Amelioration of collagen II-induced arthritis in rats by the type IV phosphodiesterase inhibitor Rolipram

Abstract

SUMMARYThe effect of Rolipram, a selective inhibitor of the cyclic AMP specific phosphodiesterase (PDE IV) was evaluated in the rat collagen type II (RCII)-induced arthritis model in the DA rat. Rolipram was given either shortly before expected onset of disease (days 10-14) or shortly after the onset of clinically evident arthritis (days 15-19 after immunization). Administration at days 10-14 delayed the onset of arthritis for approximately 5 days, but the severity of arthritis was thereafter comparable to that seen in a non-treated control group. Rolipram treatment of animals with manifest arthritis inhibited further arthritis development and also tended to diminish its severity at a phase of disease where non-treated control animals showed a rapidly progressing disease development. Serum levels of antibodies to RCII were in all experiments similar between Rolipram-treated and control animals. An in situ hybridization method for determining cytokine mRNA synthesis in regional lymph nodes, after administration of Rolipram (at days 2-7), demonstrated a strong inhibitory effect on tumour necrosis factor-alpha (TNF-a) and interferon-gamma (IFN-g) mRNA expression, whereas no effects were seen on IL-2 mRNA synthesis after in vivo challenge with native RCII emulsified in Freund 0 s incomplete adjuvant. The results thus demonstrate strong preventive as well as therapeutic effects of Rolipram in a model for arthritis that is very similar to human rheumatoid arthritis with respect to cytokine regulation, and suggest that Rolipram has its major effects in the effector stage of the arthritogenic immune response.

Selective Inhibition of Phosphodiesterase-4 Ameliorates Chronic Colitis and Prevents Intestinal Fibrosis

“…In an experimental model of autoimmune demyelinating disease, rolipram also protected against this condition even when administered after sensitization to central nervous system antigens (Genain et al, 1995). In another experimental model in rats, rolipram also decreased clinical activity of experimental arthritis (Nyman et al, 1997). Interestingly, our study shows that rolipram effectively induced histopathological remission of chronic colonic inflammatory lesions, with a marked reduction of colonic collagen content compared with methylprednisolone and control groups on day 21 after induction of colitis.…”

The Specific Type-4 Phosphodiesterase Inhibitor Mesopram Alleviates Experimental Colitis in Mice

“…A recent study reports on the successful inhibition of experimental autoimmune encephalitis in rodents by mesopram (Dinter et al, 2000). Future indications for these agents as anti-inflammatory drugs could comprise rheumatoid arthritis (Nyman et al, 1997;Francischi et al, 2000;Hogan et al, 2001) and, as demonstrated here, chronic inflammatory bowel diseases.…”

Differential regulation of rheumatoid synovial cell interleukin-12 production by tumor necrosis factor ? and CD40 signals

“…In contrast, rolipram inhibited spontaneous IL-12 production only at high concentrations. It was reported that the therapeutic effects of rolipram on collagen-induced arthritis overlap with TNF␣ blockade but are complementary to anti-CD4 treatment (41). Taken together, this evidence suggests that IL-12 production via a CD4ϩ T cell and CD40-CD154 dependent pathway in SC may be less susceptible to cAMP regulation than TNF␣-mediated IL-12 production.…”

“…Rolipram, an authentic PDE IV selective inhibitor, exhibits many antiinflammatory effects, especially strong inhibition of TNF␣ production (38,39). Additionally, rolipram ameliorates collagen-induced arthritis through suppression of TNF␣ expression and inhibition of Th1 activity (40,41). Thus, rolipram is a useful probe in clarifying the contribution of TNF␣ to the regulation of IL-12 production by rheumatoid SC.…”