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  • 1.
    Alhouayek, Mireille
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology. Catholic Univ Louvain, Brussels, Belgium.
    Gouveia-Figueira, Sandra
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Swedish Univ Agr Sci, Umea, Sweden.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Involvement of CYP1B1 in interferon gamma-induced alterations of epithelial barrier integrity2018In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 175, no 6, p. 877-890Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE CYP1B1 and CYP1A1 are important extra-hepatic cytochromes, expressed in the colon and involved in the metabolism of dietary constituents and exogenous compounds. CYP1B1 expression is increased by pro-inflammatory cytokines, and it has been recently implicated in regulation of blood brain barrier function. We investigated its involvement in the increased permeability of the intestinal epithelial barrier observed in inflammatory conditions. EXPERIMENTAL APPROACH Epithelial monolayers formed by human T84 colon carcinoma cells cultured on transwells, were disrupted by incubation with IFN gamma (10 ng.mL(-1)). Monolayer integrity was measured using transepithelial electrical resistance. CYP1A1 and CYP1B1 inhibitors or inducers were applied apically. Potential mechanisms of action were investigated using RT-qPCR. KEY RESULTS IFN gamma disrupts the barrier integrity of the T84 monolayers and increases CYP1B1 and HIF1 alpha mRNA expression. CYP1B1 induction is inhibited by the NF-kappa B inhibitor ammonium pyrrolidinedithiocarbamate (100 mu M) but not by the HIF1 alpha inhibitor 3-(5-hydroxymethyl-2-furyl)-1-benzyl indazole (50 mu M). Inhibition of CYP1B1 with the selective inhibitor 2,4,3,5-tetramethoxystilbene (100 nM) partly reverses the effects of IFN gamma on epithelial permeability. CONCLUSIONS AND IMPLICATIONS These data suggest that increased expression of CYP1B1 is involved in the effects of IFN gamma on epithelial permeability. Inhibition of CYP1B1 counteracts the alterations of epithelial barrier integrity induced by IFN gamma and could thus have a therapeutic potential in disorders of intestinal permeability associated with inflammation.

  • 2.
    Alhouayek, Mireille
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Rankin, Linda
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Gouveia-Figueira, Sandra C.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Interferon γ treatment increases endocannabinoid and related N-acylethanolamine levels in T84 human colon carcinoma cells2019In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 176, no 10, p. 1470-1480Article in journal (Refereed)
    Abstract [en]

    Background and purpose: Endocannabinoids and related N-acylethanolamines (NAEs) are involved in regulation of gut function, but relatively little is known as to whether inflammatory cytokines such as IFN affect their levels. We have investigated this in vitro using cultures of T84 colon cancer cells.

    Experimental approach: T84 cells, when cultured in monolayers, differentiate to form adult colonic crypt-like cells with excellent permeability barrier properties. The integrity of the permeability barrier in these monolayers was measured using transepithelial electrical resistance (TEER). NAE levels were determined by ultra-performance liquid chromatography-tandem mass spectrometric analysis. Expression of the enzymes involved in NAE and 2-arachidonoylglycerol (2-AG) turnover were assessed with qPCR.

    Key results: IFN treatment for 8 or 24h increased levels of both endocannabinoids (anandamide and 2-AG) and the related NAEs. The treatment did not affect the rate of hydrolysis of either anandamide or palmitoylethanolamide by intact cells, and in both cases, fatty acid amide hydrolase (FAAH) rather than NAE-hydrolysing acid amidase (NAAA) was mainly responsible for the hydrolysis of these NAEs. IFN treatment reduced the TEER of the cells in a manner that was not prevented by inhibition of either FAAH or NAAA but was partially reversed by apical administration of the NAE palmitoylethanolamide.

    Conclusion and implications: IFN treatment mobilized endocannabinoid and related NAE levels in T84 cells. However, blockade of anandamide or NAE hydrolysis was insufficient to negate the deleterious effects of this cytokine upon the permeability barrier of the cell monolayers.

  • 3.
    Björklund, Emmelie
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Norén, E
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Nilsson, J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Inhibition of monoacylglycerol lipase by troglitazone, N-arachidonoyl dopamine and the irreversible inhibitor JZL184: comparison of two different assays2010In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 161, no 7, p. 1512-1526Article in journal (Refereed)
    Abstract [en]

    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.

  • 4.
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Monoacylglycerol lipase: a target for drug development?2012In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 166, no 5, p. 1568-1585Article, review/survey (Refereed)
    Abstract [en]

    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.

  • 5.
    Fowler, Christopher J
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Naidu, P S
    Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
    Lichtman, A
    Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
    Onnis, V
    Department of Toxicology, Unit of Medicinal Chemistry, University of Cagliari, Cagliari, Italy.
    The case for the development of novel analgesic agents targeting both fatty acid amide hydrolase and either cyclooxygenase or TRPV12009In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 156, no 3, p. 412-419Article in journal (Refereed)
    Abstract [en]

    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.

  • 6.
    Ghafouri, Nazdar
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Tiger, Gunnar
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Razdan, Raj K
    Mahadevan, Anu
    Pertwee, Roger G
    Martin, Billy R
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Inhibition of monoacylglycerol lipase and fatty acid amide hydrolase by analogues of 2-arachidonoylglycerol2004In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 143, no 6, p. 774-784Article in journal (Refereed)
  • 7.
    Holt, Sandra
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Omeir, Romelda
    Tiger, Gunnar
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Effects of pH on the inhibition of fatty acid amidohydrolase by ibuprofen.2001In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 133, no 4, p. 513-520Article in journal (Refereed)
    Abstract [en]

    The pharmacological properties of fatty acid amidohydrolase (FAAH) at different assay pH values were investigated using [(3)H]-anandamide ([(3)H]-AEA) as substrate in rat brain homogenates and in COS-1 [corrected] cells transfected with wild type and mutant FAAH. Rat brain hydrolysis of [(3)H]-AEA showed pH dependency with an optimum around pH 8-9. Between pH 6.3 and 8.2, the difference in activity was due to differences in the V(max), rather than the K(M) values. For inhibition of rat brain [(3)H]-AEA metabolism by a series of known FAAH inhibitors, the potencies of the enantiomers of ibuprofen and phenylmethylsulphonyl fluoride (PMSF) were higher at pH 5.28 than at pH 8.37, whereas the reverse was true for oleyl trifluoromethylketone (OTMK) and arachidonoylserotonin. At both pH values, (-)ibuprofen was a mixed-type inhibitor of FAAH. The K(i)((slope)) and K(i)((intercept)) values for (-)ibuprofen at pH 5.28 were 11 and 143 microM, respectively. At pH 8.37, the corresponding values were 185 and 3950 microM, respectively. The pH dependency for the inhibition by OTMK and (-)ibuprofen was also seen in COS-1 [corrected] cells transiently transfected with either wild type, S152A or C249A FAAH. No differences in potencies between the wild type and mutant enzymes were seen. It is concluded that the pharmacological properties of FAAH are highly pH-dependent. The higher potency of ibuprofen at lower pH values raises the possibility that in certain types of inflamed tissue, the concentration of this compound following oral administration may be sufficient to inhibit FAAH.

  • 8. Hugoson-Seligsohn, E E
    et al.
    Koskinen, L O
    TRH-induced blood flow and mean arterial pressure changes in the rabbit are not dependent on the anaesthetic used.1989In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 97, no 1, p. 190-6Article in journal (Refereed)
    Abstract [en]

    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.

  • 9.
    Jonsson, Kent-Olov
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Vandevoorde, Séverine
    Lambert, Didier
    Tiger, Gunnar
    Fowler, Christopher
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Effects of homologues and analogues of palmitoylethanolamide upon the inactivation of the endocannabinoid anandamide.2001In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 133, no 8, p. 1263-1275Article in journal (Refereed)
    Abstract [en]

    The ability of a series of homologues and analogues of palmitoylethanolamide to inhibit the uptake and fatty acid amidohydrolase (FAAH)-catalysed hydrolysis of [3H]-anandamide ([3H]-AEA) has been investigated.Palmitoylethanolamide and homologues with chain lengths from 12–18 carbon atoms inhibited rat brain [3H]-AEA metabolism with pI50 values of ∼5. Homologues with chain lengths eight carbon atoms gave <20% inhibition at 100 μM.R-palmitoyl-(2-methyl)ethanolamide, palmitoylisopropylamide and oleoylethanolamide inhibited [3H]-AEA metabolism with pI50 values of 5.39 (competitive inhibition), 4.89 (mixed type inhibition) and 5.33 (mixed type inhibition), respectively.With the exception of oleoylethanolamide, the compounds did not produce dramatic inhibition of [3H]-WIN 55,212-2 binding to human CB2 receptors expressed on CHO cells. Palmitoylethanolamide, palmitoylisopropylamide and R-palmitoyl-(2-methyl)ethanolamide had modest effects upon [3H]-CP 55,940 binding to human CB1 receptors expressed on CHO cells.Most of the compounds had little effect upon the uptake of [3H]-AEA into C6 and/or RBL-2H3 cells. However, palmitoylcyclohexamide (100 μM) and palmitoylisopropylamide (30 and 100 μM) produced more inhibition of [3H]-AEA uptake than expected to result from inhibition of [3H]-AEA metabolism alone.In intact C6 cells, palmitoylisopropylamide and oleoylethanolamide inhibited formation of [3H]-ethanolamine from [3H]-AEA to a similar extent as AM404, whereas palmitoylethanolamide, palmitoylcyclohexamide and R-palmitoyl-(2-methyl)ethanolamide were less effective.These data provide useful information upon the ability of palmitoylethanolamide analogues to act as 'entourage' compounds. Palmitoylisopropylamide may prove useful as a template for design of compounds that reduce the cellular accumulation and metabolism of AEA without affecting either CB1 or CB2 receptors.

  • 10.
    Koskinen, Lars-Owe D.
    Department of Physiology and Medical Biophysics, Biomedical Centre, University of Uppsala, Uppsala, Sweden.
    Effect of low intravenous doses of TRH, acid-TRH and cyclo(His-Pro) on cerebral and peripheral blood flows.1986In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 87, no 3, p. 509-519Article in journal (Refereed)
    Abstract [en]

    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.

  • 11.
    Koskinen, Lars-Owe D.
    Department of Physiology and Medical Biophysics, Biomedical Centre, University of Uppsala, Uppsala, Sweden..
    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.1985In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 85, no 2, p. 489-497Article in journal (Refereed)
    Abstract [en]

    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.

  • 12.
    Souza, P. P. C.
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Brechter, A. B.
    Reis, R. I.
    Costa, C. A. S.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Lerner, U. H.
    Umeå University, Faculty of Medicine, Department of Odontology.
    IL-4 and IL-13 inhibit IL-1 beta and TNF-alpha induced kinin B-1 and B-2 receptors through a STAT6-dependent mechanism2013In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 169, no 2, p. 400-412Article in journal (Refereed)
    Abstract [en]

    Background and Purpose Bone resorption induced by interleukin-1 (IL-1) and tumour necrosis factor (TNF-) is synergistically potentiated by kinins, partially due to enhanced kinin receptor expression. Inflammation-induced bone resorption can be impaired by IL-4 and IL-13. The aim was to investigate if expression of B1 and B2 kinin receptors can be affected by IL-4 and IL-13. Experimental Approach We examined effects in a human osteoblastic cell line (MG-63), primary human gingival fibroblasts and mouse bones by IL-4 and IL-13 on mRNA and protein expression of the B1 and B2 kinin receptors. We also examined the role of STAT6 by RNA interference and using Stat6-/- mice. Key Results IL-4 and IL-13 decreased the mRNA expression of B1 and B2 kinin receptors induced by either IL-1 or TNF- in MG-63 cells, intact mouse calvarial bones or primary human gingival fibroblasts. The burst of intracellular calcium induced by either bradykinin (B2 agonist) or des-Arg10-Lys-bradykinin (B1 agonist) in gingival fibroblasts pretreated with IL-1 was impaired by IL-4. Similarly, the increased binding of B1 and B2 ligands induced by IL-1 was decreased by IL-4. In calvarial bones from Stat6-deficient mice, and in fibroblasts in which STAT6 was knocked down by siRNA, the effect of IL-4 was decreased. Conclusions and Implications These data show, for the first time, that IL-4 and IL-13 decrease kinin receptors in a STAT6-dependent mechanism, which can be one important mechanism by which these cytokines exert their anti-inflammatory effects and impair bone resorption.

  • 13.
    Thors, L
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Burston, J J
    Alter, B J
    McKinney, M K
    Cravatt, B F
    Ross, R A
    Pertwee, R G
    Gereau, R W
    Wiley, J L
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Biochanin A, a naturally occurring inhibitor of fatty acid amide hydrolase.2010In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 160, no 3, p. 549-560Article in journal (Refereed)
    Abstract [en]

    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.

  • 14.
    Thors, Lina
    et al.
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology. Farmakologi.
    Alajakku, K
    Fowler, C J
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology. Farmakologi.
    The 'specific' tyrosine kinase inhibitor genistein inhibits the enzymic hydrolysis of anandamide: implications for anandamide uptake2007In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 150, no 7, p. 951-960Article in journal (Refereed)
    Abstract [en]

    Background and Purpose: The cellular uptake of anandamide is reduced by inhibitors of fatty acid amide hydrolase (FAAH) and by agents disrupting endocytotic mechanisms. However, it is not clear if these events occur over the same time frame and if they occur to the same extent in different cells. We have therefore investigated the effects of such compounds in three cell lines of different origins using different assay incubation times and temperatures.

    Experimental approach: FAAH activity and cellular uptake of anandamide was measured using anandamide, radio-labelled either in the ethanolamine or arachidonoyl part of the molecule.

    Key results: The FAAH inhibitor URB597 inhibited the uptake of anandamide into C6 glioma, RBL2H3 basophilic leukaemia cells and P19 embryonic carcinoma cells at incubation time 4 min. However, a time-dependent and temperature-sensitive residual uptake remained after URB597 treatment. The combination of progesterone and nystatin reduced the uptake, but also decreased the amount of anandamide retained by the wells. Genistein inhibited anandamide uptake in a manner that was not additive to that of URB597. However, genistein was a potent competitive inhibitor of FAAH (Ki value 8 mM).

    Conclusions and implications: The reduction of anandamide uptake by genistein can be explained by its ability to inhibit FAAH with a potency which overlaps that for inhibition of tyrosine kinase. The FAAH- resistant but time-dependent uptake of anandamide is seen in all three cell lines studied and is thus presumably a generally occurring process.

  • 15.
    Thors, Lina
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Belghiti, M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Fowler, C J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Inhibition of fatty acid amide hydrolase by kaempferol and related naturally occurring flavonoids2008In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 155, no 2, p. 244-252Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Recent studies have demonstrated that the naturally occurring isoflavone compounds genistein and daidzein inhibit the hydrolysis of anandamide by fatty acid amide hydrolase (FAAH) in the low micromolar concentration range. The purpose of the present study was to determine whether this property is shared by flavonoids.

    EXPERIMENTAL APPROACH:The hydrolysis of anandamide in homogenates and intact cells was measured using the substrate labelled in the ethanolamine part of the molecule.

    KEY RESULTS: Twenty compounds were tested. Among the commonly occurring flavonoids, kaempferol was the most potent, inhibiting FAAH in a competitive manner with a K(i) value of 5 microM. Among flavonoids with a more restricted distribution in nature, the two most active toward FAAH were 7-hydroxyflavone (IC(50) value of 0.5-1 microM depending on the solvent used) and 3,7-dihydroxyflavone (IC(50) value 2.2 microM). All three compounds reduced the FAAH-dependent uptake of anandamide and its metabolism by intact RBL2H3 basophilic leukaemia cells.

    CONCLUSIONS AND IMPLICATIONS: Inhibition of FAAH is an additional in vitro biochemical property of flavonoids. Kaempferol, 7-hydroxyflavone and 3,7-dihydroxyflavone may be useful as templates for the synthesis of novel compounds, which target several systems that are involved in the control of inflammation and cancer.

  • 16.
    Thors, Lina
    et al.
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology. Farmakologi.
    Eriksson, J
    Fowler, C J
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology. Farmakologi.
    Inhibition of the cellular uptake of anandamide by genistein and its analogue daidzein in cells with different levels of fatty acid amide hydrolase-driven uptake2007In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 152, no 5, p. 744-750Article in journal (Refereed)
    Abstract [en]

    Background and purpose: Genistein, a tyrosine kinase inhibitor used to block caveolae dependent endocytosis, reduces the cellular uptake of anandamide in RBL2H3 basophilic leukaemia cells. However, genistein is also a competitive inhibitor of fatty acid amide hydrolase, the enzyme responsible for anandamide hydrolysis. Here we have investigated whether inhibition of fatty acid amide hydrolase rather than inhibition of endocytosis is the primary determinant of genistein actions upon anandamide uptake.

    Experimental approach: Cellular uptake of anandamide, labelled in the arachidonoyl part of the molecule was assessed in four different cell lines using a standard method. Fatty acid amide hydrolase activity in homogenates and intact cells was measured using anandamide labelled in the ethanolamine part of the molecule.

    Key results: The fatty acid amide hydrolase inhibitor URB597 inhibited anandamide uptake into RBL2H3 cells and R3327 AT-1 prostate cancer cells, but not into 3T3-L1 preadipocytes or PC-3 prostate cancer cells. An identical pattern was seen with genistein. The related compound daidzein inhibited anandamide hydrolysis in homogenates and intact cells, and reduced its uptake into RBL2H3 and R3327 AT-1, but not PC-3 cells. Anandamide hydrolysis by cell homogenates was in the order RBL2H3 4 R3327 AT-1 4 PC-3 E3T3-L1.

    Conclusions and implications: The ability of genistein to inhibit anandamide uptake is mimicked by daidzein (which does not affect tyrosine kinase), and is only seen in cells that show sensitivity to URB597. This indicates that blockade of fatty acid amide hydrolase is the primary determinant of the effects of genistein on cellular anandamide uptake.

  • 17.
    Thors, Lina
    et al.
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology. Farmakologi.
    Fowler, C J
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology. Farmakologi.
    Is there a temperature-dependent uptake of anandamide into cells?2006In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 149, no 1, p. 73-81Article in journal (Refereed)
  • 18.
    Turkmen, Sahruh
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Department of Obstetrics & Gynaecology, Sundsvall County Hospital, Sundsvall, Sweden.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wahlström, Göran
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Andréen, Lotta
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Department of Obstetrics & Gynaecology, Sundsvall County Hospital, Sundsvall, Sweden.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Tolerance to allopregnanolone with focus on the GABA-A receptor2011In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 162, no 2, p. 311-327Article in journal (Refereed)
    Abstract [en]

    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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