Banca de DEFESA: JOYCE MATTOS DE OLIVEIRA

Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.
STUDENT : JOYCE MATTOS DE OLIVEIRA
DATE: 11/03/2022
TIME: 13:30
LOCAL: Jitsi meet
TITLE:

Pharmacological evaluation of the antinociceptive and anti-inflammatory activities of the Diclofenac hybrid compound

KEY WORDS:

nociception, opioid system, inflammation, leukocyte migration.

PAGES: 93
BIG AREA: Ciências Biológicas
AREA: Farmacologia
SUBÁREA: Farmacologia Geral
SUMMARY:

Analgesics are among one of the most commonly used drug classes for the treatment or relief of painful and inflammatory conditions. However, due to the large number of side effects and often the ineffectiveness of these drugs, it is necessary to search for new drugs. When a new compound shows promising responses, the conjugation of specific bioactive structures in a single molecule can be performed through molecular hybridization. An effective way to rationally plan new drugs that have synergistic action and/or decrease adverse effects. The aim of this study was to evaluate the acute and chronic antinociceptive and anti-inflammatory activity of the new hybrid compound: (±-cis) (6-ethyl-tetrahydro-2H-pyran-2-yl)methyl 2-(2-(2, 6-dichlorophenylamino) phenyl acetate (LS26), synthesized from the hybridization of the compound [(±)-Cys)(6-ethyl-Tetrahydro-2H-Pyran-2-yl]Methanol (LS20) and the non-inflammatory anti-inflammatory steroid diclofenac sodium. The compound LS26 was administered orally in all animals and in all experimental models. According to the results, the compound has acute antinociceptive activity observed in the abdominal writhing models, formalin (both phases) and immersion of the tail in hot water. The mechanism of action of the compound involves the opioid system, considering that the application of selective opioid antagonists were able to reduce the antinociceptive effect of the hybrid compound. The NO/cGMP/K+ATP pathway is also one of the mechanisms of action of LS26 due to the reduction of the antinociceptive effect with the administration prior L-NAME, ODQ and glibenclamide. Acute and chronic antinociceptive activity on allodynia induced by chronic constriction of the sciatic nerve was also observed in the neuropathic pain model due to inhibition of IL-1β and IL-6 production in the sciatic nerve. The compound shows no relationship between the antinociceptive effect and a motor deficit, according to the results of the rota-rod test. As for anti-inflammatory activity, the LS26 compound showed anti-edematogenic activity, as it was able to reduce leukocyte migration and the production of pro-inflammatory cytokines such as IL-1β, TNF-α and IL-6 and increase cytokine synthesis anti-inflammatory IL-10 in the subcutaneous air bag model. The compound showed selectivity for COX-2 inhibition observed in in vitro evaluation. In the toxicological test, the compound did not present acute and subchronic alterations in the microscopic and macroscopic evaluations. These results indicate antinociceptive activity through opioid receptors and the NO/cGMP/K+ATP pathway, in addition to anti-inflammatory activity with inhibition of leukocyte migration, reduction of IL-1β, TNF-α and IL-6 levels, increase of IL-10 and selective inhibitory activity on COX-2.

BANKING MEMBERS:
Presidente - 1674073 - BRUNO GUIMARAES MARINHO
Interno - 1519567 - FABIO FAGUNDES DA ROCHA
Interno - 386960 - WELLINGTON DA SILVA CORTES
Externo à Instituição - THIAGO ROBERTO LIMA ROMERO - UFMG
Externo à Instituição - BEATRIZ FERREIRA DE CARVALHO PATRÍCIO - UNIRIO