (peer-reviewed)abstract
- Background and purpose: Leucocyte infiltration is a rate-limiting step in the pathophysiology of acute pancreatitis (AP) although the adhesive mechanisms supporting leucocyte-endothelium interactions in the pancreas remain elusive. The aim of this study was to define the role of lymphocyte function antigen-1 (LFA-1) in regulating neutrophil-endothelium interactions and tissue damage in severe AP. Experimental approach: Pancreatitis was induced by retrograde infusion of sodium taurocholate into the pancreatic duct in mice. LFA-1 gene-targeted mice and an antibody directed against LFA-1 were used to define the role of LFA-1. Key results: Taurocholate challenge caused a clear-cut increase in serum amylase, neutrophil infiltration, CXCL2 (macrophage inflammatory protein-2) formation, trypsinogen activation and tissue damage in the pancreas. Inhibition of LFA-1 function markedly reduced taurocholate-induced amylase levels, accumulation of neutrophils, production of CXC chemokines and tissue damage in the pancreas. Notably, intravital microscopy revealed that inhibition of LFA-1 abolished taurocholate-induced leucocyte adhesion in postcapillray venules of the pancreas. In addition, pulmonary infiltration of neutrophils was attenuated by inhibition of LFA-1 in mice challenged with taurocholate. However, interference with LFA-1 had no effect on taurocholate-induced activation of trypsinogen in the pancreas. Conclusions and Implications: Our novel data suggest that LFA-1 plays a key role in regulating neutrophil recruitment, CXCL2 formation and tissue injury in the pancreas. Moreover, these results suggest that LFA-1-mediated inflammation is a downstream component of trypsinogen activation in the pathophysiology of AP. Thus, we conclude that targeting LFA-1 may be a useful approach to protect against pathological inflammation in the pancreas.
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| 7. |
- Awla, Darbaz, et al.
(author)
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Rho-kinase signalling regulates trypsinogen activation and tissue damage in severe acute pancreatitis.
- 2011
-
In: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 162, s. 648-658
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Journal article (peer-reviewed)abstract
- Background and purpose: Severe acute pancreatitis (SAP) is characterized by trypsinogen activation, infiltration of leucocytes and tissue necrosis but the intracellular signalling mechanisms regulating organ injury in the pancreas remain elusive. Rho-kinase is a potent regulator of specific cellular processes effecting several pro-inflammatory activities. Herein, we examined the role of Rho-kinase signalling in acute pancreatitis. Experimental approach: Pancreatitis was induced by infusion of taurocholate into the pancreatic duct in C57BL/6 mice. Animals were treated with a Rho-kinase inhibitor Y-27632 (0.5-5 mg kg(-1) ) before induction of pancreatitis. Key results: Taurocholate infusion caused a clear-cut increase in serum amylase, pancreatic neutrophil infiltration, acinar cell necrosis and oedema formation in the pancreas. Levels of pancreatic myeloperoxidase (MPO), macrophage inflammatory protein-2 (MIP-2), trypsinogen activation peptide (TAP) and lung MPO were significantly increased, indicating local and systemic disease. Inhibition of Rho-kinase activity dose-dependently protected against pancreatitis. For example, 5 mg kg(-1) Y-27632 reduced acinar cell necrosis, leucocyte infiltration and pancreatic oedema by 90%, 89% and 58% respectively as well as tissue levels of MPO by 75% and MIP-2 by 84%. Moreover, Rho-kinase inhibition decreased lung MPO by 75% and serum amylase by 83%. Pancreatitis-induced TAP levels were reduced by 61% in Y-27632-treated mice. Inhibition of Rho-kinase abolished secretagogue-induced activation of trypsinogen in pancreatic acinar cells in vitro. Conclusions and Implications: Our novel data suggest that Rho-kinase signalling plays an important role in acute pancreatitis by regulating trypsinogen activation and subsequent CXC chemokine formation, neutrophil infiltration and tissue injury. Thus, these results indicate that Rho-kinase may constitute a novel target in the management of SAP.
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| 8. |
- Brandelius, Angelica, et al.
(author)
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Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors.
- 2012
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In: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188.
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Journal article (peer-reviewed)abstract
- Background and purpose: Statin treatment may ameliorate viral infection-induced exacerbations of chronic obstructive pulmonary disease (COPD), which exhibit Th2-type bronchial inflammation. Thymic stromal lymphopoietin (TSLP), a hub cytokine switching on Th2-inflammation, is overproduced in viral and dsRNA-stimulated bronchial epithelial cells from COPD donors. Hence, TSLP may be causally involved in exacerbations. This study tests our hypothesis that simvastatin may inhibit dsRNA-induced TSLP. Experimental approach: Epithelial cells, obtained by bronchoscopy from COPD (n=7) and smoker control (n=8) donors, were grown and stimulated with viral infection and danger signal surrogate, dsRNA (10 µg·mL(-1) ). Cells were treated with simvastatin (0.2-5 µg·mL(-1) ), with or without mevalonate (13-26 µg·mL(-1) ), or dexamethasone (1 µg·mL(-1) ) prior to dsRNA. Cytokine expression and production, and transcription factor (IRF3 and NF-κB) activation were determined. Key results: dsRNA induced TSLP, TNFα, CXCL8, and IFNβ. TSLP was overproduced in dsRNA-exposed COPD cells compared to control. Simvastatin, concentration-dependently, but not dexamethasone, inhibited dsRNA-induced TSLP. Unexpectedly, simvastatin acted independent of mevalonate and did not affect dsRNA-induced NF-κB activation nor did it reduce production of TNFα and CXCL8. Instead, simvastatin inhibited dsRNA-induced IRF3 phosphorylation and generation of IFNβ. Conclusions and implications: Independent of mevalonate and NF-κB, previously acknowledged anti-inflammatory mechanisms of pleiotropic statins, simvastatin selectively inhibited dsRNA-induced IRF3 activation and production of TSLP and IFNβ in COPD epithelium. These data provide novel insight into epithelial generation of TSLP and suggest paths to be exploited in drug discovery aimed at inhibiting TSLP-induced pulmonary immunopathology.
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| 9. |
- Nilsson, Bengt-Olof, et al.
(author)
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G protein-coupled oestrogen receptor 1 (GPER1)/GPR30: a new player in cardiovascular and metabolic oestrogenic signalling
- 2011
-
In: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 163:6, s. 1131-1139
-
Research review (peer-reviewed)abstract
- Oestrogens are important sex hormones central to health and disease in both genders that have protective effects on the cardiovascular and metabolic systems. These hormones act in complex ways via both genomic and non-genomic mechanisms. The genomic mechanisms are relatively well characterized, whereas the non-genomic ones are only beginning to be explored. Two oestrogen receptors (ER), ER alpha and ER beta, have been described that act as nuclear transcription factors but can also associate with the plasma membrane and influence cytosolic signalling. ERa has been shown to mediate both anti-atherogenic effects and pro-survival effects in pancreatic beta-cells. In recent years, a third membrane-bound ER has emerged, G protein-coupled receptor 30 or G protein-coupled oestrogen receptor 1 (GPER1), which mediates oestrogenic responses in cardiovascular and metabolic regulation. Both GPER1 knock-out models and pharmacological agents are now available to study GPER1 function. These tools have revealed that GPER1 activation may have several beneficial effects in the cardiovascular system including vasorelaxation, inhibition of smooth muscle cell proliferation, and protection of the myocardium against ischaemia/reperfusion injury, and in the metabolic system including stimulation of insulin release and protection against pancreatic beta-cell apoptosis. Thus, GPER1 is emerging as a candidate therapeutic target in both cardiovascular and metabolic disease.
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| 10. |
- Persson, Carl, et al.
(author)
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Resolution of leucocyte-mediated mucosal diseases. A novel in vivo paradigm for drug development
- 2012
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In: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 165:7, s. 2100-2109
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Research review (peer-reviewed)abstract
- Removal of disease-driving inflammatory leucocytes is central to resolution of inflammation. The current pharmacological dogma teaches leucocyte elimination through apoptosis followed by phagocytosis. However, actual resolving roles of apoptotic-phagocytic processes have been difficult to demonstrate in the major diseases that are characterized by mucosal tissue inflammation. Many current in vivo observations rather demonstrate that leucocyte elimination occurs by transepithelial locomotion. Findings in diseased gut and bladder mucosae support this notion. Respiratory disease data are particularly compelling. Eosinophils and neutrophils abound in sputum and tracheal aspirates during treatment-induced recovery from severe asthma. Prolonged sputum neutrophilia, along with clinical improvement, follows upon smoking cessation in COPD. Eosinophils, neutrophils, lymphocytes, mast cells, and dendritic cells also move in large numbers into the bronchial lumen at spontaneous inflammation resolution following allergen challenge in allergic rhinitis and asthma. A corresponding reduction of infiltrated cells in the bronchial mucosal tissue demonstrates efficiency of the transepithelial elimination pathway. Underscoring its operational role, drugs impeding transepithelial elimination of leucocytes aggravate mucosal/parenchymal inflammation. Hence, relying on lumen cell data alone can lead to paradoxical conclusions regarding anti-inflammatory drug efficacy. Conversely, drugs promoting non-injurious transepithelial elimination of leucocytes could resolve mucosal inflammatory diseases.
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| 11. |
- Berge, Odd-Geir
(author)
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Predictive validity of behavioural animal models for chronic pain
- 2011
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In: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 164:4, s. 1195-1206
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Research review (peer-reviewed)abstract
- Rodent models of chronic pain may elucidate pathophysiological mechanisms and identify potential drug targets, but whether they predict clinical efficacy of novel compounds is controversial. Several potential analgesics have failed in clinical trials, in spite of strong animal modelling support for efficacy, but there are also examples of successful modelling. Significant differences in how methods are implemented and results are reported means that a literature-based comparison between preclinical data and clinical trials will not reveal whether a particular model is generally predictive. Limited reports on negative outcomes prevents reliable estimate of specificity of any model. Animal models tend to be validated with standard analgesics and may be biased towards tractable pain mechanisms. But preclinical publications rarely contain drug exposure data, and drugs are usually given in high doses and as a single administration, which may lead to drug distribution and exposure deviating significantly from clinical conditions. The greatest challenge for predictive modelling is, however, the heterogeneity of the target patient populations, in terms of both symptoms and pharmacology, probably reflecting differences in pathophysiology. In well-controlled clinical trials, a majority of patients shows less than 50% reduction in pain. A model that responds well to current analgesics should therefore predict efficacy only in a subset of patients within a diagnostic group. It follows that successful translation requires several models for each indication, reflecting critical pathophysiological processes, combined with data linking exposure levels with effect on target.
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| 12. |
- Björklund, Emmelie, et al.
(author)
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Inhibition of monoacylglycerol lipase by troglitazone, N-arachidonoyl dopamine and the irreversible inhibitor JZL184 : comparison of two different assays
- 2010
-
In: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 161:7, s. 1512-1526
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Journal article (peer-reviewed)abstract
- BACKGROUND AND PURPOSE: Drugs used clinically usually have a primary mechanism of action, but additional effects on other biological targets can contribute to their effects. A potentially useful additional target is the endocannabinoid metabolizing enzyme monoacylglycerol lipase (MGL). We have screened a range of drugs for inhibition of MGL and compared the observed potencies using different MGL enzyme assays.EXPERIMENTAL APPROACH: MGL activity was screened using recombinant human MGL (cell lysates and purified enzyme) with 4-nitrophenyl acetate (NPA) as substrate. 2-Oleolyglycerol metabolism by rat cerebellar cytosolic MGL and by recombinant MGL was also investigated.KEY RESULTS: Among the 96 compounds screened in the NPA assay, troglitazone, CP55,940, N-arachidonoyl dopamine and AM404 inhibited NPA hydrolysis by the lysates with IC(50) values of 1.1, 4.9, 0.78 and 3.1µM, respectively. The potency for troglitazone is in the same range as its primary pharmacological activity, activation of peroxisome proliferator-activated receptor (PPAR) γ. Among PPARγ ligands, the potency order towards human MGL was troglitazone > ciglitazone > rosiglitazone > 15-deoxy-Δ(12,14) -prostaglandin J(2) ≈ CAY 10415 > CAY 10514. In contrast to the time-dependent inhibitor JZL184, the potency of troglitazone was dependent upon the enzyme assay system used. Thus, troglitazone inhibited rat cytosolic 2-oleoylglycerol hydrolysis less potently (IC(50) 41µM) than hydrolysis of NPA by the human MGL lysates.CONCLUSIONS AND IMPLICATIONS: 'Hits' in screening programmes for MGL inhibitors should be assessed in different MGL assays. Troglitazone may be a useful lead for the design of novel, dual action MGL inhibitors/PPARγ activators.
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| 13. |
- Dehvari, Nodi, et al.
(author)
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β2‐Adrenoceptors increase translocation of GLUT4 via GPCR kinase sites in the receptor C‐terminal tail
- 2012
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In: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 165:5, s. 1442-1456
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Journal article (peer-reviewed)abstract
- BACKGROUND AND PURPOSEbeta-Adrenoceptor stimulation induces glucose uptake in several insulin-sensitive tissues by poorly understood mechanisms.EXPERIMENTAL APPROACHWe used a model system in CHO-K1 cells expressing the human beta(2)-adrenoceptor and glucose transporter 4 (GLUT4) to investigate the signalling mechanisms involved.KEY RESULTSIn CHO-K1 cells, there was no response to b-adrenoceptor agonists. The introduction of b2-adrenoceptors and GLUT4 into these cells caused increased glucose uptake in response to beta-adrenoceptor agonists. GLUT4 translocation occurred in response to insulin and beta(2)-adrenoceptor stimulation, although the key insulin signalling intermediate PKB was not phosphorylated in response to beta(2)-adrenoceptor stimulation. Truncation of the C-terminus of the beta(2)-adrenoceptor at position 349 to remove known phosphorylation sites for GPCR kinases (GRKs) or at position 344 to remove an additional PKA site together with the GRK phosphorylation sites did not significantly affect cAMP accumulation but decreased beta(2)-adrenoceptor-stimulated glucose uptake. Furthermore, inhibition of GRK by transfection of the bARKct construct inhibited beta(2)-adrenoceptor-mediated glucose uptake and GLUT4 translocation, and overexpression of a kinase-dead GRK2 mutant (GRK2 K220R) also inhibited GLUT4 translocation. Introducing beta(2)-adrenoceptors lacking phosphorylation sites for GRK or PKA demonstrated that the GRK sites, but not the PKA sites, were necessary for GLUT4 translocation.CONCLUSIONS AND IMPLICATIONSGlucose uptake in response to activation of beta(2)-adrenoceptors involves translocation of GLUT4 in this model system. The mechanism is dependent on the C-terminus of the beta(2)-adrenoceptor, requires GRK phosphorylation sites, and involves a signalling pathway distinct from that stimulated by insulin.
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| 14. |
- Hugoson-Seligsohn, Eva E., et al.
(author)
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TRH-induced blood flow and mean arterial pressure changes in the rabbit are not dependent on the anaesthetic used.
- 1989
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In: British Journal of Pharmacology. - : Macmillan Publishers Ltd.. - 0007-1188 .- 1476-5381. ; 97:1, s. 190-196
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Journal article (peer-reviewed)abstract
- 1. The effects of thyrotropin releasing hormone (TRH) on regional cerebral blood flow were studied in rabbits anaesthetized with pentobarbitone or ketamine. The blood flow was determined with the labelled microsphere method before and after the i.v. administration of either 50 micrograms kg-1 or 2 mg kg-1 TRH.2. In order to measure the cerebral O2 consumption the arteriovenous difference in oxygen saturation in the brain (CAVOD) was measured before and after the administration of 2 mg kg-1 TRH.3. In animals under pentobarbitone anaesthesia 50 micrograms kg-1 TRH elicited an increase in mean arterial blood pressure (MAP) of about 1 kPa and 2 mg kg-1 TRH elevated the MAP by about 2 kPa. With ketamine as the anaesthetic the corresponding values were 0.5 kPa and 7 kPa, respectively. TRH induced significant vasoconstriction in several peripheral tissues.4. The total cerebral blood flow (CBFtot) increased from 54 +/- 4 to 78 +/- 5 g min-1 100 g-1 after the administration of 50 micrograms kg-1 TRH in pentobarbitone-anaesthetized animals. An even greater effect was elicited by 2 mg kg-1 TRH, from 48 +/- 6 to 113 +/- 19 g min-1 100 g-1. In ketamine-anaesthetized rabbits, 50 micrograms kg-1 TRH tended to enhance the CBFtot and 2 mg kg-1 increased it from 71 +/- 6 to 141 +/- 19 g min-1 100 g-1.5. In animals anaesthetized with pentobarbitone, the CAVOD decreased from 47.3 +/- 1.7% to 35.1 +/- 2.2% at 3 min after TRH delivery, and then gradually increased to the control level. In animals under ketamine anaesthesia the CAVOD decreased from 63.3 + 2.0% to 45.2 + 7.4% after the administration of 2 mg kg'- TRH.6. It is concluded that TRH elicits cerebral vasodilatation in excess of that required by the change in cerebral metabolism which may have taken place. The pattern of responses was similar to that produced in rabbits under urethane anaesthesia.
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| 15. |
- Koskinen, Lars-Owe D., Professor, 1955-
(author)
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Effect of low intravenous doses of TRH, acid-TRH and cyclo(His-Pro) on cerebral and peripheral blood flows.
- 1986
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In: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 87:3, s. 509-519
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Journal article (peer-reviewed)abstract
- Local cerebral and peripheral blood flow in conscious and anaesthetized rabbits were investigated with the microsphere method, before and after the i.v. administration of 25 or 50 micrograms kg-1 thyrotropin-releasing hormone (TRH). Before the experiment, the cervical sympathetic chain was sectioned on one side in order to evaluate the possible effect of the sympathetic nerves on cranial and extracranial blood flows. Blood flow was also determined in anaesthetized rabbits before and after the administration of the TRH metabolites cyclo(His-Pro) and acid-TRH and after subsequent administration of 50 micrograms kg-1 TRH. TRH caused an increase in mean arterial blood pressure (MAP) of about 1 to 2 kPa whereas cyclo(His-Pro) and acid-TRH had no effect on MAP. In the anaesthetized animal an increase in total cerebral blood flow (CBFtot), from 71 +/- 7 to 107 +/- 12 g min-1 100 g-1 (P less than 0.05) was observed on the sympathetic intact side after 25 micrograms kg-1 TRH and a further increase to 130 +/- 9 g min-1 100g-1 (P less than 0.01) after 50 micrograms kg-1 TRH. A similar effect was observed on the sympathotomized side. An effect on CBF in the conscious animal was not detected. The control CBFtot (104 +/- 8 g min-1 100g-1) was higher in these animals than in the anaesthetized animals (P less than 0.02). Neither cyclo(His-Pro) nor acid-TRH mimicked the effect of TRH on CBF. In several peripheral tissues, e.g. skin, pancreas and gastric mucosa, a reduction in blood flow was noted after the administration of TRH in both anaesthetized and conscious rabbits. It was concluded that TRH can induce cerebral vasodilatation in animals with a depressed CBF, whereas the vasoconstrictor effect of TRH in peripheral organs is not markedly affected by the state of consciousness.
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| 16. |
- Koskinen, Lars-Owe D., Professor, 1955-
(author)
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Effects of raised intracranial pressure on regional cerebral blood flow : a comparison of effects of naloxone and TRH on the microcirculation in partial cerebral ischaemia.
- 1985
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In: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 85:2, s. 489-497
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Journal article (peer-reviewed)abstract
- The effects on regional cerebral blood flow (rCBF) of raised intracranial pressure (ICP) and of naloxone and thyrotropin releasing hormone (TRH) during this condition were studied in anaesthetized rabbits. The ICP was elevated until a central ischaemic response was observed. The regional blood flow was determined with the microsphere technique before and during elevation of the ICP (ICPe) and after drug treatment. Total CBF was reduced by about 70% during ICPe while the uveal blood flow increased slightly and some other peripheral tissue blood flows remained unaffected. The administration of TRH caused an increase in mean arterial blood pressure (MAP) from 11.9 +/- 0.6 to 14.6 +/- 0.7 kPa and a normalization of the rCBF. In some peripheral tissues, e.g. gastric mucosa and spleen, TRH reduced the blood flow by 53% and 76%, respectively. In blood pressure stabilized animals no effect on rCBF was seen after TRH. Naloxone had no consistent effect on MAP or local blood flow. It was concluded that in the range of cerebral perfusion pressure studied there was a passive relationship between cerebral blood flow and perfusion pressure. The lack of effect of naloxone and the marked effect of TRH during cerebral ischaemia are consistent with a mechanism of action of TRH not related to a 'physiological' antagonism of opioids.
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| 17. |
- Thors, L, et al.
(author)
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Biochanin A, a naturally occurring inhibitor of fatty acid amide hydrolase.
- 2010
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In: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 160:3, s. 549-560
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Journal article (peer-reviewed)abstract
- BACKGROUND AND PURPOSE: Inhibitors of fatty acid amide hydrolase (FAAH), the enzyme responsible for the metabolism of the endogenous cannabinoid (CB) receptor ligand anandamide (AEA), are effective in a number of animal models of pain. Here, we investigated a series of isoflavones with respect to their abilities to inhibit FAAH. EXPERIMENTAL APPROACH: In vitro assays of FAAH activity and affinity for CB receptors were used to characterize key compounds. In vivo assays used were biochemical responses to formalin in anaesthetized mice and the 'tetrad' test for central CB receptor activation. KEY RESULTS: Of the compounds tested, biochanin A was adjudged to be the most promising. Biochanin A inhibited the hydrolysis of 0.5 microM AEA by mouse, rat and human FAAH with IC(50) values of 1.8, 1.4 and 2.4 microM respectively. The compound did not interact to any major extent with CB(1) or CB(2) receptors, nor with FAAH-2. In anaesthetized mice, URB597 (30 microg i.pl.) and biochanin A (100 microg i.pl.) both inhibited the spinal phosphorylation of extracellular signal-regulated kinase produced by the intraplantar injection of formalin. The effects of both compounds were significantly reduced by the CB(1) receptor antagonist/inverse agonist AM251 (30 microg i.pl.). Biochanin A (15 mg.kg(-1) i.v.) did not increase brain AEA concentrations, but produced a modest potentiation of the effects of 10 mg.kg(-1) i.v. AEA in the tetrad test. CONCLUSIONS AND IMPLICATIONS: It is concluded that biochanin A, in addition to its other biochemical properties, inhibits FAAH both in vitro and peripherally in vivo.
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| 18. |
- Turkmen, Sahruh, et al.
(author)
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Tolerance to allopregnanolone with focus on the GABA-A receptor
- 2011
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In: British Journal of Pharmacology. - : Wiley-Blackwell. - 0007-1188 .- 1476-5381. ; 162:2, s. 311-327
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Journal article (peer-reviewed)abstract
- Many studies have suggested a relationship between stress, sex steroids, and negative mental and mood changes in humans. The progesterone metabolite allopregnanolone is a potent endogenous ligand of the γ-amino butyric acid -A (GABA-A) receptor, and the most discussed neuroactive steroid. Variations in the levels of neuroactive steroids that influence the activity of the GABA-A receptor cause a vulnerability to mental and emotional pathology. There are physiological conditions in which allopregnanolone production increases acutely (e.g. stress) or chronically (e.g. menstrual cycle, pregnancy), thus exposing the GABA-A receptor to high and continuous allopregnanolone concentrations. In such conditions, tolerance to allopregnanolone may develop. We have shown that both acute and chronic tolerances can develop to the effects of allopregnanolone. Following the development of acute allopregnanolone tolerance, there is a decrease in the abundance of the GABA-A receptor α4 subunit and the expression of the α4 subunit mRNA in the ventral-posteriomedial (VPM) nucleus of the thalamus. Little is known about the mechanism behind allopregnanolone tolerance and its effects on assembly of the GABA-A receptor composition. The exact mechanism of the allopregnanolone tolerance phenomena remains unclear. The purpose of this review is to summarize certain aspects of current knowledge concerning allopregnanolone tolerance and changes in the GABA-A receptors.
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| 19. |
- Turunen, Pauli M, et al.
(author)
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Arachidonic acid release mediated by OX1 orexin receptors
- 2010
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In: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 159:1, s. 212-221
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Journal article (peer-reviewed)abstract
- Background and purpose: We have previously shown that lipid mediators, produced by phospholipase D and C, are generated in OX1 orexin receptor signalling with high potency, and presumably mediate some of the physiological responses to orexin. In this study, we investigated whether the ubiquitous phospholipase A2 (PLA2) signalling system is also involved in orexin receptor signalling.Experimental approach: Recombinant Chinese hamster ovary-K1 cells, expressing human OX1 receptors, were used as a model system. Arachidonic acid (AA) release was measured from 3H-AA-labelled cells. Ca2+ signalling was assessed using single-cell imaging.Key results: Orexins strongly stimulated [3H]-AA release (maximally 4.4-fold). Orexin-A was somewhat more potent than orexin-B (pEC50= 8.90 and 8.38 respectively). The concentration2013response curves appeared biphasic. The release was fully inhibited by the potent cPLA2 and iPLA2 inhibitor, methyl arachidonyl fluorophosphonate, whereas the iPLA2 inhibitors, R- and S-bromoenol lactone, caused only a partial inhibition. The response was also fully dependent on Ca2+ influx, and the inhibitor studies suggested involvement of the receptor-operated influx pathway. The receptor-operated pathway, on the other hand, was partially dependent on PLA2 activity. The extracellular signal-regulated kinase, but not protein kinase C, were involved in the PLA2 activation at low orexin concentrations.Conclusions and implications: Activation of OX1 orexin receptors induced a strong, high-potency AA release, possibly via multiple PLA2 species, and this response may be important for the receptor-operated Ca2+ influx. The response coincided with other high-potency lipid messenger responses, and may interact with these signals.
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| 20. |
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| 21. |
- Bosnyak, S., et al.
(author)
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Stimulation of angiotensin AT(2) receptors by the non-peptide agonist, Compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats
- 2010
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In: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 159:3, s. 709-716
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Journal article (peer-reviewed)abstract
- Background and purpose: Angiotensin type 2 receptor (AT(2) receptor) stimulation evokes vasodilator effects in vitro and in vivo that oppose the vasoconstrictor effects of angiotensin type 1 receptors (AT(1) receptors). Recently, a novel non-peptide AT(2) receptor agonist, Compound 21, was described, which exhibited high AT(2) receptor selectivity. Experimental approach: Functional cardiovascular effects of the drug candidate Compound 21 were assessed, using mouse isolated aorta and rat mesenteric arteries in vitro and in conscious spontaneously hypertensive rats (SHR). Key results: Compound 21 evoked dose-dependent vasorelaxations in aortic and mesenteric vessels, abolished by the AT(2) receptor antagonist, PD123319. In vivo, Compound 21 administered alone, at doses ranging from 50 to 1000 ng center dot kg-1 center dot min-1 over 4 h did not decrease blood pressure in conscious normotensive Wistar-Kyoto rats or SHR. However, when given in combination with the AT(1) receptor antagonist, candesartan, Compound 21 (300 ng center dot kg-1 center dot min-1) lowered blood pressure in SHR only. Further analysis in separate groups of conscious SHR revealed that, at a sixfold lower dose, Compound 21 (50 ng center dot kg-1 center dot min-1) still evoked a significant depressor response in adult SHR (similar to 30 mmHg) when combined with different doses of candesartan (0.01 or 0.1 mg center dot kg-1). Moreover, the Compound 21-evoked depressor effect was abolished when co-infused (50 mu g center dot kg-1 center dot min-1 for 2 h) with the AT(2) receptor antagonist PD123319. Conclusion and implications: Collectively, our results indicate that acute administration of Compound 21 evoked blood pressure reductions via AT(2) receptor stimulation. Thus Compound 21 can be considered an excellent drug candidate for further study of AT(2) receptor function in cardiovascular disease.
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| 22. |
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| 23. |
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| 24. |
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| 25. |
- Fowler, Christopher J.
(author)
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Monoacylglycerol lipase : a target for drug development?
- 2012
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In: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 166:5, s. 1568-1585
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Research review (peer-reviewed)abstract
- The endocannabinoid (eCB) system is involved in processes as diverse as control of appetite, perception of pain and the limitation of cancer cell growth and invasion. The enzymes responsible for eCB breakdown are attractive pharmacological targets, and fatty acid amide hydrolase inhibitors, which potentiate the levels of the eCB anandamide, are now undergoing pharmaceutical development. Drugable selective inhibitors of monoacylglycerol lipase, a key enzyme regulating the levels of the other main eCB, 2-arachidonoylglycerol, were however not identified until very recently. Their availability has resulted in a large expansion of our knowledge concerning the pharmacological consequences of monoacylglycerol lipase inhibition and hence the role(s) played by the enzyme in the body. In this review, the pharmacology of monoacylglycerol lipase will be discussed, together with an analysis of the therapeutic potential of monoacylglycerol lipase inhibitors as analgesics and anticancer agents.
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| 26. |
- Fowler, Christopher J, et al.
(author)
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The case for the development of novel analgesic agents targeting both fatty acid amide hydrolase and either cyclooxygenase or TRPV1
- 2009
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In: British Journal of Pharmacology. - : John Wiley & Sons. - 0007-1188 .- 1476-5381. ; 156:3, s. 412-419
-
Journal article (peer-reviewed)abstract
- Although the dominant approach to drug development is the design of compounds selective for a given target, compounds targeting more than one biological process may have superior efficacy, or alternatively a better safety profile than standard selective compounds. Here, this possibility has been explored with respect to the endocannabinoid system and pain. Compounds inhibiting the enzyme fatty acid amide hydrolase (FAAH), by increasing local endocannabinoid tone, produce potentially useful effects in models of inflammatory and possibly neuropathic pain. Local increases in levels of the endocannabinoid anandamide potentiate the actions of cyclooxygenase inhibitors, raising the possibility that compounds inhibiting both FAAH and cyclooxygenase can be as effective as non-steroidal anti-inflammatory drugs but with a reduced cyclooxygenase inhibitory 'load'. An ibuprofen analogue active in models of visceral pain and with FAAH and cyclooxygenase inhibitory properties has been identified. Another approach, built in to the experimental analgesic compound N-arachidonoylserotonin, is the combination of FAAH inhibitory and transient receptor potential vanilloid type 1 antagonist properties. Although finding the right balance of actions upon the two targets is a key to success, it is hoped that dual-action compounds of the types illustrated in this review will prove to be useful analgesic drugs.
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| 27. |
- Kehr, J., et al.
(author)
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Mephedrone, compared with MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and 5-HT levels in nucleus accumbens of awake rats
- 2011
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In: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 164:8, s. 1949-1958
-
Journal article (peer-reviewed)abstract
- BACKGROUND AND PURPOSE The designer drug 1-(4-methylphenyl)-2-methylaminopropan-1-one (4-methylmethcathinone, mephedrone) is reported to possess psychostimulant, entactogenic and hallucinogenic effects. The purpose of this study was to examine the effects of acute administration of mephedrone on extracellular levels of dopamine (DA) and 5-HT in the nucleus accumbens of awake rats and compare these effects with those induced by 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and amphetamine. EXPERIMENTAL APPROACH Microdialysis sampling was performed while simultaneously recording locomotor activity in rats and the monoamines were determined by HPLC with electrochemical detection. KEY RESULTS Mephedrone (3 mg·kg−1 s.c.) and (+)-amphetamine (1 mg·kg−1 s.c.) caused rapid increases in extracellular DA levels of 496% and 412%, respectively, whereas MDMA (3 mg·kg−1 s.c.) showed only a moderate effect (235%). The corresponding 5-HT levels increased to 941% (mephedrone) and 911% (MDMA), but only to 165% following amphetamine. The calculated t1/2 values for elimination rate of mephedrone, MDMA and amphetamine-induced increases in extracellular DA levels were 25, 303 and 51 min, the corresponding t1/2 values for 5-HT were 26, 48 and 84 min, respectively. Locomotor activity was increased most by amphetamine, whereas both mephedrone and MDMA showed about three times lower and shorter-lasting effects. CONCLUSIONS AND IMPLICATIONS The neurochemical and functional properties of mephedrone resemble those of MDMA, but it also shows an amphetamine-like effect in that it evokes a rapid release and elimination of DA in the brain reward system, a feature that may contribute to its potent re-inforcing properties.
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| 28. |
- Marklund, Niklas, et al.
(author)
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Animal modeling of traumatic brain injury in pre-clinical drug development : where do we go from here?
- 2011
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In: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 164:4, s. 1207-1229
-
Journal article (peer-reviewed)abstract
- Traumatic brain injury (TBI) is the leading cause of death and disability in young adults. Survivors of TBI frequently suffer from long term personality changes and deficits in cognitive and motor performance, urgently calling for novel pharmacological treatment options. To date, all clinical trials evaluating neuroprotective compounds have failed in demonstrating clinical efficacy in cohorts of severely injured TBI patients. The purpose of the present review is to describe the utility of animal models of TBI for pre-clinical evaluation of pharmacological compounds. No single animal model can adequately mimic all aspects of human TBI owing to the heterogeneity of clinical TBI. To successfully develop compounds for clinical TBI, a thorough evaluation in several TBI models and injury severities is crucial. Additionally, brain pharmacokinetics and the time window must be carefully evaluated. Although the search for a single-compound, "silver bullet" therapy is ongoing, a combination of drugs targeting various aspects of neuroprotection, neuroinflammation and regeneration may be needed. In summary, finding drugs and prove clinical efficacy in TBI is a major challenge ahead for the research community and the drug industry. For a successful translation of basic science knowledge to the clinic to occur we believe that a further refinement of animal models and functional outcome methods is important. In the clinical setting, improved patient classification, more homogenous patient cohorts in clinical trials, standardized treatment strategies, improved CNS drug delivery systems and monitoring of target drug levels and drug effects is warranted.
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| 29. |
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| 30. |
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| 32. |
- van der Hoorn, Jwa, et al.
(author)
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Low dose of the liver X receptor agonist, AZ876, reduces atherosclerosis in APOE*3Leiden mice without affecting liver or plasma triglyceride levels
- 2011
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In: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 162:7, s. 1553-1563
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Journal article (peer-reviewed)abstract
- BACKGROUND AND PURPOSE: Liver X receptor (LXR) agonists are atheroprotective but often induce hypertriglyceridaemia and liver steatosis. We investigated the effect of a novel high-affinity LXR activator, AZ876, on plasma lipids, inflammation and atherosclerosis, and compared the effects with another LXR agonist, GW3965. EXPERIMENTAL APPROACH: APOE*3Leiden mice were fed an atherogenic diet alone or supplemented with either AZ876 (5 or 20 µmol·kg−1·day−1) or GW3965 (17 µmol·kg−1·day−1) for 20 weeks. Total cholesterol and triglyceride levels were measured using commercial kits. Plasma cytokines were determined by using bead-based multiplex suspension array kits with the Luminex technology. Atherosclerosis was assessed histochemically and lesion composition was assessed by immunohistochemical methods. KEY RESULTS: Low-dose AZ876 had no effect on plasma or liver lipids, whereas high-dose AZ876 increased plasma triglycerides (+110%) and reduced cholesterol (-16%) compared with controls. GW3965 increased plasma triglycerides (+70%). Low-dose AZ876 reduced lesion area (-47%); and high-dose AZ876 strongly decreased lesion area (-91%), lesion number (-59%) and severity. In either dose, AZ876 did not affect lesion composition. GW3965 reduced atherosclerosis and collagen content of lesions (-23%; P < 0.01). High-dose AZ876 and GW3965, but not low-dose AZ876, reduced inflammation as reflected by lower cytokine levels and vessel wall activation. CONCLUSIONS AND IMPLICATIONS: We have identified a novel LXR agonist that when given in a low dose inhibits the progression of atherosclerosis without inducing anti-inflammatory effects, liver steatosis or hypertriglyceridaemia. Therefore, the primary protective action of a low-dose AZ876 is likely to be an increased reverse cholesterol transport.
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| 33. |
- Varin, Thibault, et al.
(author)
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Phe369(7.38) at human 5-HT7 receptors confers interspecies selectivity to antagonists and partial agonists
- 2010
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In: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 159:5, s. 1069-1081
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Journal article (peer-reviewed)abstract
- Background and purpose: Human and rat 5-HT7 receptors were studied with a particular emphasis on the molecular interactions involved in ligand binding, searching for an explanation to the interspecies selectivity observed for a set of compounds. We performed affinity studies, molecular modelling and site-directed mutagenesis, with special focus on residue Phe(7.38) of the human 5-HT7 receptor [Cys(7.38) in rat]. Experimental approach: Competition binding studies were performed for seven 5-HT7 receptor ligands at three different 5-HT7 receptors. The functional behaviour was evaluated by measuring 5-carboxytryptamine-stimulated cAMP production. Computational simulations were carried out to explore the structural bases in ligand binding observed for these compounds. Key results: Competition experiments showed a remarkable selectivity for the human receptor when compared with the rat receptor. These results indicate that mutating Cys to Phe at position 7.38 profoundly affects the binding affinities at the 5-HT7 receptor. Computational simulations provide a structural interpretation for this key finding. Pharmacological characterization of compounds mr25020, mr25040 and mr25053 revealed a competitive antagonistic behaviour. Compounds mr22423, mr22433, mr23284 and mr25052 behaved as partial agonists. Conclusions and implications: We propose that the interspecies difference in binding affinities observed for the compounds at human and rat 5-HT7 receptors is due to the nature of the residue at position 7.38. Our molecular modelling simulations suggest that Phe(7.38) in the human receptor is integrated in the hydrophobic pocket in the central part of the binding site [Phe(6.51)-Phe(6.52)] and allows a tighter binding of the ligands when compared with the rat receptor.
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| 34. |
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| 35. |
- Abrams, P, et al.
(author)
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Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder
- 2006
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In: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 148:5, s. 565-578
-
Research review (peer-reviewed)abstract
- 1 The effectiveness of antimuscarinic agents in the treatment of the overactive bladder (OAB) syndrome is thought to arise through blockade of bladder muscarinic receptors located on detrusor smooth muscle cells, as well as on nondetrusor structures. 2 Muscarinic M-3 receptors are primarily responsible for detrusor contraction. Limited evidence exists to suggest that M-2 receptors may have a role in mediating indirect contractions and/or inhibition of detrusor relaxation. In addition, there is evidence that muscarinic receptors located in the urothelium/suburothelium and on afferent nerves may contribute to the pathophysiology of OAB. Blockade of these receptors may also contribute to the clinical efficacy of antimuscarinic agents. 3 Although the role of muscarinic receptors in the bladder, other than M3 receptors, remains unclear, their role in other body systems is becoming increasingly well established, with emerging evidence supporting a wide range of diverse functions. Blockade of these functions by muscarinic receptor antagonists can lead to similarly diverse adverse effects associated with antimuscarinic treatment, with the range of effects observed varying according to the different receptor subtypes affected. 4 This review explores the evolving understanding of muscarinic receptor functions throughout the body, with particular focus on the bladder, gastrointestinal tract, eye, heart, brain and salivary glands, and the implications for drugs used to treat OAB. The key factors that might determine the ideal antimuscarinic drug for treatment of OAB are also discussed. Further research is needed to show whether the M-3 selective receptor antagonists have any advantage over less selective drugs, in leading to fewer adverse events.
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| 36. |
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| 37. |
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| 38. |
- Alexander, Stephen P. H., et al.
(author)
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The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors
- 2023
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In: BRITISH JOURNAL OF PHARMACOLOGY. - : British pharmacological society. - 0007-1188 .- 1476-5381. ; 180
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Journal article (peer-reviewed)abstract
- The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at . G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
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