THERAPEUTIC POTENTIAL OF PHOSPHODIESTERASE TYPE-4 INHIBITION IN CHRONIC AUTOIMMUNE DEMYELINATING DISEASE

It was recently demonstrated that selective phosphodiesterase type 4 ( PDE4) inhibition suppresses the clinical manifestations of acute exper imental autoimmune encephalomyelitis (EAE), an animal model of multipl e sclerosis (MS), and inhibits the production of tumor necrosis factor -alpha (TNF-alpha), a pathogenetically central cytokine. Since the mos t common presentation of MS in humans is a relapsing-remitting course, we investigated the therapeutic potential of PDE4 inhibition in the r elapsing-remitting EAE model of the SJL mouse. Administration of rolip ram. the prototypic PDE4 inhibitor, reduced the clinical signs of EAE during both the initial episode of disease and subsequent relapses. In parallel, there was marked reduction of demyelination and also less i nflammation throughout the central nervous system (CNS) of rolipram-tr eated animals. Gene expression of proinflammatory cytokines in the CNS was reduced in most of the rolipram-treated animals. Additional exper iments demonstrated that PDE I inhibition acted principally by inhibit ing the secretion of Thl cytokines, however, the encephalitogenic pote ntial of myelin basic protein-specific T cells was not impaired. Our f indings suggest that PDE4 inhibitors are a promising cytokine-directed therapy in chronic demyelinating disease. (C) 1997 Elsevier Science B .V.