The effect of ebselen on polymorphonuclear leukocyte and lymphocyte migration to inflammatory reactions in rats

Ebselen, a selinyl organic compound with anti-inflammatory properties was found by us previously to inhibit in vitro human polymorphonuclear leukocyte (PMNL) adhesion to and migration through umbilical vein endothelium monolayers. Here we investigated in rats the effect of ebselen on PMNL and spleen T lymphocyte (SPLT) migration to inflamed joints induced by intra-articular (i.a) injection of recombinant murine tumor necrosis factor alpha (mTNF alpha) and to dermal inflammatory reactions. Inflammation was induced in the carpal and talar joints of rats by intra-articular (i.a.) injection (100 ng) of mTNF alpha once daily for 2 days. Corresponding joints in the opposite limb received diluent. Simultaneously, the rats were treated p.o. with either ebselen (100 mg/kg/day) or indomethacin (2 mg/kg/day) or vehicle for 2 days. Dermal inflammation was induced by intradermal injection (0.05 ml) of inflammatory stimuli. Accumulation of 51Cr-labelled rat blood PMNL, 111In-labeled SPLT, and extravasation of 125I-labelled human serum albumin (HSA) in the joints and in skin sites were measured. Treatment of rats with ebselen inhibited by 33-65% PMNL migration to the mTNF alpha inflamed joints, and to dermal inflammation induced by zymosan activated serum (ZAS; containing C5adesArg), endotoxin (LPS), mIL-1 beta and mTNF alpha. Migration of SPLT to dermal inflammation induced by interferon gamma (IFN gamma), poly-inosine-cytosine (poly I:C) and LPS was also significantly inhibited (22-33%), but SPLT migration into the inflamed joints was not effected by ebselen. Indomethacin treatment of rats also inhibited PMNL migration into the inflamed joints, but unlike ebselen, indomethacin inhibited only ZAS induced dermal PMNL accumulation. In contrast to ebselen, indomethacin inhibited SPLT migration into the inflamed joints as well as to the dermal inflammation induced by poly I:C and a delayed-type hypersensitivity reaction (DTH). In addition, treatment of rats with indomethacin significantly inhibited plasma protein (125I-HSA) extravasation in the inflamed joints and the dermal inflammatory reaction induced by ZAS, but ebselen had no such effect. In conclusion, ebselen appears to have a distinct antiinflammatory mechanism of action from indomethacin and the PMNL findings are consistent with a direct inhibitory action on PMNL activation and PMNL transendothelial migration as observed previously in vitro.