Background & Aims

Rheumatoid arthritis (RA), osteoarthritis (OA) and gout are chronic painful inflammatory conditions that limit the quality of life of patients. Experimental models of articular inflammation allow investigation of the pathogenesis of the diseases, establishment of potential molecular targets for new drugs that can reduce the discomfort and prevent the progression of tissue destruction which accompanies these inflammatory processes and to identify new pharmacotherapeutic alternatives. Nicotinamide, a vitamin of the B complex, has exhibited activities is some acute pain/inflammation models. Previously, our group (DUTRA et al, 2015) has shown antiallodynic effect of nicotinamide in CFA model of rheumatoid arthritis in rats, mediated by TNF-alfa. Also, a B-vitamine derivate with a NO-donor radical (nicorandil), has exhibited anti-inflammatory, antinociceptive and antiallodynic effects in the selected experimental models of RA, OA and MSU in mice.

Methods

Tree different models of joint inflammation were selected: induced by zymosan (GUERRERO et al., 2006), induced by CFA (LOPES et al, 2016) and induced by MSU (AMARAL et al., 2016; VIEIRA et al., 2015), corresponding to experimental models of OA, RA and gout, respectively. Swiss male mice (25-30g) provided by UFMG were used and all experiments were approved by the Committee on Ethics in Animal Use. Briefly, all models consist of the intra-articular injection of the arthritogenic agent, followed by evaluations of joint edema (by Mitutoyo digital paquymeter) and mechanical allodynia (by Insight digital algesimeter) at predetermined moments for each standardization performed previously. Quantifications of cytokines (TNF-alpha, CXCL-1 or IL-1beta) and MPO activity were performed following the recommendations of the manufacturers of the respective commercial ELISA kits, when statistical difference of total leucocytes in intra-articular lavage was detected (using N

Results

Nicotinamide, in different doses (ranging from 125 – 1000 mg/day, p.o.) exhibit anti-allodynic effect in CFA, zymosan and MSU experimental models of joint inflammation. Further investigation of possible mechanisms involved in this activity confirmed that nicotinamide reduce neutrophil recruitment into the articular cavity and periarticular tissues in models of joint inflammation induced by zymosan and MSU. For this last model, nicotinamide also reduced IL-1? and CXCL-1 production. For the CFA model, nicotinamide did not affect the TNF-alpha levels in mice, which differs from the results from female Holtzman rats previously reported, neither reduces CXCL-1 production.

Conclusions

Nicotinamide shows antiallodynic activity and reduces inflammatory cell recruitment and cytokines/chemokines production in different models of joint inflammation in mice. Even though the effect in tissue destruction and its progression were not investigated for this study, the results indicate that nicotinamide, a cheap, relatively safe and well-known molecule, is a drug that should be further studied aiming their repositioning in the pain management of patients with RA, OA and gout.

References

DUTRA, M. M. G. B.; NASCIMENTO JUNIOR, E. B.; GODIN, A. M.; BRITO, A. M. S.; MELO, I. S.; AUGUSTO, P. S.; RODRIGUES, F. F.; ARAUJO, D. P.; DE FÁTIMA, A.; COELHO, M. M.; MACHADO, R. R. Opioid pathways activation of nicorandil mediates the activity of nicorandil in experimental models of nociceptive and inflammatory pain. Eur. J. Pharmacol., Amsterdam, v. 768, p. 160-164, dec. 2015.
GUERRERO, A. T.; VERRI, W. A. Jr.; CUNHA T. M.; SILVA T. A.; ROCHA, F. A.; FERREIRA, S. H.; CUNHA F. Q.; PARADA, C. A. Hypernociception elicited by tíbio-tarsal joint flexion in mice: a novel experimental arthritis model for pharmacological screening. Pharmacol. Biochem. Behav., Phoenix, v. 84, n. 2, p.244-251, jun. 2006.
AMARAL, F. A.; COSTA V. V.; TAVARES, L.D.; SACHS, D.; COELHO, F. M.; FAGUNDES, C. T.; SORIANI, F. M.; SILVEIRA, T. N.; CUNHA, L. D.; ZAMBONI, D. S.; QUESNIAUX, V.; PERES, R. S.; CUNHA, T. M.; CUNHA, F. Q.; RYFFEL, B.; SOUZA, D. G.; TEIXEIRA, M. M. NLRP3 inflammasome-mediated neutrphil recruitment and hypernociception depend on leukotriene B(4) in murine model of gout. Arthritis Rheumatol., Atlanta, v. 64, n. 2, p. 474-484, feb. 2016.
LOPES, F.; GRAEPEL, R.; REYES, J. L.; WANG, A.; MCDOUGALL, J. J.; SHARKEY, K. A.; MCKAY, D. M. Involvement of mast cells in a ?7 nicotinic receptor agonist-exacerbation of complete Freund’s adjuvant-induced mono-arthritis in mice. Arthritis Rheumatol., Malden, v. 68, n. 2, p. 542-552, feb. 2016.
VIEIRA, A. T.; MACIA, L.; GALVÃO, I.; MARTINS, F. S.; CANESSO, M. C.; AMARAL, F. A.; GARCIA, C. C.; MASLOWSKI, K. M.; DE ELON, E.; SHIM, D.; NICOLI, J. R.; HARPER, J. L.; TEIXEIRA, M. M.; MACKAY, C. R. A role for gout micorbiota and the metabolite-sensing receptor GPR43 in a murine model of gout. Arthritis Rheumatol., Malden, v. 67, n. 6, p. 1646-1656, jun. 2015.
ZIMMERMANN, M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain, Amsterdam, v.16, n. 2, p.109-110, jun 1983.

Presenting Author

Marcela Bini Dutra

Poster Authors

Marcela Bini Dutra

PhD

Federal University of Minas Gerais - UFMG

Lead Author

E-mail

Topics

  • Models: Chronic Pain - Inflammatory