Patricia D Fernandes1, Renata S Zardo2, Gabriella S M Figueiredo2, Bárbara V Silva3, Angelo C Pinto3. 1. Universidade Federal do Rio de Janeiro, Instituto de Ciências Biomédicas, Laboratório de Farmacologia da Dor e da Inflamação, Av. Carlos Chagas Filho, 373. Prédio do CCS, bloco J, sala 10, 21941-902 Rio de Janeiro, Brazil. Electronic address: patricia.dias@icb.ufrj.br. 2. Universidade Federal do Rio de Janeiro, Instituto de Ciências Biomédicas, Laboratório de Farmacologia da Dor e da Inflamação, Av. Carlos Chagas Filho, 373. Prédio do CCS, bloco J, sala 10, 21941-902 Rio de Janeiro, Brazil. 3. Universidade Federal do Rio de Janeiro, Instituto de Química, Rio de Janeiro, Brazil.
Abstract
AIMS: Convolutamydine A is an oxindole alkaloid that can be isolated from a marine bryozoan. Due to the variety of biological effects, two analogues were synthesized and their anti-inflammatory properties were evaluated. MAIN METHODS: The anti-inflammatory effects of convolutamydine A and its analogues (ISA003 and ISA147) were investigated in a formalin-induced licking behaviour model, where mice received an intraplantar injection of formalin and their licking behaviour was evaluated for 30min. Additionally, inflammatory parameters were evaluated in a subcutaneous air pouch (SAP) model of carrageenan-induced inflammation. Exudates were collected for leukocyte counts; measurement of protein, prostaglandin E2 (PGE2) and cytokines by ELISA; and analysis of nitric oxide (NO) using a nitrate conversion protocol. Cyclooxygenase-2 (COX2) and inducible nitric oxide synthase (iNOS) from RAW 264.7 cells were quantified by immunoblotting. KEY FINDINGS: Convolutamydine A and its two analogues inhibited the formalin-induced licking response at doses as low as 0.01mg/kg. An inhibitory effect was also observed on leukocyte migration and the production of NO, PGE2 and cytokines (IL-6 and TNF-α). The reduction in inflammatory parameters did not appear to be correlated with a direct reduction in the number of cells in the SAP, because a reduction in NO and PGE2 production by cultured macrophages was observed in addition to the inhibition of iNOS and COX2 enzyme expression. SIGNIFICANCE: These results indicate that convolutamydine A and its two analogues have significant anti-inflammatory effects. These substances can be improved to generate lead compounds for the synthesis of new anti-inflammatory drugs.
AIMS: Convolutamydine A is an oxindole alkaloid that can be isolated from a marine bryozoan. Due to the variety of biological effects, two analogues were synthesized and their anti-inflammatory properties were evaluated. MAIN METHODS: The anti-inflammatory effects of convolutamydine A and its analogues (ISA003 and ISA147) were investigated in a formalin-induced licking behaviour model, where mice received an intraplantar injection of formalin and their licking behaviour was evaluated for 30min. Additionally, inflammatory parameters were evaluated in a subcutaneous air pouch (SAP) model of carrageenan-induced inflammation. Exudates were collected for leukocyte counts; measurement of protein, prostaglandin E2 (PGE2) and cytokines by ELISA; and analysis of nitric oxide (NO) using a nitrate conversion protocol. Cyclooxygenase-2 (COX2) and inducible nitric oxide synthase (iNOS) from RAW 264.7 cells were quantified by immunoblotting. KEY FINDINGS:Convolutamydine A and its two analogues inhibited the formalin-induced licking response at doses as low as 0.01mg/kg. An inhibitory effect was also observed on leukocyte migration and the production of NO, PGE2 and cytokines (IL-6 and TNF-α). The reduction in inflammatory parameters did not appear to be correlated with a direct reduction in the number of cells in the SAP, because a reduction in NO and PGE2 production by cultured macrophages was observed in addition to the inhibition of iNOS and COX2 enzyme expression. SIGNIFICANCE: These results indicate that convolutamydine A and its two analogues have significant anti-inflammatory effects. These substances can be improved to generate lead compounds for the synthesis of new anti-inflammatory drugs.