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  • 1.
    Babateen, Omar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Jin, Zhe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Bhandage, Amol K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Korol, Sergiy V
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Westermark, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Forsberg Nilsson, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Uhrbom, Lene
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
    Smits, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Birnir, Bryndis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Etomidate, propofol and diazepam potentiate GABA-evoked GABAA currents in a cell line derived from Human glioblastoma2015Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 748, s. 101-107Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    GABAA receptors are pentameric chloride ion channels that are opened by GABA. We have screened a cell line derived from human glioblastoma, U3047MG, for expression of GABAA receptor subunit isoforms and formation of functional ion channels. We identified GABAA receptors subunit α2, α3, α5, β1, β2, β3, δ, γ3, π, and θ mRNAs in the U3047MG cell line. Whole-cell GABA-activated currents were recorded and the half-maximal concentration (EC50) for the GABA-activated current was 36μM. The currents were activated by THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) and enhanced by the benzodiazepine diazepam (1μM) and the general anesthetics etomidate and propofol (50μM). In line with the expressed GABAA receptors containing at least the α3β3θ subunits, the receptors were highly sensitive to etomidate (EC50=55nM). Immunocytochemistry identified expression of the α3 and β3 subunit proteins. Our results show that the GABAA receptors in the glial cell line are functional and are modulated by classical GABAA receptor drugs. We propose that the U3047MG cell line may be used as a model system to study GABAA receptors function and pharmacology in glial cells.

  • 2. Cappendijk, Susanne L T
    et al.
    Hurd, Yasmin L
    Nylander, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    van Ree, Jan M
    Terenius, Lars
    A heroin-, but not a cocaine expecting, self-administration state preferentially alters brain endogenous peptides1999Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 365, nr 2-3, s. 175-182Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The purpose of the current study was to assess neuropeptidergic alterations during a phase of the drug addiction cycle associated with drug craving as compared to a time period when the drug had been recently self-administered. Male Wistar rats were allowed to self-administer cocaine, heroin or saline for 6 h for 5 consecutive days. Immediately following the last self-administration session ('acute drug on board' state), and just before the next scheduled session ('drug expecting' state), the animals were decapitated and the levels of dynorphin A and B, [Met5]- and [Leu5]-enkephalin and substance P were measured in different brain areas. During the 'acute drug on board' state, peptide levels in animals that self-administered heroin or cocaine were not significantly changed. In contrast, during the 'drug expecting' state, heroin-treated animals had increased levels of dynorphin A, dynorphin B and [Met5]-enkephalin in the caudal striatum as compared to the cocaine- and saline-treated animals, and the level of [Leu5]-enkephalin was increased as compared to the cocaine-treated group. In the septum, an increase of [Met5]-enkephalin and substance P was observed in the animals expecting heroin as compared to the saline- and/or cocaine-treated animals. In the caudal striatum, substance P levels were elevated in the heroin- and cocaine-expecting animals. In conclusion, heroin, as compared to cocaine, appears to have a more pronounced effect on dynorphin, enkephalin and substance P levels in the caudal striatum and septum, especially during periods when self-administration of the drug is expected.

  • 3.
    Carlsson, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Ohsawa, Masahiro
    Hallberg, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nyberg, Fred J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kamei, Junzo
    Substance P1-7 induces antihyperalgesia in diabetic mice through a mechanism involving the naloxone-sensitive sigma receptors2010Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 626, nr 2-3, s. 250-255Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have recently explored the role of the tachykinin substance P neuroactive fragment substance P1-7 in the mediation of anti-inflammatory effects using a blister model in the rat paw (Wiktelius et al., 2006). We observed that this heptapeptide induced a dose-dependent inhibitory effect on the substance P-induced response, which was reversible by the non-selective opioid receptor antagonist naloxone. In the present study, we examined the ability of substance P1-7 to induce antihyperalgesic effects in streptozotocin-induced diabetic mice. We found that the substance P fragment strongly and dose-dependently produced antihyperalgesia in diabetic mice. This effect was reversed by naloxone but not by the selective opioid receptor antagonist beta-funaltrexamine, naltrindole or nor-binaltorphimine. selective for the mu-, delta- or kappa-Opioid receptor, respectively. In addition, the anti hyperalgesic effect induced by substance P1-7 was partly reversed by a sigma(1) receptor agonist (+)-pentazocine. but not a a, receptor antagonist BD1047 ([2-(3,4-dichlorophenyl) ethyl]-N-methyl-2-(diamino)ethylamine), suggesting that involvement of the naloxone-sensitive sigma-receptor for the action of the SP related heptapeptides. These results suggest that hyperalgesia in diabetic mice may be, in part, due to the enhanced endogenous sigma(1) receptor systems in the spinal cord.

  • 4.
    Carlsson-Jonsson, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gao, Tianle
    Hao, Jing-Xia
    Fransson, Rebecca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sandström, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wiesenfeld-Hallin, Zsuzsanna
    Xu, Xiao-Jun
    N-terminal truncations of substance P1-7 amide affect its action on spinal cord injury-induced mechanical allodynia in rats2014Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 738, s. 319-325Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Central neuropathic pain can arise from injury of the spinal cord and can become chronic. Treatment is difficult and, because complete pain relief is currently very hard to achieve, there is a need for new, more effective treatment options. In this study we used an animal model of spinal cord injury to evaluate the potency of a bioactive fragment of substance P (SP), i.e. SP1-7, in alleviating signs of allodynia and acute pain. SP1-7 is known from earlier studies to possess antinociceptive properties. We also studied the effects of intraperitoneal injection of an amidated analog of this heptapeptide and of its truncated analogs, all of which had high affinity to the SP1-7 binding site, to evaluate the importance of the removed amino acids for the bioclistribution and stability of the peptides. Most of the examined compounds alleviated mechanical alloclynia without any signs of sedation or motor impairment in the rats. In contrast, the response threshold to acute nociceptive stimulation was not affected by arty of the compounds tested. Most of the amino acids in the heptapepticle structure were essential for retaining the biological effect after peripheral injection. These observations suggest that the heptapepticle and its N-Lerminal truncated hexa- and pentapeptide analogs could be of interest for further development of analgesics in the management of mechanical allodynia.

  • 5. Dalziel, J E
    et al.
    Birnir, Bryndis
    John Curtin School of Medical Research, Australian National University.
    Everitt, A B
    Tierney, M L
    Cox, G B
    Gage, P W
    A threonine residue in the M2 region of the beta1 subunit is needed for expression of functional alpha1beta1 GABA(A) receptors.1999Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 370, nr 3, s. 345-8Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Although there is a high degree of homology in the M2 transmembrane segments of alpha1 and beta1 subunits, subunit-specific effects were observed in alpha1beta1 GABA(A) receptors expressed in Spodoptera frugipedra (Sf9) cells when the conserved 13' threonine residue in the M2 transmembrane region was mutated to alanine. When threonine 263 (13') was mutated to alanine in the beta1 subunit, high-affinity muscimol binding and the response to GABA were abolished. This did not occur when the threonine 263 (13') was mutated to alanine in the alpha1 subunit, but the rate of desensitisation increased and the effect of bicuculline, a competitive inhibitor, was reduced. The results show differential effects of subunits on receptor function and support a role for M2 in desensitisation.

  • 6. Dalziel, J E
    et al.
    Cox, G B
    Gage, P W
    Birnir, Bryndis
    John Curtin School of Medical Research, Australian National University.
    Mutant human alpha(1)beta(1)(T262Q) GABA(A) receptors are directly activated but not modulated by pentobarbital.1999Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 385, nr 2-3, s. 283-6Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Pentobarbital activates GABA(A) receptors and enhances GABA-activated currents. A threonine residue (262) in the second membrane spanning region at the 12' position in the beta(1) subunit, alpha(1)beta(1)(T12'Q), is necessary for the potentiating action of pentobarbital. We examined whether T12'Q-mutated receptors expressed in Spodoptera frugipedra (Sf 9) cells responded to direct activation by pentobarbital. In both mutant and wild type receptors, pentobarbital (100 microM to 1 mM) evoked a current response. The pentobarbital EC(50) values were similar; 119 and 158 microM for alpha(1)beta(1) and alpha(1)beta(1)(T12'Q) receptors, respectively. The results show it is possible to discriminate between agonistic and potentiating effects of pentobarbital, suggesting these actions involve separate mechanisms.

  • 7. Eghbali, Mansoureh
    et al.
    Gage, Peter W
    Birnir, Bryndis
    John Curtin School of Medical Research, Australian National University.
    Effects of propofol on GABAA channel conductance in rat-cultured hippocampal neurons.2003Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 468, nr 2, s. 75-82Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Channels were activated, in ripped-off patches from rat-cultured hippocampal neurons, by propofol alone, propofol plus 0.5 microM GABA (gamma-aminobutyric acid) or GABA alone. The propofol-activated currents were chloride-selective, showed outward-rectification and were enhanced by 1 microM diazepam. The maximum propofol-activated channel conductance increased with propofol concentration from less than 15 pS (10 microM) to about 60 pS (500 microM) but decreased to 40 pS in 1 mM propofol. Fitting the data from 10 to 500 microM propofol with a Hill-type equation gave a maximum conductance of 64 pS, an EC50 value of 32 microM and a Hill coefficient of 1.1. Addition of 0.5 microM GABA shifted the propofol EC50 value to 10 microM and increased the maximum channel conductance to about 100 pS. The Hill coefficient was 0.8. The maximum channel conductance did not increase further when 1 microM diazepam was added together with a saturating propofol concentration and GABA. The results are compared to effects other drugs have on GABAA channels conductance.

  • 8. Gradin, Kathryn A
    et al.
    Zhu, Hong
    Jeansson, Marie
    Göteborgs Universitet.
    Simonsen, Ulf
    Enhanced neuropeptide Y immunoreactivity and vasoconstriction in mesenteric small arteries from the early non-obese diabetic mouse2006Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 539, nr 3, s. 184-191Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The present study investigated whether sympathetic neurotransmission is altered at an early stage of diabetes in mesenteric small arteries isolated from female non-obese diabetic (NOD) and control animals without diabetes from the same mouse strain. The NOD diabetic mice had increased plasma glucose and hypertension. Confocal microscopy showed distribution of nerve terminals was similar, but immunoreaction intensity for neuropeptide Y (NPY) and tyrosine hydroxylase was higher in small arteries from NOD diabetic compared with NOD control mice. In the presence of prazosin and activated with vasopressin, electrical field stimulation evoked contractions which were more pronounced in mesenteric arteries from NOD diabetic versus NOD control mice and inhibited by the NPY Y(1) receptor antagonist, BIBP 3226. NPY concentration-response curves were leftward shifted in arteries from NOD diabetic versus NOD control both in arteries with and without endothelium, but not in the presence of the BIBP 3226. The present findings suggest that enhanced NPY content and vasoconstriction to NPY by activation of NPY Y(1) receptors in arteries from diabetic mice may contribute to the enhanced sympathetic nerve activity and vascular resistance in female non-obese early diabetic animals.

  • 9.
    Isaksson, Rebecka
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Casselbrant, Anna
    Department of Gastrosurgical Research and Education, Sahlgrenska Academy.
    Elebring, Erik
    Department of Gastrosurgical Research and Education, Sahlgrenska Academy.
    Hallberg, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Larhed, Mats
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Lars, Fändriks
    Department of Gastrosurgical Research and Education, Sahlgrenska Academy.
    Direct stimulation of angiotensin II type 2 receptor reduces nitric oxideproduction in lipopolysaccharide treated mouse macrophages2020Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 868, artikkel-id 172855Artikkel i tidsskrift (Fagfellevurdert)
  • 10. Karlsson, Lars O.
    et al.
    Grip, Lars
    Bissessar, Erik
    Bobrova, Irina
    Gustafsson, Thomas
    Kavianipour, Mohammad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Odenstedt, Jacob
    Wikström, Gerhard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Gonon, Adrian T.
    Opioid receptor agonist Eribis peptide 94 reduces infarct size in different porcine models for myocardial ischaemia and reperfusion2011Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 651, nr 1-3, s. 146-151Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Eribis peptide 94 (EP 94) is a novel enkephalin analog, thought to interact with the and delta-opioid receptors. The purpose of the present study was to examine the cardioprotective potential of EP 94 in two clinically relevant porcine models of myocardial ischaemia and reperfusion, and to investigate if such an effect is associated with an increased expression of endothelial nitric oxide synthase (eNOS). Forty-one anesthetized pigs underwent 40 min of coronary occlusion followed by 4 h of reperfusion. In Protocol I, balloon occlusion of the left anterior descending artery was performed with concurrent intravenous administration of (A) vehicle (n = 7), (B) EP 94 (1 ug/kg) after 5, 12, 19 and 26 min of ischaemia (n = 4) or (C) EP 94 (1 ug/kg) after 26, 33, 40 min of ischaemia (n = 6). In Protocol II, open-chest pigs were administered (D) vehicle (n = 6) or (E) 0.2 ug/kg/min of EP 94 (n = 6) through an intracoronary infusion into the jeopardized myocardium, started after 30 min of ischaemia and maintained for 15 min. The hearts were stained and the protein content of eNOS measured. EP 94 reduces infarct size when administered both early and late during ischaemia compared with vehicle (infarct size group A 61.6 +/- 2%, group B 50.2 +/- 3% and group C 49.2 +/- 2%, respectively, P < 0.05), as well as when infused intracoronary (infarct size group D 82.2 +/- 3.9% and group E 61.2 +/- 2.5% respectively, P < 0.01). Phosphorylated eNOS Ser(I177) in relation to total eNOS was significantly increased in the group administered EP 94. indicating activation of nitric oxide production.

  • 11.
    Kommalage, Mahinda
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Höglund, Urban
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Involvement of spinal GABA receptors in the regulation of intraspinal acetylcholine relase2005Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 525, nr 1-3, s. 69-73Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    It has been shown that analgesics such as morphine, lidocaine and clonidine increase the release of spinal acetylcholine. Acetylcholine may therefore play an important role in the regulation of spinal pain threshold. Since behavioral as well as in vitro studies have shown a clear involvement of GABA (gamma-amino butyric acid) receptors in the regulation of spinal nociceptive mechanisms, the present study focused on the role of GABA receptors for spinal acetylcholine release control. GABA receptor agonists and antagonists were infused via a spinal microdialysis probe and acetylcholine release was measured. The GABA(A) receptor agonist muscimol decreased acetylcholine release and the antagonist bicuculline increased acetylcholine release. The GABA(B) receptor agonist baclofen decreased acetylcholine release whereas the antagonist saclofen did not change acetylcholine release. The results suggest that both GABA receptor subtypes have an inhibitory role on spinal dorsal horn acetylcholine release and that the GABA(A) receptors are tonically regulating acetylcholine release.

  • 12.
    Kopanchuk, Sergei
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Veiksina, Santa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Petrovska, Ramona
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Mutule, Ilze
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Szardenings, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Rinken, Ago
    Wikberg, Jarl E S
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Co-operative regulation of ligand binding to melanocortin receptor subtypes: evidence for interacting binding sites2005Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 512, nr 2-3, s. 85-95Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This study evaluates the binding the melanocyte stimulating hormone peptide analogue [125I]NDP-MSH to melanocortin receptors MC1, MC3, MC4 and MC5 in insect cell membranes produced by baculovirus expression systems. The presence of Ca2+ was found to be mandatory to achieve specific [125I]NDP-MSH binding to the melanocortin receptors. Although association kinetics of [125I]NDP-MSH followed the regularities of simple bimolecular reactions, the dissociation of [125I]NDP-MSH from the melanocortin receptors was heterogeneous. Eleven linear and cyclic MSH peptides studied displaced the [125I]NDP-MSH binding to the studied melanocortin receptors, with the shapes of their competition curves varying from biphasic or shallow to super-steep (Hill coefficients ranging from 0.4 to 1.5). Notably the same peptide often gave highly different patterns on different melanocortin receptor subtypes; e.g. the MC4 receptor selective antagonist HS131 gave a Hill coefficient of 1.5 on the MC1 receptor but 0.5-0.7 on the MC(3-5) receptors. Adding a mask of one of the peptides to block its high affinity binding did not prevent other competing peptides to yield biphasic competition curves. The data indicate that the binding of MSH peptides to melanocortin receptors are governed by a complex dynamic homotropic co-operative regulations.

  • 13. Lindquist, Catarina E L
    et al.
    Dalziel, Julie E
    Cromer, Brett A
    Birnir, Bryndis
    Molecular and Cellular Physiology, Department of Physiological Sciences, Lund University.
    Penicillin blocks human alpha 1 beta 1 and alpha 1 beta 1 gamma 2S GABAA channels that open spontaneously.2004Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 496, nr 1-3, s. 23-32Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We used the open-channel blocker, penicillin (10 mM), as a tool to investigate if the human alpha1beta1 or alpha1beta1gamma2S gamma-aminobutyric acid type A (GABAA) receptor channels opened in the absence of GABA. Application of penicillin to cells expressing the receptors resulted in a transient inward whole-cell current, the off-current, upon penicillin removal. The amplitude of the off-current was dependent on the duration of the penicillin application, it reversed in polarity at depolarized potentials and exhibited "run-down" similar to the GABA-activated currents. Bicuculline (100 microM) blocked the off-current response. Pentobarbital (50 microM) enhanced the peak off-current amplitude by 2.8 and 3.4 in alpha1beta1 and alpha1beta1gamma2S receptors, respectively. Diazepam (1 microM) only enhanced the off-current peak response in alpha1beta1gamma2S receptors (1.6) and induced the development of an inward current when applied alone. The results are consistent with that the alpha1beta1 or alpha1beta1gamma2) GABAA receptors can open in the absence of GABA and raise the question of what role spontaneous channel openings have in the function of GABAA receptors.

  • 14.
    Lindqvist, Niclas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Näpänkangas, Ulla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Lindblom, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Farmakologi.
    Hallböök, Finn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Proopiomelanocortin and melanocortin receptors in the adult rat retino-tectal system and their regulation after optic nerve transection2003Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 482, nr 1-3, s. 85-94Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of this study was to characterise the expression of the melanocortin system in the normal and injured rat visual system. Using real-time polymerase chain reaction and immunohistochemistry, we detected melanocortin MC3, MC4 and MC5 receptors and proopiomelanocortin in adult retina and superior colliculus. Melanocortin MC4 receptor mRNA was the most abundant receptor. Melanocortin MC3, MC4 and MC5 receptors were localised to the ganglion cell and inner nuclear layers and the melanocortin MC3 and MC4 receptors were localised to retinal ganglion cells. Transection of the optic nerve leads to ganglion cell death and both melanocortin receptor and proopiomelanocortin expression decreased in superior colliculus after transection whereas the expression was unchanged or even increased in the retina. α-Melanocyte-stimulating hormone elicited neurite outgrowth from embryonic retinal explants. Together, these data implicate a role for the melanocortin system in the adult rat retina and that melanocortins can stimulate neurite growth from retinal neurons.

  • 15. Magnusson, Marie
    et al.
    Gunnarsson, Margoth
    Berntorp, Erik
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Höglund, Peter
    Effects of pentoxifylline and its metabolites on platelet aggregation in whole blood from healthy humans2008Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 581, nr 3, s. 290-5Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    It is known that pentoxifylline inhibits platelet aggregation in vitro, but the effects from pentoxifylline and its main metabolites: 3,7-dimetyl-1(5 hydroxyhexyl)xanthine (R-M1 and S-M1), 3,7-dimetyl -1(4-carboxybutyl)xanthine (M4), 3,7-dimetyl -1(3-carboxypropyl)xanthine (M5), on platelet aggregation in whole blood in vitro and in vivo have not been studied. We found that pentoxifylline, rac-M1, R-M1, S-M1 and M4 significantly inhibit ADP induced platelet aggregation in whole blood in vitro in a concentration-dependent manner, R-M1 being the most potent followed by rac-M1, S-M1, pentoxifylline, and M4. In this series of experiments the effects on aggregation induced ATP-release were less pronounced and were only significant after treatment with pentoxifylline, rac-M1 and R-M1, but the potency order appears to be the same. Since the metabolites are not available for use in humans, and also since each substance would be extensively metabolised in vivo, we made an attempt to estimate the relative contribution of each substance to the total effect of pentoxifylline in vivo. Previously published concentrations of pentoxifylline and these metabolites in humans, after administration of pentoxifylline, were used in combination with the potency ratios from this study. The findings from these calculations were that the main effect in vivo comes from S-M1 followed by pentoxifylline, the other metabolites contribute less than 10% each. In conclusion: in the following potency order R-M1, rac-M1, pentoxifylline, S-M1 and M4 all have significant effects on platelet aggregation in whole blood in vitro. However, it appears that the main effects in vivo are caused by S-M1 and pentoxifylline.

  • 16.
    Mizoguchi, Hirokazu
    et al.
    Tohoku Med & Pharmaceut Univ, Fac Pharmaceut Sci, Dept Physiol & Anat, Aoba Ku, 4-4-1 Komatsushima, Sendai, Miyagi 9818558, Japan..
    Watanabe, Chizuko
    Tohoku Med & Pharmaceut Univ, Fac Pharmaceut Sci, Dept Physiol & Anat, Aoba Ku, 4-4-1 Komatsushima, Sendai, Miyagi 9818558, Japan..
    Hayashi, Takafumi
    Tohoku Med & Pharmaceut Univ, Fac Pharmaceut Sci, Dept Pharmaceut Sci, Aoba Ku, 4-4-1 Komatsushima, Sendai, Miyagi 9818558, Japan..
    Iwata, Yoko
    Tohoku Med & Pharmaceut Univ, Fac Pharmaceut Sci, Dept Physiol & Anat, Aoba Ku, 4-4-1 Komatsushima, Sendai, Miyagi 9818558, Japan..
    Watanabe, Hiroyuki
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Katsuyama, Soh
    Tokyo Univ Pharm & Life Sci, Ctr Experiential Pharm Practice, Sch Pharm, 1432-1 Horinouchi, Hachioji, Tokyo 1920392, Japan..
    Hamamura, Kengo
    Daiichi Coll Pharmaceut Sci, Dept Pharmacol 1, Minami Ku, 22-1 Tamagawa Cho, Fukuoka 8158511, Japan..
    Sakurada, Tsukasa
    Daiichi Coll Pharmaceut Sci, Dept Pharmacol 1, Minami Ku, 22-1 Tamagawa Cho, Fukuoka 8158511, Japan..
    Ohtsu, Hiroshi
    Tohoku Univ, Grad Sch Engn, Dept Quantum Sci & Energy Engn, Aoba Ku, 6-6-01-2 Aobayama, Sendai, Miyagi 9808579, Japan..
    Yanai, Kazuhiko
    Tohoku Univ, Grad Sch Med, Dept Pharmacol, Aoba Ku, 2-1 Seiryo Machi, Sendai, Miyagi 9808575, Japan..
    Sakurada, Shinobu
    Tohoku Med & Pharmaceut Univ, Fac Pharmaceut Sci, Dept Physiol & Anat, Aoba Ku, 4-4-1 Komatsushima, Sendai, Miyagi 9818558, Japan..
    The involvement of spinal release of histamine on nociceptive behaviors induced by intrathecally administered spermine2017Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 800, s. 9-15Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The involvement of spinal release of histamine on nociceptive behaviors induced by spermine was examined in mice. Intrathecal spermine produced dose-dependent nociceptive behaviors, consisting of scratching, biting and licking. The nociceptive behaviors induced by spermine at 0.02 amol and 10 pmol were markedly suppressed by i.t. pretreatment with antiserum against histamine and were abolished in histidine decarboxylase-deficient mice. In histamine H-1 receptor-deficient mice, the nociceptive behaviors induced by spermine were completely abolished after treatment with 0.02 amol of spermine and significantly suppressed after treatment with 10 pmol of spermine. The i.t. pretreatment with takykinin NK1 receptor antagonists eliminated the nociceptive behaviors induced by 0.02 amol of spermine, but did not affect the nociceptive behaviors induced by 10 pmol of spermine. On the other hand, the nociceptive behaviors induced by spermine at both 0.02 amol and 10 pmol were suppressed by i.t. pretreatment with antagonists for the NMDA receptor polyamine-binding site. The present results suggest that the nociceptive behaviors induced by i.t. administration of spermine are mediated through the spinal release of histamine and are elicited via activation of NMDA receptors.

  • 17.
    Moller, Kristina Angeby
    et al.
    CNSP iMed Sci, AstraZeneca R&D Sodertalje, SE-15185 Sodertalje, Sweden.;Karolinska Inst, Dept Physiol & Pharmacol, SE-17177 Stockholm, Sweden..
    Berge, Odd-Geir
    CNSP iMed Sci, AstraZeneca R&D Sodertalje, SE-15185 Sodertalje, Sweden.;Univ Uppsala Hosp, Multidisciplinary Pain Ctr, SE-75185 Uppsala, Sweden..
    Finn, Anja
    Karolinska Inst, Dept Physiol & Pharmacol, SE-17177 Stockholm, Sweden..
    Stenfors, Carina
    CNSP iMed Sci, AstraZeneca R&D Sodertalje, SE-15185 Sodertalje, Sweden..
    Svensson, Camilla I.
    Karolinska Inst, Dept Physiol & Pharmacol, SE-17177 Stockholm, Sweden..
    Using gait analysis to assess weight bearing in rats with Freund's complete adjuvant-induced monoarthritis to improve predictivity: Interfering with the cyclooxygenase and nerve growth factor pathways2015Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 756, s. 75-84Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Lack of predictive power for drug effects has been a major criticism against animal pain models. It is therefore important to define the utility and limitations of different models. The aim of this study was to extend previous work on gait analysis as a tool to investigate pharmacological effects in monoarthritic rats, specifically to test the hypothesis that monoarthritis induced by Freund's complete adjuvant (FCA) provides a better estimate of overall analgesic efficacy of established, and novel, clinically effective and ineffective therapeutic approaches. Male rats injected intra-articularly into one ankle joint with FCA (1.0mg/ml) were treated with the monoclonal antibody to nerve growth factor (NGF), MEDI-578, the inhibitors of tropomyosin receptor kinases A, B and C (pan-Trk) AZ6623 or AZ7092, the transient receptor potential vanilloid 1 (TRPV1) inhibitor AZD1386, or the cyclooxygenase (COX) inhibitors naproxen, ibuprofen, valdecoxib or rofecoxib. Effects on weight bearing during locomotion were tested using video capture of print images. The apparent efficacy in this model was Trk inhibitors >= anti-NGF antibody > COX inhibitors. The TRPV1 inhibitor was ineffective. Together with previous data, the results support using gait-related parameters in the monoarthritis model. FCA as induction agent seems to provide a good overall prediction of analgesic efficacy in disorders with inflammatory joint pain. (C) 2015 Elsevier B.V. All rights reserved.

  • 18. Ohsawa, Masahiro
    et al.
    Miyata, Shigeo
    Carlsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kamei, Junzo
    Preventive effect of acetyl-L-carnitine on the thermal hypoalgesia in streptozotocin-induced diabetic mice2008Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 588, nr 2-3, s. 213-216Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hypoalgesia is one of the serious complications in diabetes. Since there are few therapeutic treatments for this diabetic hypoalgesia, the present study was designed to examine the effect of acetyl-L-carnitine (ALC) on the changes of nociceptive threshold in diabetic mice. For prophylactic study, ALC was administered once daily from 1 day after the streptozotocin treatment. Diabetic mice showed shorter tail-flick latency at 1-4 weeks after the streptozotocin treatment and longer tail-flick latency at 6-9 weeks after the streptozotocin treatment. The shortened tail-flick latency in early stage of diabetic mice was not affected by prophylactic treatment with ALC. On the other hand, ALC dose-dependently improved the hypoalgesia in diabetic mice. For therapeutic study, ALC was administered once daily from 7 weeks after the streptozotocin treatment, when tail-flick latency was already prolonged. The therapeutic treatment with ALC also ameliorated the prolonged tail-flick latency in diabetic mice. Both prophylactic and therapeutic treatment with ALC did not affect the tail-flick latency in non-diabetic mice, indicating ALC did not affect the general nociceptive transmission. These results provide evidence of the prophylactic and therapeutic potential of ALC on the progressive diabetic neuropathy.

  • 19.
    Olivier, Jocelien D A
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Akerud, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Sundström Poromaa, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Antenatal depression and antidepressants during pregnancy: Unraveling the complex interactions for the offspring2015Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 753, s. 257-262Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    During pregnancy the risk for a woman to develop a depressive episode is as high as 20%. Antenatal depression is not harmless for the developing child as several changes, including neurodevelopmental alterations, have been reported. Sometimes it is unavoidable to treat a pregnant mother with antidepressants, especially when she is suicidal. Currently, selective serotonin reuptake inhibitors (SSRIs) are the pharmacological choice of antidepressant treatment. SSRIs do not cause gross teratogenic alterations and are generally considered safe for use in pregnancy. However, although SSRIs may relieve the maternal symptoms, they definitively cross the placenta partially influencing the neurodevelopment of the fetus. In this review an overview is given of the effects on the offspring of maternal antenatal depression and the putative neurodevelopmental effects of SSRI treatment during pregnancy. Although we primarily focus on human data, some animal data are discussed to describe possible mechanisms on how SSRIs are affecting underlying biological mechanisms associated with depression. In summary, maternal depression may have long-lasting effects on the offspring, whereas prenatal SSRI exposure also increases the risk for long-lasting effects. It remains to be determined whether the effects found after SSRI treatment in pregnant women are only due to the SSRI exposure or if the underlying depression is also contributing to these effects. The possibility of epigenetic alterations as one of the underlying mechanisms that is altered by SSRI exposure is discussed. However much more research in this area is needed to explain the exact role of epigenetic mechanisms in SSRI exposure during pregnancy.

  • 20. Papathanou, Maria
    et al.
    Jenner, Peter
    Iravani, Mahmoud
    Jackson, Michael
    Stockwell, Kim
    Strang, Isabel
    Zeng, Bai-Yun
    McCreary, Andrew C
    Rose, Sarah
    The H3 receptor agonist immepip does not affect l-dopa-induced abnormal involuntary movements in 6-OHDA-lesioned rats2014Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 741, s. 304-310Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The treatment of dyskinesia in Parkinson׳s disease remains poor but H3 receptor agonists have been suggested as a novel pharmacological approach. We examined the effects of the H3 agonist, immepip, in 6-OHDA-lesioned rats exhibiting AIMs (abnormal involuntary movements), a rat analogue of dyskinesia, in response to l-dopa compared to the known anti-dyskinetic agents amantadine, MK-801 and 8-OHDPAT. We then attempted to extend these studies in to dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated common marmosets.

    Amantadine, MK-801 and 8-OHDPAT all dose-dependently reduced l-dopa-induced axial, lingual and oral (ALO) AIMs in 6-OHDA-lesioned animals accompanied by a reduction in contralateral rotation with higher doses of amantadine and MK-801. By contrast, immepip had no effect on AIMs expression or contralateral rotation. In the MPTP-treated common marmoset exhibiting dyskinesia to l-dopa, immepip alone induced retching and in combination with l-dopa administered subcutaneously or orally induced the rapid onset of retching and vomiting which was not controlled by pretreatment with domperidone. Administration of the unrelated H3 agonist, imetit had the same effect. Despite causing negative side-effects, it appears that both agonists reduced the antiparkinsonian response to l-dopa resulting in reduced dyskinesia.

    H3 agonists appear unlikely candidates for the treatment of dyskinesia in PD based on lack of evidence of efficacy and potential adverse effects.

  • 21. Rowland, N E
    et al.
    Marshall, Misty
    Robertson, K
    Anorectic effect of dehydroepiandrosterone combined with dexfenfluramine or thionisoxetine2001Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 419, nr 1Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Free feeding rats given supplementary 1 h access per day to a palatable dessert test meal were tested for the anorectic effect of dehydroepiandrosterone alone or in combination with either the serotonin releasing agent dexfenfluramine or the norepinephrine uptake inhibitor thionisoxetine (LY 368975). Isobolographic analysis showed that the effect of dehydroepiandrosterone combined with either dexfenfluramine or thionisoxetine was within the range predicted for additivity of action.

  • 22. Smith, Morten
    et al.
    Lindquist, Catarina E L
    Birnir, Bryndis
    Molecular and Cellular Physiology, Department of Physiological Sciences, Lund University.
    Evidence for inhibitory effect of the agonist gaboxadol at human alpha 1 beta 2 gamma 2S GABAA receptors.2003Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 478, nr 1, s. 21-6Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Gaboxadol (THIP; 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) is an agonist at GABA(A) receptors. THIP concentrations (0.01-50 mM) were applied rapidly to Sf9 cells expressing the human alpha(1)beta(2)gamma(2S) GABA(A) receptors. The EC(50) values for the peak current in THIP alone or THIP plus 1 microM diazepam were 154 and 53 microM, respectively. In supersaturating THIP (10-50 mM) the rate of current decay increased and an off-current developed when THIP was rapidly removed. The mean currents measured over the first 4 s in 10 mM and higher THIP concentrations were 0.6 or less of the 1 mM THIP mean current. Diazepam (1 microM) increased the 4 s mean current when evoked by 10 to 20 mM THIP but not 50 mM THIP. No similar effects on the current time-course were recorded in supersaturating gamma-aminobutyric acid (GABA) concentrations (50 and 80 mM). The results demonstrate an inhibitory as well as agonist effect of THIP at alpha(1)beta(2)gamma(2S) GABA(A) receptors.

  • 23. Spetea, M
    et al.
    Rydelius, G
    Nylander, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Ahmed, M
    Bileviciute-Ljungar, I
    Lundeberg, T
    Svensson, S
    Kreicbergs, A
    Alteration in endogenous systems during chronic inflammatory pain conditions2002Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 435, nr 2-3, s. 245-252Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The influence of chronic arthritic pain on two endogenous opioid peptides, dynorphin B and [Met5]enkephalin-Arg6-Phe7, and multiple opioid receptors in discrete brain, lumbar spinal cord and pituitary pools was investigated. Using radioimmunoassay and receptor binding assay, we examined the changes in regional opioid peptide levels and opioid receptor activity due to chronic inflammation in adjuvant arthritic rats. At 4 weeks post-inoculation, increased levels of immunoreactive dynorphin B and [Met5]enkephalin-Arg6-Phe7 were measured in tissues of arthritic rats compared with controls. No significant changes in mu-, delta- or kappa-opioid receptors were seen after chronic inflammation. Taken together, these results indicate that in chronic arthritis, opioid receptor changes do not follow the peptide alterations of pro-dynorphin and pro-enkephalin systems. Thus, dynamic modification and modulation of nociceptive information takes place during chronic inflammation. This supports the key role of the central nervous system in chronic inflammatory pain conditions.

  • 24.
    Turpaev, Kyril
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Russian Acad Sci, Ctr Theoret Problems Physicochem Pharmacol, Moscow 119991, Russia..
    Welsh, Nils
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Aromatic malononitriles stimulate the resistance of insulin-producing beta-cells to oxidants and inflammatory cytokines2016Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 784, s. 69-80Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We presently report that treatment with tyrphostin AG-126 (2-(3-hydroxy-4-nitrobenzylidene)malononitrile) and ten other aromatic malononitrile compounds (AMN) improves the resistance of insulin producing beta TC6, RIN-5AH, and MIN6 cells to oxidative stress and pro-inflammatory cytokines. On the molecular level AMN compounds promote nuclear accumulation of the Nrf2 transcription factor and expression of the cytoprotective genes heme ogygenase 1 (HO-1) and NAD(P)H/quinone oxidoreductase 1 (NQO1), inhibit cytokine-dependent inducible nitric oxide synthase (iNOS) induction, suppress intracellular production of reactive oxygen species in beta TC6 and counteract to impairments of glucose stimulated insulin secretion induced by pro-inflammatory cytokines in MIN6 cells. Nrf2 up-regulation and HO-1 induction by AG-126 are attenuated at the presence of siRNA against Nrf2 and brusatol, an inhibitor of the Nrf2 signaling pathway. Our present results indicate that in respect of inhibition of IL-1 beta-dependent iNOS induction, beta TC6 cells are more sensitive to EMK 1071 (2-((5-methylthiophen-2-yl) methylene)malononitrile) and EMK 31 (2-(4-hydroxy-3-methoxybenzylidene)malononitrile) as compared to other analyzed AMN compounds. We suggest that the ability of AMN compounds to inhibit iNOS induction and other cytokine-induced transcriptional events might be a tool to achieve improved beta-cell survival and functionality.

  • 25.
    Uhlén, Staffan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi. Univ Bergen, Dept Clin Sci, Ctr Pharm, Pharmacol Sect, Bergen, Norway..
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Jahnsen, Jan Anker
    Univ Bergen, Dept Clin Sci, Ctr Pharm, Pharmacol Sect, Bergen, Norway..
    A new, simple and robust radioligand binding method used to determine kinetic off-rate constants for unlabeled ligands. Application at alpha(2A)- and alpha(2C)-adrenoceptors2016Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 788, s. 113-121Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Kinetic on and off rate constants for many receptor ligands are difficult to determine with regular radioligand binding technique since only few of the ligands are available in labeled form. Here we developed a new and simple radioligand binding method for determining the kinetic off-rate constant for unlabeled ligands, using whole cells expressing alpha(2A)- and alpha(2C)-adrenoceptors. The new method involves pre-incubation with unlabeled ligand, centrifugation of microtiter plates in order to adhere the cells to the bottom surface, and then upside-down centrifugation of the plates for few seconds to wash away the non-bound fraction of the pre-incubated ligand. The final on-reaction assay for the radioligand is then started by quick addition of a relatively fast-associating radioligand to the cells. The curve obtained is defined by a fairly simple mathematical formula that reflects the simultaneous dissociation of pre-incubated ligand and association of the radioligand. The method proved to produce highly reproducible results in determining the k(off) constants for various unlabeled ligands. The results show that the alpha(2C)-selectivity of MK912 depends mainly on a very slow off-rate at the alpha(2C)-adrenoceptor subtype. Regarding the markedly alpha(2C)- over alpha(2A)-selective compound spiroxatrine, its much faster on-rate at alpha(2C)- than alpha(2A)-adrenoceptors explains much of its exceptional alpha(2C)-selectivity. Several new techniques for determining the kinetic component of ligand-receptor interactions at molecular level are currently developing. As a reference, based on standard radioligand binding techniques, the present study describes a simple and robust experimental and mathematical procedure for determining k(off) constants of unlabeled drugs.

  • 26.
    Västermark, Åke
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    The early origin of melanocortin receptors, agouti-related peptide, agouti signalling peptide, and melanocortin receptor-accessory proteins, with emphasis on pufferfishes, elephant shark, lampreys, and amphioxus2011Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 660, nr 1, s. 61-69Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There are conflicting theories about the evolution of melanocortin MC receptors while only few studies have addressed the evolution of agouti-related peptide (AgRP) and agouti signalling peptide (ASIP), which are antagonists at the melanocortin receptors (MCRs), or the melanocortin MC(2) receptor accessory proteins (MRAP1 and MRAP2). Previously we have cloned melanocortin MC receptors (MC(a) and MC(b)) genes in river lamprey and here we identify orthologues to these melanocortin MC receptor sequences in the sea lamprey. We investigate the putative presence of the melanocortin MC receptor genes in lancelet (amphioxus; Branchiostoma floridae) but we find it unlikely that such gene exists, due to a sharp drop in sequence similarity beyond sequence clusters of known receptors. We show the presence of AgRP and ASIP in elephant shark, a cartilaginous fish belonging to the subclass of Elasmobranchii. However, we do not find any of these genes in lamprey or lancelet after detailed analysis of both targeted and whole proteome regular expression scans. We found MRAP2, but not MRAP1, to be present in elephant shark and sea lamprey while Fugu (T. rubripes) has both genes. This study shows that the most ancient presence of these melanocortin-related sequences is found in elephant shark and lampreys considering the current available sequence data.

  • 27.
    Zemgulis, Vitas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Wikström, Gerhard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Henze, Axel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Waldenström, Anders
    Thelin, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Ronquist, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Nucleoside transport inhibition in ischemic myocardium results in enhanced taurine efflux2001Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 411, nr 1-2, s. 143-154Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    We measured with the microdialysis technique energy-related metabolites in ischemic myocardium over time in an experimental pig model. Emphasis was put on the dipyridamole effect when administered in the microdialysis probe inserted in ischemic myocardium. Not only adenosine but also taurine and pyruvate concentrations were significantly higher in the microdialysate during the periods of ischemia and extracorporeal circulation with cardioplegia. The enhanced efflux of taurine in ischemic myocardium induced by dipyridamole is a new finding. A mechanistic role of taurine in the prevention of Ca(2+) overload in ischemic myocytes is discussed. Also, taurine may have stimulatory effects on glycolysis in ischemic heart.

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