Effects of lipoxygenase inhibitors on the arachidonic acid cascade in the rabbit cornea after injury.

A cryogenic lesion in the rabbit cornea that promotes the formation of arachidonic acid metabolites was used as a model to test the action of two new lipoxygenase inhibitors, TEI-8005 and TEI-8006. The action of these two inhibitors was compared with that of CBS-113A, a new dual inhibitor of cyclooxygenase and lipoxygenase reactions, and with that of nordihydroguaiaretic acid (NDGA), a monooxygenase inhibitor and antioxidant. Injured corneas were incubated for 1 h at 36 degrees with 1-14C-arachidonic acid. Inhibitors at concentrations of 1, 10 and 100 uM were added 10 minutes prior to the addition of arachidonic acid. TEI-8006 inhibited 5-hydroxyeicosatetraenoic acid (HETE) at 10 uM, and both 5- and 12-HETE at 100 uM. At 100 uM, CBS-113A also had the same effect, while TEI-8005 at 100 uM induced a more selective inhibition of 5-lipoxygenase. NDGA was the most potent inhibitor of lipoxygenase reactions, but was not selective. Prostaglandins were also affected differentially by the inhibitors. TEI-8006 and NDGA partially inhibited cyclooxygenase products at all concentrations, and CBS-113A produced inhibition at 10 and 100 uM. TEI-8005 did not affect the total cyclooxygenase products, but selectively inhibited thromboxane B2 and increased prostacyclin production at 100 uM. The effects of these inhibitors may be of value in understanding the mechanisms involved in corneal inflammation.