Abstract

Tenidap (TD) was initially defined as a dual inhibitor of cyclooxygenase and lipoxygenase. This study was designed to assess its inhibitory activity against proinflammatory phospholipase A₂. This study shows that TD inhibits the synthesis of pro-inflammatory secretory non-pancreatic phospholipase A₂ (sPLA₂). Concentrations as low as 0.25 μg/ml (0.725 μM) reduced the release of sPLA₂ by 40% from foetal rat calvarial osteoblasts stimulated with IL-1β and TNFα, whereas a concentration of 2.5 μg/ml (7.25 μM) reduced the release by over 80%. TD also markedly reduced the release of sPLA₂ from unstimulated cells. There was no direct inhibition of sPLA₂ enzymatic activity by TD in vitro. Northern blot analysis showed that TD did not affect the sPLA₂ mRNA levels; however, immunoblotting showed a dose-dependent reduction in sPLA₂ enzyme. These results, together with a marked reduction in sPLA₂ enzymatic activity, suggest that TD inhibits sPLA₂ synthesis at the post-transcriptional level. Therefore TD seems to inhibit the arachidonic acid cascade proximally to cyclooxygenase and lipoxygenase and its anti-inflammatory activity may be related at least in part to the inhibition of sPLA₂ synthesis.