Pharmacological studies on role of cAMP/cGMP-PDE inhibitors and their interactions with L-arginine & L-NAME in adjuvant induced rheumatoid arthritis in rats

R. Pal. Pharmacology & Therapeutics, King George\'s Medical University, UP, Lucknow, India.

Introduction: Phosphodiesterase (PDE) inhibitors are known to increase cAMP/cGMP and leads to signal transduction process in various cell systems (1). Nitric oxide (NO), a free radical molecule play significant role in health and diseases (2). Therefore, in this study we focused on to evaluate anti-inflammatory & immunomodulatory protective roles of some cAMP/cGMP-PDE inhibitors and their interactions with NO modulators in complete Freund\'s adjuvant (CFA) induced rheumatoid arthritis in rats.

Method: Wistar rats (200-300 gm, n=6/group) of either sex were used in the study. On day \'0\' rats were injected 0.2 ml of (CFA) in sub-planter region of right hind paw along with 0.1 ml of squalene to develop RA while controls received only vehicle. PDE inhibitors drugs theophylline, pentoxifylline, sildinafil & rolipram 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-α 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: It was found that CFA significantly increased arthritis-index, paw volume, ankle diameter and serum TNF-α and NF-kB levels while body weight and serum IL-10 levels was significantly decreased (p<0.05). These CFA-induced changes in arthris parameters and molecular markers were found 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 for all drugs in all parameters (p<0.05). The maximum protective effects was observed as theophylline > pentoxifylline > rolipram > sildinafil with L-NAME (10 mg/kg) combination treatment group (p<0.001). The data obtained was substantiated by histopathological analysis.

Conclusion: These results suggest involvement of PDE inhibitors in pathogenesis of RA. NO plays significant role in protection of RA pathogenesis mediated through PDE inhibition. Further, studies are needed to dissect out roles of PDE inhibitors and their interactions with NO at cellular level in RA.

References:

1. Pal R, Chaudhary MJ et al. (2016). Inflammopharmacology. 24 (5):221-231.

2. Pal R, Chaudhary MJ et al. (2015). Int Immunopharmacol. 29 (2):854-862.