PHARMACOLOGICAL EVALUATION OF NEW MULTI-TARGET COMPOUNDS HDAC6 INHIBITORS AND GPR40 AGONISTS IN ACUTE NOCICEPTION MODELS

HDAC6 inhibitors [1] and GPR40 agonists [2] can relieve inflammatory pain and suppress the expression of inflammatory cytokines in peripheral neuropathy models. The aim of this study was to evaluate the pharmacological activity of new HDAC6 inhibitors with agonist action in GPR40 (LASSBio 2308 and LASSBio 2309) using in vivo models of acute nociception. Swiss Webster mice (25-40g, n=6-8) were treated with LASSBio 2308 or 2309, orally (1, 3 or 10 µmol/kg) and evaluated in formalin-induced paw licking and hot plate test. The experimental protocols were approved by the Ethics Commission for the Use of Animals (CEUA/CCS/UFRJ - 31/19, 34/19 and 43/23). Statistical analysis was performed by ANOVA/Bonferroni post-test(*p<0.05). The 2308 (3 and 10 µmol/kg) and 2309 (1 and 10 µmol/kg) significantly reduced the paw licking time in the 1^st phase (2308: 3 µmol/kg=59.7±19.8*sec (11.7% inhibition) and 10 µmol/kg=38.3±9.9*sec (58.1%); 2309:1 µmol/kg=35.8±18.7*sec(47.0%) and 10 µmol/kg=49.4±20.0*sec(27.0%), versus vehicle=67.6±12.9sec. In the 2^nd phase, 2308 significantly reduced the licking time at doses of 1, 3 and 10 µmol/kg and 2309 at doses of 3 and 10 µmol/kg (2308: 1 µmol/kg=204.6±99.4*sec (10.5%), 3 µmol/kg=116.1±24.5*sec (49.2%) and 10 µmol/kg=102.2±16.9* (55.3%)sec; 2309: 3 µmol/kg=139.9±29.6*sec(38.8%) and 3 µmol/kg=87.3±19.2*sec(61.8%) versus vehicle=228.6±42.9sec). In the hot plate test, animals treated with 2308 showed percentages of increase in ASC of 389.2%, 211.8% and 266.6% and those treated with 2309, increased ASC in 316.1%, 252.5% and 132.9% (1, 3 and 10 μmol/kg), respectively, when compared with vehicle. The data obtained show that 2308 and 2309 have peripheral and central antinociceptive effects, but the mechanisms of action is still under investigation. Acknowledgements: Alan Minho (technical support), Instituto Vital Brazil (animal donation), FAPERJ, CNPq (financial support). [1] Chem. Biol. Interact.(2022) 353: 1. [2] J. Neuroinflammation (2019) 16: 84.