Involvement of pro-inflammatory cytokines and nociceptive pathways on the pharmacological activity of hydantoin derivative 5-(4-isopropylphenyl)-3-phenyl-imidazolidine-2,4-dione

Hydantoins are often reported as potent anticonvulsant drugs; however, recent studies have highlighted their antinociceptive potential.Based on these reports, this study investigated the antinociceptive and anti-inflammatory activities of the hydantoin derivative 5-(4-isopropylphenyl)-3phenyl-imidazolidine-2,4-dione (IM-7) using animal models.Treated mice submitted to the acetic acidinduced writhing test showed increase (p<0.01 or p<0.001) in the latency to the first writhing and reduction in the number of abdominal writhing (p<0.001).Furthermore, all doses reduced the nociceptive response in the first (p<0.05or p<0.001) and second (p<0.001)phases of the formalin test.This effect was inhibited by pretreatment with the antagonists naloxone, sulpiride and caffeine.Additionally, IM-7 (75, 150 and 300 mg/kg, i.p.) reduced (p<0.05or p<0.001) the glutamate-induced nociceptive response.Carrageenan-induced paw edema was strongly reduced following treatment with all doses of IM-7 (p<0.05,p<0.01 or p<0.001), and so were leukocyte migration and levels of interleukin-1β (300 mg/kg: p<0.001) and tumor necrosis factor-α (300 mg/kg: p<0.01) in carrageenan-induced peritonitis.Therefore, IM-7 decreased the nociceptive response via a mechanism involving the opioid, dopaminergic, and adenosinergic receptors.Its anti-inflammatory action also contributed by decreasing the release of pro-inflammatory cytokines.