ANTIINFLAMMATORY PROPERTIES OF THE PROTEIN-KINASE-C INHIBITOR, INDOL-3-YL]-4-(1H-INDOL-3-YL)-1H-PYRROLE-2,5-DIONE MONOHYDROCHLORIDE (GF109203X) IN THE PMA-MOUSE EAR EDEMA MODEL

Protein kinase C (PKC) mediates a number of intracellular signal trans duction pathways implicated in the pathogenesis of inflammation, inclu ding phospholipase A2-dependent arachidonic acid release and eicosanoi d production. Recent studies demonstrate that the PKC inhibitor GF1092 03X significantly reduces a number of inflammatory processes resulting from PKC activation by the topical application of phorbol myristate a cetate (PMA) to mouse ears. In this model, GF 109203X significantly re duced edema at doses similar to the PKC inhibitor staurosporine, and m ore effectively than indomethacin, zileuton, or sodium meclofenamate. Histological and biochemical analysis of biopsies from control and dru g-treated ears revealed a marked reduction in edema, infiltrating neut rophils, and levels of the neutrophil-specific marker, myeloperoxidase , in GF109203X-treated mice. Prostaglandin E2 levels were also reduced in ears treated with GF109203X. These data suggest that GF109203X is an effective antiinflammatory agent as evaluated in the PMA model of e dema, and implicates PKC as a potential target in the development of n ovel anti-inflammatory agents.