Abstract
Backgrong: Phosphodiesterase (PDE) inhibitors are known to increase cAMP/cGMP in cellular compartment and leads to signal transduction process in various cell systems. Here we focused on the anti-inflammatory and immunomodulatory protective role of cAMP/cGMP-PDE inhibitors theophylline, pentoxifylline, sildinafil, rolipram and their interactions with nitric oxide (NO) modulators in complete Freund's adjuvant induced RA in rats. Method: Wistar rats (200-300 g, n=6 per group) of either sex were used in study. On day '0' rats were injected with 0.2 ml of complete Freund's adjuvant (CFA) in sub-planter region of right hind paw along with 0.1 ml of squalene to develop RA, controls received only vehicle. PDE inhibitors drug treatment alone and in combination with NO modulators was given from day '14' to '28'. Arthritic parameters a) arthritis index, b) ankle diameter c) paw volume and their body weight were noted to evaluate progression of RA on day 0, 7, 14, 21 and 28. On day '28' rats were sacrificed and their blood and paws were collected for TNF-alpha and IL-10 cytokine estimation, pathological examination and NF-kB expression. Data obtained was analysed using two-way ANOVA followed by Newman-Keul's posthoc test and p<0.05 was considered for significance. Result: CFA significantly increased arthritis-index, paw volume, ankle diameter and serum TNF-alpha and NF-kB levels while body weight and serum IL-10 levels was significantly decreased (P<0.05). These CFA-induced changes were significantly reversed by theophylline (10 & 20 mg/kg), P<0.0001; pentoxifylline (5 & 10 mg/kg), P<0.002; rolipram (1 & 2 mg/kg), P<0.05; sildenafil (50 & 50 mg/kg) alone and in combination with L-arginine (100 mg/kg) and or L-NAME (10 mg/kg) in dose dependent manner (p<0.005) in all parameters (1). The maximum protective effects was observed in theophylline > pentoxifylline > rolipram > sildinafil with L-NAME 10 mg/kg combination treatment group (p<0.001). The data obtained was substantiated histopathological analysis (2). Conclusion: Results of this study are suggestive of the involvement & interaction of NO with different PDE inhibitors. cAMP/cGMP mediated PDE inhibition may have protective role in pathogenesis of rheumatoid arthritis. Further studies are required to dissect out the role of PDE inhibitors NO modulators in RA.
