Anti-inflammatory properties of the protein kinase C inhibitor, 3-[1-[3-(dimethylamino)propyl]-1H-indol-3-yl]-4(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride (GF109203X) in the PMA-mouse ear edema model

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Abstract
Protein kinase C (PKC) mediates a number of intracellular signal transduction pathways implicated in the pathogenesis of inflammation, including phospholipase A2-dependent arachidonic acid release and eicosanoid production. Recent studies demonstrate that the PKC inhibitor GF109203X significantly reduces a number of inflammatory processes resulting from PKC activation by the topical application of phorbol myristate acetate (PMA) to mouse ears. In this model, GF109203X significantly reduced edema at doses similar to the PKC inhibitor staurosporine, and more effectively than indomethacin, zileuton, or sodium meclofenamate. Histological and biochemical analysis of biopsies from control and drug-treated ears revealed a marked reduction in edema, infiltrating neutrophils, 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 edema, and implicates PKC as a potential target in the development of novel anti-inflammatory agents.

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