EVALUATION OF THE ANTINOCICEPTIVE ACTIVITY OF A NITROSYL RUTHENIUM COMPOUND

C S Freitas1, A C Garcia2, D W Franco2, F Q Cunha1. 1Faculdade de Medicina de Ribeirão Preto/ Universidade de São Paulo, Departamento de Farmacologia, Brazil, 2Instituto de Química de São Carlos/ Universidade de São Paulo, Departamento de Química e Física Molecular, Brazil

The current therapies for the pain states are always associated with detrimental side effects. Therefore the continuous searches for new pharmacologically active analgesic agents are important. The water solubility, low toxicity and stability toward oxygen oxidation of nitrosyl ruthenium tetra-ammines make them a class of compounds with favorable characteristics for biological applications (Tfouni et al, 2003). The purpose of this study was to evaluate the antinociceptive activity of this new ruthenium compound, RuNOina, in animal models of non-inflammatory and inflammatory pain. All procedures were approved by Animal Ethics Committee of FMRP/USP (number 091/2005). RuNOina (1, 10 and 100 µmol/kg, s.c.) was always administered 1h before the noxious stimuli (Carageenan (Cg) 100 µg/paw; Prostaglandin E2 (PGE2) 100 ng/paw; Acetic acid 0.6%, 450 µl/ intraperitoneal cavity; Capsaicin 1.6 mg/paw; Cinnamaldehyde 10 nmol/paw) in Swiss male mice (20 g). After the paw injections of Carageenan and PGE2, the mechanical hypernociception was determined with a dynamic plantar aesthesiometer (Ugo Basile, Italy). After the challenge with acetic acid, mice were placed in separate boxes and the number of abdominal constrictions was cumulatively counted over a period of 20 min. Animals were observed individually for 5 min following capsaicin or cinnamaldehyde injection. The amount of time spent licking the injected paw was recorded with a chronometer and was considered as indicative of nociception. Experimental arthritis was induced by the injection of methylated bovine serum albumin (mBSA 30µg/10µl) into the knee joint of pre-immunized Balb C male mice (subcutaneous injection of mBSA 500μg/100 μl of saline mixed with 100μl of complete Freud’s adjuvant, CFA on day “0” and “7”). The articular hypernociception was measured using an electronic version of the von Frey test (IITC Life Science). The leukocytes recruitment was assessed directly in knee joint exudates. The pretreatment with RuNOina reduced the hypernociception induced by Cg and PGE2 in 99±12 and 74±9%, with ID50 of 4.4 and 14.5 µmol/kg, respectively (p<0.05). The nociception induced by acetic acid, capsaicin and cinnamaldehyde was inhibited in 63±5, 75±6 and 59±8% with ID50 of 45.6, 24.9 and 63.4 µmol/kg, respectively (p<0.05). The pretreatment with RuNOina (100 μmol/kg, s.c.) was able to revert mBSA-induced mechanical hypernociception (41±2% of reversion, control: 4.0±0.4g, p<0.05), but the number of total leucocytes was not altered. The ID 50 was determined by linear regression from individual experiments using GraphPad software (San Diego, CA, USA). The statistical significance of differences between groups was analyzed by one way ANOVA followed by Bonferroni’s multiple comparison tests. p< 0.05 was considered as indicative of significance. In summary, the novel nitrosyl ruthenium compound shows potent anti-hypernociceptive activity in relevant biological assays. Further investigation of the pharmacological profiles of this novel compound is in progress.

Sources of research support: CNPq, FAPESP.

References:

Tfouni et al. Coord Chem Rev 2003; 236: 57-69.