Pro-Apoptotic Effects of Tepoxalin, a Cyclooxygenase/Lipoxygenase Dual Inhibitor, on Canine Synovial Fibroblasts

Abstract

Canine osteoarthritis occurs frequently and causes secondary synovitis. Administration of non-steroidal anti-inflammatory drugs (NSAIDs) is one of major therapeutic options for pain management of joint diseases. Tepoxalin has an unique property as NSAIDs, which suppress both cyclooxygenase and lipoxygenase. The purpose of this study was to evaluate anti-proliferative effects of tepoxalin on cultured canine synovial cells. Cytotoxic effects of tepoxalin, carprofen, meloxicam and AA-861 on cultured canine synoviocytes were evaluated by MTT colorimetric assay. Apoptosis was detected by morphological observations with giemsa or annexin-V/hoechst 33342 staining, and by the inhibition of caspase-3 activity with N-Ac-Asp-Glu-Val-Asp-CHO (Ac-DEVD-CHO). Cytotoxic effects of tepoxalin were evident in comparison with those of carprofen or meloxicam. Same tendency of the cytotoxicity was observed when 5-lipoxigenase was inhibited by AA-861. Morphological findings and contradictory effects of Ac-DEVD-CHO to the cytotoxicity proved pro-apoptotic effects of tepoxalin. In conclusion, tepoxalin might control osteoarthritic synovitis by inducing apoptosis on proliferated synoviocytes, while most NSAIDs with selective inhibition of cyclooxygenase-2 most likely would not suppress synovial proliferation.