Anti-nociceptive activity and toxicity evaluation of Cu(II)-fenoprofenate complexes in mice

The proposed curative properties of copper(II)-non-steroidal anti-inflammatory drugs (NSAIDs) have led to the development of numerous copper(II)-NSAID complexes with enhanced anti-inflammatory activity. In this work, the antinociceptive and toxic effects of two new coordination complexes: Cu₂(fen)₄(caf)₂ [fen: fenoprofenate anion; caf: caffeine] and Cu₂(fen)₄(dmf)₂ [dmf: N-N'-dimethylformamide] were evaluated in mice. The antinociceptive effect was evaluated with two models: acetic acid-induced writhing response and formalin test. For the sub-acute exposure, the complexes were added to the diet at different doses for 28days. Behavioral and functional nervous system parameters in a functional observational battery were assessed. Also, hematological, biochemical and histopathological studies were performed. Cu₂(fen)₄(caf)₂ and Cu₂(fen)₄(dmf)₂ significantly decreased the acetic acid-induced writhing response and the licking time on the late phase in the formalin test with respect to the control and fenoprofen salt groups. The sub-acute exposure to Cu₂(fen)₄(caf)₂ complex increased the motor activity, the number of rearings and the arousal with respect to the control and fenoprofen salt groups. These impaired parameters in mice exposed to Cu₂(fen)₄(caf)₂ can be attributable to the presence of caffeine as stimulating agent. On the other hand, all exposed groups decreased the urine pools in the functional observational battery and increased the plasmatic urea. These effects could be due to the decrease in the glomerular filtration caused by NSAIDs. In conclusion, both complexes Cu₂(fen)₄(dmf)₂ and Cu₂(fen)₄(caf)₂ were more potent antinociceptive agents than fenoprofen salt. Sub-acute exposure to different doses of these complexes did not produce significant changes in the parameters that evaluate toxicity.