5-hydroxy-6-8-11-14-eicosatetraenoic-acid and ebselen

Ebselen, a seleno-organic compound which inhibits arachidonic acid lipoxygenase activity and exerts glutathione peroxidase-like activity, ameliorated delayed cerebral vasospasm in a canine two-hemorrhage model. Twenty-five dogs were exposed to subarachnoid hemorrhage and divided into two groups. In the Ebselen-treated group (6 dogs), 50 mg kg-1 of Ebselen was administered twice a day, for 7 days. The other 19 dogs without administration of Ebselen were used as a control group. In the Ebselen-treated group, the basilar artery on Day 7 after subarachnoid hemorrhage was constricted to 68.1 +/- 6.4% (mean +/- SD, n = 6) of the angiographic diameter on Day 0, before subarachnoid hemorrhage. This percentage was significantly larger than the 41.3 +/- 4.6% (n = 19) in the control group. The basilar artery segment obtained on Day 7 in the Ebselen-treated group produced 3.32 +/- 1.82 nmol of 5-hydroxyeicosatetraenoic acid/mg protein/5 minutes (n = 5), significantly less than the 6.73 +/- 0.95 (n = 3) produced by the artery in the control group. Thus, administration of Ebselen suppressed arachidonate 5-lipoxygenase activation and had a beneficial effect on angiographically detected delayed vasospasm.

Topics: Animals; Arachidonate 5-Lipoxygenase; Azoles; Basilar Artery; Dogs; Hydroxyeicosatetraenoic Acids; Ischemic Attack, Transient; Isoindoles; Organoselenium Compounds; Subarachnoid Hemorrhage; Time Factors; Vasoconstriction

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