Biochemical pharmacology
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Biochemical pharmacology · Aug 2001
Attenuation of liver normothermic ischemia--reperfusion injury by preservation of mitochondrial functions with S-15176, a potent trimetazidine derivative.
We investigated the antiischemic properties of a new compound, S-15176, in an experimental model of rat liver subjected to 120-min normothermic ischemia followed by 30-min reperfusion. Rats were divided into groups, pretreated with different doses of S-15176 (1.25, 2.5, 5 and 10 mg/kg/day by intramuscular injection) or solvent alone, and subjected to the ischemia--reperfusion process. Another group served as the sham-operated controls. ⋯ The protection of mitochondrial functions was almost complete at a dosage of 10 mg/kg/day. In addition, in vitro, S-15176 totally abolished the swelling of isolated mitochondria induced by a calcium overload with an IC(50) value of 10 microM. These data demonstrate that S-15176 protects mitochondria against the deleterious effects of ischemia-reperfusion and suggest that this protective effect could be related to the inhibition of the mitochondrial permeability transition.
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Biochemical pharmacology · Jun 2001
The effect of a paracetamol and morphine combination on dynorphin A levels in the rat brain.
The purpose of this study was to find out whether the combination of inactive doses of paracetamol (PARA) and morphine was able to change dynorphin (DYN) A levels, evaluated by radioimmunoassay, and whether naloxone or [(-)-2-(3 furylmethyl)-normetazocine] (MR 2266), a kappa-opioid antagonist, modifies or prevents the activity of this combination on nociception and on DYN levels. The work was suggested by our previous findings which demonstrated that inactive doses of PARA and morphine, when given in combination, share an antinociceptive effect, and that PARA, at antinociceptive doses, decreases DYN levels in the frontal cortex, thus indicating a selective action within the CNS. Our present results demonstrate that the combination of inactive doses of PARA (100 mg/kg) and morphine (3 mg/kg) is just as effective in decreasing the levels of DYN A as full antinociceptive doses of PARA or morphine alone in the frontal cortex of the rat. ⋯ The decrease was partially antagonised by MR 2266, but not by naloxone, suggesting that the activity of PARA and morphine in combination on DYN A levels could be mediated, at least in part, through kappa-receptors, although other systems may be involved. On the other hand, both naloxone and MR 2266 prevented the antinociceptive effect of the combination in the hot plate test. All our experimental data suggest that PARA and morphine in combination exert their antinociceptive effect through the opioidergic system, which in turn may cause a decrease in DYN levels in the CNS of the rat.
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Biochemical pharmacology · May 2001
Kappa-opioid receptor agonist suppression of HIV-1 expression in CD4+ lymphocytes.
Synthetic kappa-opioid receptor (KOR) agonists have been shown to suppress HIV-1 expression in acutely infected macrophages. In the present study, we examined the effects of the KOR ligand trans-3,4-dichloro-N-methyl-N[2-(1-pyrolidinyl)cyclohexyl]benzeneaceamide methanesulfonate (U50,488) on HIV-1 expression in CD4+ lymphocytes, the main target cell of this virus. ⋯ Support for the involvement of KOR was provided by the findings that 34% of activated CD4+ lymphocytes were positive for KOR, using an immunofluorescence technique, and that seven additional synthetic KOR ligands also inhibited HIV-1 expression. The results of this study broaden understanding of the antiviral properties of KOR ligands to include cells outside of the nervous system and suggest a potential role for these agents in the treatment of HIV-1 infection.
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Biochemical pharmacology · Apr 2001
Effects of genistein on cell proliferation and cell cycle arrest in nonneoplastic human mammary epithelial cells: involvement of Cdc2, p21(waf/cip1), p27(kip1), and Cdc25C expression.
Genistein, a soy isoflavone, has been reported to inhibit the multiplication of numerous neoplastic cells, including those in the breast. However, there is limited information on the effect of genistein on nonneoplastic human breast cells. In the present studies, genistein inhibited proliferation of, and DNA synthesis in, the nonneoplastic human mammary epithelial cell line MCF-10F with an IC(50) of approximately 19-22 microM, and caused a reversible G2/M block in cell cycle progression. ⋯ Furthermore, genistein inhibited the expression of the cell cycle-associated phosphatase Cdc25C by 80%. From these results, we conclude that genistein inhibits the growth of nonneoplastic MCF-10F human breast cells by preventing the G2/M phase transition, induces the expression of the cell cycle inhibitor p21(waf/cip1) as well as its interaction with Cdc2, and inhibits the activity of Cdc2 in a phosphorylation-related manner. Down-regulation of the cell cycle-associated phosphatase Cdc25C combined with up-regulation of p21(waf/cip1) expression appear to be important mechanisms by which genistein decreases Cdc2 kinase activity and causes G2 cell cycle arrest.
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Biochemical pharmacology · Apr 2001
Evidence for bradykinin mediation of carrageenin-induced inflammatory pain: a study using kininogen-deficient Brown Norway Katholiek rats.
Inflammatory pain was induced following an intradermal injection of carrageenin into rat paws, and the hyperalgesia was measured in terms of withdrawal time following thermal pain stimulation of the inflamed paw. This hyperalgesia was significantly less in kininogen-deficient Brown Norway (B/N)-Katholiek rats, which also showed less swelling in carrageenin-induced paw edema, than in normal B/N-Kitasato rats at 1 approximately 4 hr after the carrageenin injection (at the early phase). ⋯ Pretreatment with indomethacin, a cyclooxygenase inhibitor, also inhibited the carrageenin-induced responses significantly in normal rats. These results indicate that bradykinin, acting on the B2 receptor, is the main mediator at the early phase of inflammatory pain of carrageenin edema and that prostaglandins, produced by cyclooxygenase, potentiate the effects of bradykinin.