leukotriene-b4 and ebselen

Ebselen is a seleno-organic anti-inflammatory compound with glutathione peroxidase-like activity that has the unique characteristic of mediating the isomerization of 5-HETE and LTB4 to their biologically inactive trans isomers, both directly in fluid phase and indirectly through metabolic pathways in stimulated peripheral blood leukocytes. LTB4 is an inflammatory mediator with potent chemotactic activity for neutrophilic leukocytes. We studied the effects of ebselen on the chemotactic and chemokinetic responses with human-blood-derived neutrophils. With the use of 120-microns-thick 5-microns-pore durapore filters and low BSA concentrations (0.05%) in the chemotaxis buffers, ebselen was evaluated for its effect on both chemotactic and chemokinetic responses to LTB4, C5a, and fMLP. Ebselen at 3-20 microM concentrations inhibited both chemotactic and chemokinetic responses to optimal concentrations of LTB4 without altering chemotactic responses to C5a or fMLP. Likewise, ebselen at 20 microM specifically inhibited LTB4-stimulated transendothelial migration of neutrophils, while not altering responses to C5a nor fMLP.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Azoles; Chemotaxis, Leukocyte; Complement C5a; Endothelium, Vascular; Humans; In Vitro Techniques; Isoindoles; Leukotriene B4; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Organoselenium Compounds

Leukotrienes (LTs) are a group of metabolites of arachidonic acid through the 5-lipoxygenase pathway. Among these metabolites, LTB4 is an important mediator of inflammatory disease. Recently, it has been shown that seleno-organic compounds are very biologically active. One of them, Ebselen [2-phenyl-1,2-benzoisoselenazol-3 (2H) one] is a new seleno-organic compound with very low toxicity while exhibits anti-inflammatory activity. Attempt to search for seleno-organic compounds as anti-inflammatory drugs and establish structure-activity relationships, ten ebselen derivatives with modifications in the 2-phenyl moiety were studied with respect to their effects on LTB4 biosynthesis. p-substituted compounds were shown to have stronger inhibitory activity on LTB4 biosynthesis than o-substituted compounds and ebselen itself. Among the p-substituted compounds, polar-inducing group-substituted compounds showed stronger activity than compounds substituted with polar-conjugated groups. Among the compounds substituted with polar-inducing groups, strongpolar groups exhibited stronger activity than weakpolar groups.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Azoles; Isoindoles; Leukocytes; Leukotriene B4; Male; Organoselenium Compounds; Rats; Rats, Wistar; Structure-Activity Relationship

Ebselen is a novel organo-selenium compound which catalytically inactivates peroxides in vitro in a manner similar to that of glutathione peroxidase (GSH-Px). In addition, ebselen also inactivates leukotriene B4 (LTB4) generated by pig leukocytes in vitro by isomerizing this eicosanoid to its biologically inactive 6-trans isomer. In vivo, ebselen is a weak oral inhibitor of carrageenan paw oedema and adjuvant arthritis in the rat, differentiating it from classical NSAIDs such as indomethacin and diclofenac. In contrast, oral ebselen, like (intra-articular) catalase, is an effective inhibitor of monoarthritis induced in mice with amidated glucose oxidase (aGO) and dose-dependently inhibits cobra-venom-factor-induced paw oedema in rats. Indomethacin and piroxicam are weakly active or ineffective in these models. The data indicate that ebselen is likely to be useful in the therapy of inflammatory conditions in which reactive oxygen species, such as peroxides, play an aetiological role.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Azoles; Edema; Female; Indomethacin; Inflammation; Isoindoles; Leukotriene B4; Male; Organoselenium Compounds; Peroxides; Piroxicam; Rats; Rats, Inbred Strains; Selenium

Topics: Animals; Anti-Inflammatory Agents; Arachidonic Acids; Azoles; Blood Platelets; Humans; In Vitro Techniques; Isoindoles; Leukocytes; Leukotriene A4; Leukotriene B4; Leukotrienes; Organoselenium Compounds; Selenium; Swine

Ebselen, a new organoselenium compound with pronounced anti-inflammatory properties, selectively inhibits the formation of leukotriene B4 in human and porcine leukocytes with half-maximal inhibition at 4.0 and 2.7 mumol/1, respectively. The underlying mechanism was found to be a cis-trans-isomerisation of leukotriene B4 to the 5S, 12R-6-trans-isomer. 5-Hydroxy-eicosatetraenoic acid was also isomerised to the 8-trans-isomer. At higher concentrations, ebselen induces a dose-dependent decrease in the sum of total 5-lipoxygenase products with half-maximal inhibition at 30 mumol/1. Additionally, the effects of ebselen on human platelet 12-lipoxygenase and cyclooxygenase were investigated. Human platelet 12-lipoxygenase and cyclooxygenase were inhibited in a dose dependent manner with half-maximal inhibition at 20 mumol/1 and 5 mumol/1, respectively. We suggest that suppression of leukotriene B4-formation by isomerisation to a biologically inactive compound represents a promising approach to the therapy of inflammation.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Arachidonate 12-Lipoxygenase; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Arachidonic Acids; Azoles; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Humans; Hydroxyeicosatetraenoic Acids; Isoindoles; Isomerism; Leukocytes; Leukotriene B4; Magnetic Resonance Spectroscopy; Organoselenium Compounds; Prostaglandin-Endoperoxide Synthases; Selenium; Swine

Suspensions of rat peritoneal PMNLs elicited with glycogen were stimulated by calcium and an ionophore to produce leukotrienes from endogenous arachidonic acid. We investigated the effect of the non-toxic, anti-inflammatory seleno-organic compound, ebselen (PZ 51). When ethanolic extracts of the medium of stimulated cells were analysed by HPLC, a dose-dependent inhibition by ebselen of LTB4 formation with a concomitant decrease of 5-HETE production was found. Half-maximum inhibition was observed at 20 mumoles/l ebselen. Similar findings were obtained after analysis of chloroform extracts of both cells and medium using a different HPLC system. Under these conditions, enhanced 5-HETE formation was associated with reduced production of LTB4 and other di-HETE isomers, when purified glutathione peroxidase + GSH were present. We conclude that the reported GSH peroxidase-like activity of ebselen, catalysing the reduction of 5-HPETE to 5-HETE, can not account for our findings. Therefore, the lipoxygenase reaction itself apparently represents the site of inhibition of LTB4 formation by ebselen.

Topics: Animals; Anti-Inflammatory Agents; Azoles; Glutathione Peroxidase; Hydroxyeicosatetraenoic Acids; Isoindoles; Leukotriene B4; Lipoxygenase Inhibitors; Neutrophils; Organoselenium Compounds; Rats; Rats, Inbred Strains; Selenium