The effect of ebselen on polymorphonuclear leukocyte migration to joints in rats with adjuvant arthritis

We have previously reported that ebselen (PZ 51,2-Phenyl-1,2- Benzoisoselenazol-3-(2H)-one), a selinyl organic compound with anti-inflammatory properties, inhibited human polymorphonuclear leukocyte (PMNL) adhesion to and migration through cytokine-activated human umbilical vein endothelium in vitro. Here we investigated the in vivo effect of ebselen on PMNL migration into arthritic joints and dermal inflammation in rats with adjuvant arthritis. The rats were immunized with adjuvant (Mycobacteriaum butyricum in mineral oil) and 13 days later, when arthritis was fully developed, treatment (p.o.) with ebselen, indomethacin or vehicle was initiated. The migration of 51Cr-labelled blood PMNL purified from arthritic donors and extravasation of 125I-labelled HSA in arthritic joints and dermal inflammatory reactions was quantitatively measured. Treatment of rats with 100 mg/kg/day ebselen for 3 days, inhibited by 72-79% the PMNL migration into arthritic joints and tail (spondylitis) and by 50-60% into dermal inflammatory reactions induced with zymosan-activated rat serum (ZAS; C5adesArg), endotoxin (LPS) or IL-1 alpha. The inhibitory effect of ebselen was dose-dependent, because treatment of rats with 100 mg/kg/day ebselen caused significantly more inhibition of PMNL migration than did 30 mg/kg/day, although this dose was still effective. Ebselen inhibited PMNL migration into arthritic joints and dermal inflammation within 3 h of initial oral administration (100 mg/kg). However, ebselen did not suppress plasma albumin extravasation into arthritic joints and dermal inflammatory reactions. Compared to ebselen, treatment with indomethacin (2 mg/kg/day) was significantly less effective in inhibiting PMNL accumulation in joints, but in contrast to ebselen, indomethacin did inhibit plasma albumin extravasation into carpal and talar joints. The results suggest that ebselen effectively and rapidly inhibits PMNL migration in vivo, as also observed in vitro, and that it has anti-inflammatory actions distinct from classic nonsteroidal anti-inflammatory drugs such as indomethacin.