Effect of Ebselen on polymorphonuclear leukocyte adhesion to and migration through cytokine-activated vascular endothelium.
Ebselen (PZ51, 2-Phenyl-1, 2-Benzoisoselenazol-3-(2H)-one) is a selinyl organic compound with anti-inflammatory properties. Some of its pharmacological effects are thought to result from its peroxidase activity. Here we examined the effects of Ebselen on polymorphonuclear leukocyte (PMNL) adhesion to umbilical vein endothelium and transendothelial migration in a modified Boyden chamber in which both PMNL-dependent and endothelial-dependent (IL-1, TNF alpha) PMNL adhesion and migration can be measured. Ebselen was found to dose dependently inhibit the adhesion of PMNL to IL-1 activated endothelium and to inhibit transendothelial PMNL migration induced by IL-1 alpha, and TNF alpha with an IC50 value of 28 microM. Transendothelial migration induced by the PMNL chemotactic agents C5adesArg and N-formyl-norleu-leu-phe was also inhibited at slightly higher concentrations. The effect of Ebselen was not on endothelial cell activation but on PMNL activation for adhesion and migration. This effect on PMNL was irreversible for the duration of the assay period (75 min). The results suggest that the anti-inflammatory activity of Ebselen may, in part, be due to direct inhibition of PMNL adhesion to vascular endothelium and transendothelial migration in response to a variety of inflammatory mediators.
Issekutz
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AC
Department of Pediatrics and Microbiology, Dalhousie University, Halifax, Nova Scotia, Canada.
Lopes
N
N
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D054833:Isoindoles; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D016566:Organoselenium Compounds / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001393:Azoles; D007375:Interleukin-1; D054833:Isoindoles; D009842:Oligopeptides; D016566:Organoselenium Compounds; D014409:Tumor Necrosis Factor-alpha; C042986:ebselen; C024998:N-formylnorleucyl-leucyl-4-phenylalanine