Program

OR3-5

IMPROVEMENT OF INFLAMMATORY-INDUCED PAIN AND JOINT DAMAGE BY NOVEL N-ACYLHYDRAZONE DERIVATIVE (LASSBIO-1027) IN MURINE MODELS

[Speaker] Roberto T. Sudo:1
[Co-author] Guilherme C. Montes:1, Bismarck Rezende:1, Rodolfo C. Maia:1, Tadeu L. Montagnoli:1, Carlos A. Fraga:1, Eliezer J. Barreiro:1, Gisele Zapata-Sudo:1
1:Universidade Federal do Rio de Janeiro, Brazil

Background: Activation of adenosine receptors might mediate antinociceptive and anti-inflammatory effects. Molecular docking studies and binding assays demonstrated that 3,4-methylenedioxybenzoyl-2-thienylhydrazone (LASSBio-1027) is a ligand to adenosine receptors A2A and A3. This work evaluated the antinociceptive effect of LASSBio-1027 in murine acute and chronic pain/inflammatory models. Methods: Protocols were approved by the Animal Care and Use Committee at Universidade Federal Rio de Janeiro (Protocol 113/14). Formalin injection (20 uL i.pl.) was used to induce acute/inflammation pain in male Swiss mice (25-30 g). The antinociceptive effect was tested after oral administration (gavage) of vehicle, LASSBio-1027 (25, 50 and 100 mg/kg), morphine (30 mg/kg) or acetyl salicylic acid (300 mg/kg). Chronic inflammatory pain was induced by subcutaneous injection of Complete Freund Adjuvant (CFA) around the tibiotarsal joint in male Swiss mice under 2% sevoflurane anesthesia. Thermal and mechanical hyperalgesia and paw edema were measured in the animals after 13 days of treatment with vehicle, LASSBio-1027 (25, 50 and 100 mg/kg) or acetylsalicylic acid (300 mg/kg). At the end of treatment, protein expression of TNF-alpha, iNOS, phosphorylated p-38 and c-fos in the paw and spinal cord were evaluated. Toluidine blue staining examined the histology features of the tibiotarsal joint. Results: Treatment with LASSBio-1027 reduced in a dose-dependent manner the early and later phases of formalin-induced reactivity. At 100 mg/kg, the animal reactivity reduced from 39.7 ± 5.1 (vehicle) to 18.4 ± 1.6 s (p<0.01) and from 249.2 ± 20.8 s (vehicle) to 117.2 ± 17.9 s (p<0.01) in the early and late phase, respectively. Pre-treatment with MRE 3008F20 or ZM 241385, adenosine A3 and A2A antagonists reduced both responses. LASSBio-1027 also reduced CFA-induced thermal and mechanical hyperalgesia, paw edema and normalized overexpressed TNF-alpha, iNOS, phosphorylated p-38 (paw) and c-fos (spinal cord). The joint damage and inflammation were ameliorated with LASSBio-1027 treatment. Conclusions: A novel agonist of A3 and A2A receptors, named LASSBio-1027, could be a candidate for drug development to treat inflammatory-induced acute or chronic disease.
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