The type IV phosphodiesterase specific inhibitor mesopram inhibits experimental autoimmune encephalomyelitis in rodents

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease wi th pathological features reminiscent of those seen in multiple sclerosis an d thus serves as an animal model for this disease. Inhibition of type IV ph osphodiesterase (PDE IV) in animals with this disease has been shown to res ult in amelioration of disease symptoms. Here we describe the immunomodulat ory activity of the novel potent and selective PDE IV inhibitor mesopram. I n vitro, mesopram selectively inhibits the activity of type I helper T (Th1 ) cells without affecting cytokine production or proliferation of type 2 he lper T (Th2) cells. Administration of mesopram to rodents inhibits EAE in v arious models. Clinically, EAE is completely suppressed by mesopram in Lewi s rats. This is accompanied by a reduction of inflammatory lesions in spina l cord and brain. RT-PCR analysis revealed a marked reduction in the expres sion of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-a lpha) in the brains of these animals. Furthermore, the ex vivo production o f Th1 cytokines by activated spleen cells derived from mesopram-treated ani mals is significantly reduced compared to vehicle-treated controls. Amelior ation of the clinical symptoms is also observed during chronic EAE in mesop ram-treated SJL mice as well as in relapsing-remitting EAE in SWXJ mice usi ng a therapeutic treatment regimen. These data demonstrate the anti-inflamm atory activity of mesopram and provide a rationale for its clinical develop ment. (C) 2000 Elsevier Science B.V. All rights reserved.