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See detail2,5-Dimethyl-celecoxib inhibits cell cycle progression and induces apoptosis in human leukemia cells.
Sobolewski, Cyril; Rhim, Jiyun; Legrand, Noemie et al

in Journal of Pharmacology and Experimental Therapeutics (2015), 355(2), 308-28

Cyclooxygenase-2 (COX-2) is an essential regulator of cancer promotion and progression. Extensive efforts to target this enzyme have been developed to reduce growth of cancer cells for chemopreventive and ... [more ▼]

Cyclooxygenase-2 (COX-2) is an essential regulator of cancer promotion and progression. Extensive efforts to target this enzyme have been developed to reduce growth of cancer cells for chemopreventive and therapeutic reasons. In this context, cyclooxygenase-2 inhibitors present interesting antitumor effects. However, inhibition of COX-2 by anti-COX-2 compounds such as celecoxib was recently associated with detrimental cardiovascular side effects limiting their clinical use. As many anticancer effects of celecoxib are COX-2 independent, analogs such as 2,5-dimethyl-celecoxib (DMC), which lacks COX-2-inhibitory activity, represent a promising alternative strategy. In this study, we investigated the effect of this molecule on growth of hematologic cancer cell lines (U937, Jurkat, Hel, Raji, and K562). We found that this molecule is able to reduce the growth and induces apoptosis more efficiently than celecoxib in all the leukemic cell lines tested. Cell death was associated with downregulation of Mcl-1 protein expression. We also found that DMC induces endoplasmic reticulum stress, which is associated with a decreased of GRP78 protein expression and an alteration of cell cycle progression at the G1/S transition in U937 cells. Accordingly, typical downregulation of c-Myc and cyclin D1 and an upregulation of p27 were observed. Interestingly, for shorter time points, an alteration of mitotic progression, associated with the downregulation of survivin protein expression was observed. Altogether, our data provide new evidence about the mode of action of this compound on hematologic malignancies. [less ▲]

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See detailThe Basic Property of Lys385 Is Important for Potentiation of the Human alpha1 Glycine Receptor by Ethanol.
Castro, Patricio A; Figueroa, Maximiliano ULiege; Yevenes, Gonzalo E et al

in Journal of Pharmacology and Experimental Therapeutics (2012), 340(2), 339-49

Ethanol alters the function of several members of the Cys-loop ligand-gated ion channel superfamily. Recent studies have shown that the sensitivity of the alpha1 glycine receptor (GlyR) to ethanol can be ... [more ▼]

Ethanol alters the function of several members of the Cys-loop ligand-gated ion channel superfamily. Recent studies have shown that the sensitivity of the alpha1 glycine receptor (GlyR) to ethanol can be affected by the state of G protein activation mediated by the interaction of Gbetagamma with intracellular amino acids in the GlyR. Here, we evaluated the physicochemical property of Lys385 that contributes to ethanol modulation by using mutagenesis, patch-clamp, and biochemical techniques. A conserved substitution (K385R) did not affect either the apparent glycine EC(50) (40 +/- 1 versus 41 +/- 0.5 muM) or the ethanol-induced potentiation (53 +/- 5 versus 46 +/- 5%) of the human alpha1 GlyR. On the other hand, replacement of this residue with glutamic acid (K385E), an acidic amino acid, reduced the potentiation of the GlyR to 10 +/- 1%. Furthermore, mutations with a hydrophobic leucine (K385L), a hydrogen bond donor glutamine (K385Q), or a neutral residue (K385A) also reduced ethanol modulation. Finally, substitution by a large and hydrophobic residue (K385F) and deletion of 385 (Lys385_) reduced ethanol modulation to 10 +/- 4 and 17 +/- 0.4%, respectively. Experiments using dynamic cysteine substitution with a methanethiosulfonate reagent and homology modeling indicate that the basic property and the position of Lys385, probably because of its interaction with Gbetagamma, is critical for ethanol potentiation of the receptor. [less ▲]

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See detailBlockade of ethanol-induced potentiation of glycine receptors by a peptide that interferes with Gbetagamma binding.
Guzman, Leonardo; Moraga-Cid, Gustavo; Avila, Ariel et al

in Journal of Pharmacology and Experimental Therapeutics (2009), 331(3), 933-9

The large intracellular loop (IL) of the glycine receptor (GlyR) interacts with various signaling proteins and plays a fundamental role in trafficking and regulation of several receptor properties ... [more ▼]

The large intracellular loop (IL) of the glycine receptor (GlyR) interacts with various signaling proteins and plays a fundamental role in trafficking and regulation of several receptor properties, including a direct interaction with Gbetagamma. In the present study, we found that mutation of basic residues in the N-terminal region of the IL reduced the binding of Gbetagamma to 21 +/- 10% of control. Two basic residues in the C-terminal region, on the other hand, contributed to a smaller extent to Gbetagamma binding. Using docking analysis, we found that both basic regions of the IL bind in nearby regions to the Gbetagamma dimer, within an area of high density of amino acids having an electronegative character. Thereafter, we generated a 17-amino acid peptide with the N-terminal sequence of the wild-type IL (RQH) that was able to inhibit the in vitro binding of Gbetagamma to GlyRs to 57 +/- 5% of control in glutathione S-transferase pull-down assays using purified proteins. More interestingly, when the peptide was intracellularly applied to human embryonic kidney 293 cells, it inhibited the Gbetagamma-mediated modulations of G protein-coupled inwardly rectifying potassium channel by baclofen (24 +/- 14% of control) and attenuated the GlyR potentiation by ethanol (51 +/- 10% versus 10 +/- 3%). [less ▲]

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See detailThe KCNQ channel opener retigabine inhibits the activity of mesencephalic dopaminergic systems of the rat
Hansen, H. H.; Ebbesen, C.; Mathiesen, C. et al

in Journal of Pharmacology and Experimental Therapeutics (2006), 318(3), 1006-1019

Homo- and heteromeric complexes of KCNQ channel subunits are the molecular correlate of the M-current, a neuron-specific voltage-dependent K+ current with a well established role in control of neural ... [more ▼]

Homo- and heteromeric complexes of KCNQ channel subunits are the molecular correlate of the M-current, a neuron-specific voltage-dependent K+ current with a well established role in control of neural excitability. We investigated the effect of KCNQ channel modulators on the activity of dopaminergic neurons in vitro and in vivo in the rat ventral mesencephalon. The firing of dopaminergic neurons recorded in mesencephalic slices was robustly inhibited in a concentration-dependent manner by the KCNQ channel opener N-(2-amino-4-(4-fluorobenzylamino)phenyl) carbamic acid ethyl ester ( retigabine). The effect of retigabine persisted in the presence of tetrodotoxin and simultaneous blockade of GABA A receptors, small-conductance calcium-activated K+ ( SK) channels, and hyperpolarization-activated (I-h) channels, and it was potently reversed by the KCNQ channel blocker 4- pyridinylmethyl-9(10H)-anthracenone (XE991), indicating a direct effect on KCNQ channels. Likewise, in vivo single unit recordings from dopaminergic neurons revealed a prominent reduction in spike activity after systemic administration of retigabine. Furthermore, retigabine inhibited dopamine synthesis and c-Fos expression in the striatum under basal conditions. Retigabine completely blocked the excitatory effect of dopamine D-2 auto-receptor antagonists. Again, the in vitro and in vivo effects of retigabine were completely reversed by preadministration of XE991. Dual immunocytochemistry revealed that KCNQ4 is the major KCNQ channel subunit expressed in all dopaminergic neurons in the mesolimbic and nigrostriatal pathways. Collectively, these observations indicate that retigabine negatively modulates dopaminergic neurotransmission, likely originating from stimulation of mesencephalic KCNQ4 channels. [less ▲]

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See detailEvaluation of original dual thromboxane A2 modulators as antiangiogenic agents
de Leval, Xavier; Dassesse, Thibaut; Dogné, Jean-Michel ULiege et al

in Journal of Pharmacology and Experimental Therapeutics (2006), 318(3), 1057-1067

Angiogenesis is a promising target for the therapy of several diseases including cancer. This study was undertaken to characterize the antiangiogenic properties of a series of original dual thromboxane A ... [more ▼]

Angiogenesis is a promising target for the therapy of several diseases including cancer. This study was undertaken to characterize the antiangiogenic properties of a series of original dual thromboxane A(2) (TXA(2)) inhibitors derived from torasemide, a marketed loop diuretic with TXA(2) antagonistic properties, by evaluating their effects on human endothelial cell migration, adhesion, and viability in vitro, as well as in the ex vivo rat aortic ring assay. All drugs tested exhibited a marked affinity toward human platelet TXA(2) receptor, significantly prevented platelet aggregation induced by U-46,619, a stable TXA(2) receptor agonist, and inhibited platelet TXA(2) synthase without affecting cyclooxygenase (COX)-1 or COX-2 enzymatic activities. These dual TXA(2) inhibitors dose dependently inhibited endothelial cell migration in chemotaxis assays using vascular endothelial growth factor ( VEGF) as a chemoattractant but failed to affect cell adhesion and viability. The highest rates of cell migration inhibition were obtained with original compounds BM-567 and BM-573 (50.3 and 59.4% inhibition, respectively) when used at the final concentration of 10 mu M. In addition, pretreatment of endothelial cells with these two drugs significantly prevented U-46,619-induced intracellular Ca2+ pool mobilization, thus suggesting a mechanistic link between inhibition of the TXA(2) pathway and reduced endothelial cell migration. Treatment of rat aortic explants with U-46,619 (9,11- dideoxy- 9,11- methanoepoxyprostaglandin F 2) significantly enhanced vessel sprouting whereas aortic rings treated with some of the compounds, including BM-567 (N-n-pentyl-N'-[2-(cyclohexylamino)-5-nitrobenzenesulfonyl] urea) and BM-573 (N-tert-butyl-N'-[5-nitro-2p- toluylaminobenzenesulfonyl]urea), showed a significant decrease in vessel sprouting, which was not reversed by the addition of VEGF. These data suggest that our original dual TXA(2) inhibitors bear antiangiogenic properties, mainly by inhibiting endothelial cell migration. [less ▲]

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See detailIn vitro and in vivo pharmacological characterization of BM-613 [N-n-pentyl-N'-[2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl]urea]
Hanson, Julien ULiege; Rolin, Stéphanie; Reynaud, Denis et al

in Journal of Pharmacology and Experimental Therapeutics (2005), 313

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See detailEffect of BM-573[N-terbutyl-N '-[2-(4 '-methylphenylamino)-5-nitro-benzenesulfonyl] urea], a dual thromboxane synthase inhibitor and thromboxane receptor antagonist, in a porcine model of acute pulmonary embolism
Ghuysen, Alexandre ULiege; Lambermont, Bernard ULiege; Dogné, Jean-Michel ULiege et al

in Journal of Pharmacology and Experimental Therapeutics (2004), 310(3), 964-972

The aim of this study was to evaluate the effect of BM-573 [N-terbutyl-N'-[2-(4'-methylphenylamino)-5-nitro-benzenesulfonyl] urea], a dual thromboxane A(2) synthase inhibitor and receptor antagonist, on ... [more ▼]

The aim of this study was to evaluate the effect of BM-573 [N-terbutyl-N'-[2-(4'-methylphenylamino)-5-nitro-benzenesulfonyl] urea], a dual thromboxane A(2) synthase inhibitor and receptor antagonist, on the hemodynamic response to acute pulmonary embolism. Six anesthetized pigs were infused with placebo ( placebo group) and compared with six other pigs receiving a continuous infusion of BM-573 ( BM group). Pulmonary embolization with 0.3 g/kg autologous blood clots was carried out 30 min after the start of the infusion. Right ventricular pressure-volume loops were recorded using a conductance catheter, and end-systolic ventricular elastance was periodically assessed by varying right ventricular preload. Pulmonary vascular properties were studied by use of a four-element wind-kessel model. Hemodynamic data, including assessment of right ventricular-arterial coupling, were collected at baseline and every 30 min for 4 h. Blood samples were collected to assess gas exchange, thromboxane A(2), and prostacyclin plasma levels and to evaluate platelet aggregation. Mean pulmonary arterial pressure in the placebo group increased significantly more than in the BM group, mainly because of an additional increase in pulmonary vascular resistance. Arterial and end-systolic ventricular elastances increased also more in the placebo group, whereas right ventricular efficiency decreased. BM-573 prevented both platelet aggregation induced by U-46619 (9,11-dideoxy-11alpha, 9alpha-epoxymethanoprostaglandin F-2alpha) or by arachidonic acid, and thromboxane A(2) overproduction, whereas prostacyclin liberation was preserved. Oxygenation, however, was not significantly improved. We conclude that in this animal model of acute pulmonary embolism, infusion of BM-573 reduced pulmonary vasoconstriction. As a result, right ventricular-vascular coupling values were maintained at a maximal efficiency level. [less ▲]

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See detailPharmacological characterization of N-tert-butyl-N’-[2-(4’-methylphenylamino)-5-nitrobenzenesulfonyl]urea (BM-573), a novel thromboxane A2 receptor antagonist and thromboxane synthase inhibitor in a rat model of arterial thrombosis and its effects on bleeding time
Dogné, Jean-Michel ULiege; Hanson, Julien ULiege; De leval, X. et al

in Journal of Pharmacology and Experimental Therapeutics (2004), 309(2), 498-505

The present study was undertaken to characterize the antiplatelet and antithrombotic effects of BM-573 [N-tert-butyl-N'-[2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl] urea], an original combined ... [more ▼]

The present study was undertaken to characterize the antiplatelet and antithrombotic effects of BM-573 [N-tert-butyl-N'-[2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl] urea], an original combined thromboxane receptor antagonist and thromboxane synthase inhibitor in rats, and to determine its effects on mice bleeding time. Intraperitoneal injection of a single dose of 5 mg/kg BM-573 to rats inhibited U-46619 (9,11-dideoxy-9,11-methanoepoxy-prostaglandin F-2)-induced washed platelet aggregation 30 min and 1, 2, and 4 h after drug administration with a maximum antiplatelet effect observed after 1 and 2 h. In a rat model of thrombosis induced by ferric chloride application on the abdominal aorta, BM-573 significantly reduced the thrombus weight by 92.53, 80.20, 64.75, and 18.21% at doses of 5, 2, 0.5, and 0.2 mg/kg, respectively. Time to occlusion of abdominal aorta in the BM-573-treated group (41.50+/-5.21 min) was significantly prolonged compared with the vehicle-treated rats (16.16+/-0.79 min). Like furegrelate, seratrodast, and acetylsalicylic acid, BM-573 did not affect the tail bleeding time induced by tail transection in mice compared with vehicle-treated mice. Moreover, BM-573, a close derivative of the loop diuretic torasemide, failed to induce a significant increase in diuresis in rat and did not produce a decrease in blood glucose concentration as observed with the sulfonylurea glibenclamide. In conclusion, we have demonstrated that the nitrobenzenic sulfonylurea BM-573, an original combined thromboxane receptor antagonist and thromboxane synthase inhibitor, is a potent antithrombotic agent that does not affect bleeding time. Moreover, BM-573 lost the diuretic property of torasemide and has no impact on glycemia. [less ▲]

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See detailBM-573, a dual thromboxane synthase inhibitor and thromboxane receptor antagonist, prevents pig myocardial infarction induced by coronary thrombosis
Rolin, S.; Petein, M.; Tchana-Sato, Vincent ULiege et al

in Journal of Pharmacology and Experimental Therapeutics (2003), 306(1), 59-65

The aim of this study was to characterize the effects of BM-573 [N-terbutyl-N'-[2-(4'-methylphenylamino)-5-nitro-benzenesulfonyl] urea], a novel dual thromboxane A 2 receptor antagonist and thromboxane ... [more ▼]

The aim of this study was to characterize the effects of BM-573 [N-terbutyl-N'-[2-(4'-methylphenylamino)-5-nitro-benzenesulfonyl] urea], a novel dual thromboxane A 2 receptor antagonist and thromboxane synthase inhibitor, on myocardial infarction induced by topical ferric chloride (FeCl3) application to the left anterior descending (LAD) coronary artery in anesthetized pigs. All control animals (n = 6) developed an occlusive thrombus in the LAD coronary artery. The mean infarct size, revealed by triphenyl tetrazolium chloride (TTC), and the area at risk, evidenced by Evans blue, corresponded to 35.3 +/- 2.2 and 36.9 +/- 2.1% of the left ventricular mass, respectively. In the BM-573-treated group (n = 6), a drug infusion (10 mg . kg(-1) . h(-1)) started 30 min before FeCl3 application and continued throughout the experimentation. Among the BM-573-treated group, four pigs did not develop coronary artery thrombus and their myocardium appeared healthy. Histopathological examination of FeCl3-injured coronary artery revealed an occlusive and adherent thrombus in control group, while pretreatment with BM-573 prevented thrombus formation. In infarcted zones, lack of desmin staining and muscle structure disorganization were obvious. Depletion of myocardial ATP content was observed in the myocardial necrotic region of the control group, but not in myocardial samples of BM-573-treated pigs that did not develop myocardial infarction. When BM-573 prevented LAD artery occlusion, the area under the curve of plasmatic troponin T was reduced by 77% over 6 h. These data suggest that BM-573 could be useful for the prevention of myocardial infarction. [less ▲]

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See detailIsostrychnopentamine, an indolomonoterpenic alkaloid from Strychnos usambarensis, induces cell cycle arrest and apoptosis in human colon cancer cells
Frederich, Michel ULiege; Bentires-Alj, M.; Tits, Monique ULiege et al

in Journal of Pharmacology and Experimental Therapeutics (2003), 304(3), 1103-1110

Isostrychnopentamine (ISP) is an indolomonoterpenic alkaloid that is present in the leaves of Strychnos usambarensis, a well known African shrub or little tree. The roots contain quaternary alkaloids ... [more ▼]

Isostrychnopentamine (ISP) is an indolomonoterpenic alkaloid that is present in the leaves of Strychnos usambarensis, a well known African shrub or little tree. The roots contain quaternary alkaloids, which are used to make a curare-like arrow poison. However, tertiary alkaloids isolated from the same plant possess cytotoxic activities against mammalian cells and protozoa. The effect of ISP has been investigated on the growth and viability of HCT-116 colon cancer cells during their exponentially growing phase. ISP induced apoptotic cell death as shown by the translocation of phosphatidylserine from the inner layer to the outer layer of the plasma membrane, chromatin condensation, DNA fragmentation, and caspase-3 and -9 activation. ISP provoked also cell cycle arrest in the G(2)-M phase. We also showed that the expression of p53 was not modified in ISP-treated cells, but that p21 was induced in a p53-independent manner. Finally, we demonstrated that ISP did not affect the catalytic activity of human topoisomerases I and II. In conclusion, ISP, which promotes cell death by a p53-independent apoptotic pathway, could be an interesting lead for cancer chemotherapy. [less ▲]

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See detailNovel antiangiogenic effects of the bisphosphonate compound zoledronic acid
Wood, J.; Bonjean, K.; Ruetz, S. et al

in Journal of Pharmacology and Experimental Therapeutics (2002), 302(3), 1055-1061

Bisphosphonate drugs inhibit osteoclastic bone resorption and are widely used to treat skeletal complications in patients with tumor-induced osteolysis. We now show that zoledronic acid, a new generation ... [more ▼]

Bisphosphonate drugs inhibit osteoclastic bone resorption and are widely used to treat skeletal complications in patients with tumor-induced osteolysis. We now show that zoledronic acid, a new generation bisphosphonate with a heterocyclic imidazole substituent, is also a potent inhibitor of angiogenesis. In vitro, zoledronic acid inhibits proliferation of human endothelial cells stimulated with fetal calf serum, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (IC50 values 4.1, 4.2, and 6.9 muM, respectively), and modulates endothelial cell adhesion and migration. In cultured aortic rings and in the chicken egg chorioallantoic membrane assay, zoledronic acid reduces vessel sprouting. When administered systemically to mice, zoledronic acid potently inhibits the angiogenesis induced by subcutaneous implants impregnated with bFGF [ED50, 3 mug/kg (7.5 nmol/kg) s.c.]. These findings indicate that zoledronic acid has marked antiangiogenic properties that could augment its efficacy in the treatment of malignant bone disease and extend its potential clinical use to other diseases with an angiogenic component. [less ▲]

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See detailMethyl-laudanosine: A new pharmacological tool to investigate the function of small-conductance Ca2+-activated K+ channels
Scuvée-Moreau, Jacqueline ULiege; Liégeois, Jean-François ULiege; Massotte, Laurent ULiege et al

in Journal of Pharmacology and Experimental Therapeutics (2002), 302(3), 1176-1183

Small-conductance Ca(2+)-activated K(+) channels (SK channels) underlie the prolonged postspike afterhyperpolarization (AHP) observed in many central neurons and play an important role in modulating ... [more ▼]

Small-conductance Ca(2+)-activated K(+) channels (SK channels) underlie the prolonged postspike afterhyperpolarization (AHP) observed in many central neurons and play an important role in modulating neuronal activity. However, a lack of specific and reversible blockers of these channels hampers their study in various experimental conditions. Because previous work has shown that bicuculline salts block these channels, we examined whether related alkaloids, namely laudanosine quaternary derivatives, would produce similar effects. Intracellular recordings were performed on rat midbrain dopaminergic neurons and hippocampus CA1 pyramidal cells. Binding experiments were performed on rat cerebral cortex membranes. Laudanosine, methyl-laudanosine, and ethyl-laudanosine blocked the apamin-sensitive AHP of dopaminergic neurons with mean IC(50) values of 152, 15, and 47 microM, respectively. The benzyl and butyl derivatives were less potent. Methyl-laudanosine had no effect on the I(h) current, action potential parameters, or membrane resistance of dopaminergic cells, or on the decrease in input resistance induced by muscimol, indicating a lack of antagonism at GABA(A) receptors. Interestingly, 100 microM methyl-laudanosine induced a significant increase in spiking frequency of dopaminergic neurons but not of CA1 pyramidal cells, suggesting the possibility of regional selectivity. Binding experiments on laudanosine derivatives were in good agreement with electrophysiological data. Moreover, methyl-laudanosine has no affinity for voltage-gated potassium channels, and its affinity for SK channels (IC(50) 4 microM) is superior to its affinity for muscarinic (IC(50) 114 microM) and neuronal nicotinic (IC(50) > or =367 microM) receptors. Methyl-laudanosine may be a valuable pharmacological tool to investigate the role of SK channels in various experimental models. [less ▲]

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See detailThe effects of JL 13, a pyridobenzoxazepine with potential atypical antipsychotic activity, in animal models for schizophrenia
Ellenbroek, Bart; Liégeois, Jean-François ULiege; Bruhwyler, Jacques et al

in Journal of Pharmacology and Experimental Therapeutics (2001), 298

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See detailRoles of Nuclear Factor-Kappab, P53, and P21/Waf1 in Daunomycin-Induced Cell Cycle Arrest and Apoptosis
Hellin, Anne-Cécile ULiege; Bentires-Alj, M.; Verlaet, Myriam ULiege et al

in Journal of Pharmacology and Experimental Therapeutics (2000), 295(3), 870-8

Daunomycin is a potent inducer of p53 and NF-kappaB transcription factors. It is also able to increase the amount of the p21 cyclin-dependent kinase inhibitor. The human p21 promoter harbors p53 ... [more ▼]

Daunomycin is a potent inducer of p53 and NF-kappaB transcription factors. It is also able to increase the amount of the p21 cyclin-dependent kinase inhibitor. The human p21 promoter harbors p53-responsive elements and an NF-kappaB binding site. [less ▲]

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See detailPotentiation of dopamine agonists-induced oral stereotypies by GABA-A agonists in mice : differentiation of dopamine uptake inhibitors
Tirelli, Ezio ULiege; Witkin, J. M.

in Journal of Pharmacology and Experimental Therapeutics (1998), 284

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See detailGamma-aminobutyric acid-sub(A) agonists differentially gnawing induced by indirect-acting dopamine agonists in C57BL/6J mice
Tirelli, Ezio ULiege; Geter-Douglass, B.; Witkin, J. M.

in Journal of Pharmacology and Experimental Therapeutics (1998), 284(1), 116-124

Evaluated the interaction of either gaboxadol HCl (THIP) or muscimol, both gamma-aminobutyric acid (GABA) type A agonists, with indirect-acting dopamine agonists (DAGs) methylphenidate, (+)-amphetamine ... [more ▼]

Evaluated the interaction of either gaboxadol HCl (THIP) or muscimol, both gamma-aminobutyric acid (GABA) type A agonists, with indirect-acting dopamine agonists (DAGs) methylphenidate, (+)-amphetamine, metamphetamine, amfonelic acid, indatraline, nomifensine, diclofensine, mazindol, and GBR 12935 and with direct-acting DAGs WIN 35,428, bupropion, GBR 12909, and cocaine. 1,832 male C57BL/6J mice were given either with saline or 1 of the doses of THIP or muscimol before an injection of a dopamine agonist. Gnawing on corrugated packing paper was measured. Results showed that: (1) indirect- but not direct-acting DAGs induced gnawing, (2) gnawing induced by indirect-acting DAGs GBR 12935, nomifensine and mazindol was potentiated in mice in which GABA type A receptors were stimulated either by THIP or muscimol, and (3) indirect DAGs had a differential sensitivity to the effects of THIP and muscimol. ((c) 1998 APA/PsycINFO, all rights reserved) [less ▲]

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See detailActivation of ATP-dependant K+ channels and inhibition of insulin release: effect of BPDZ 62
Lebrun, P.; Antoine, M.-H.; Ouedraogo, R. et al

in Journal of Pharmacology and Experimental Therapeutics (1996), 277

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See detailDifferential effects of drawing and indirect dopamine agonists on the induction of gnawing in C57BI/6J mice
Tirelli, Ezio ULiege; Witkin, J. M.

in Journal of Pharmacology and Experimental Therapeutics (1995), 273(1), 7-15

Compared the ability of indirect dopamine (DA) agonists to induce gnawing behavior (GB) in male C57BL/6J mice with that of direct DA agonists acting at DA D-sub-1 or D-sub-2 receptor subtypes. Eight Ss ... [more ▼]

Compared the ability of indirect dopamine (DA) agonists to induce gnawing behavior (GB) in male C57BL/6J mice with that of direct DA agonists acting at DA D-sub-1 or D-sub-2 receptor subtypes. Eight Ss were used per dose. Holes left by Ss on corrugations of packing cardboard were used as an objective index of GB. Indirect DA agonists, including DA releasers such as fencamfamine and amfonelic acid and DA uptake inhibitors such as cocaine and nomifensine, produced dose-dependent increases in GB. None of the direct agonists (e.g., apomorphine, quinpirole) increased GB. The dopaminergic nature of GB was confirmed in studies in which a host of compounds (e.g., nicotine, caffeine, dizocilpine) with primary actions at nondopaminergic sites did not induce GB. Given the general contrast between the effects of direct and indirect DA agonists, this procedure could serve as a rapid in vivo method of distinguishing direct- from indirect-acting DA agonists. ((c) 1997 APA/PsycINFO, all rights reserved) [less ▲]

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See detailGnawing induced by dopaminergic mobilzation : differential effects of direct and indirect dopamine agonists in mice
Tirelli, Ezio ULiege; Witkin, J. M.

in Journal of Pharmacology and Experimental Therapeutics (1995), 273

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