Ana Larissa de Q França1, Hellíada V Chaves1,2, Jordânia M de O Freire3, Luzia Hermínia T de Sousa4, Antônia T A Pimenta5, Mary Anne S Lima5, Bruna R de Oliveira5, Marcos Carlos de Mattos5, Vicente de Paulo T Pinto1,3, Antônia Moêmia L R Portela3, Karuza Maria A Pereira6, José Jackson do N Costa7, Paula Goes8, Roberta Jeane B Jorge6,9, João Alison de M Silveira9, Helyson Lucas B Braz6, Maria Elisabete A de Moraes9, Mirna M Bezerra10,11,12. 1. Postgraduate Program in Health Sciences, Federal University of Ceará, Sobral, Ceará, Brazil. 2. School of Dentistry, Federal University of Ceará, Sobral, Ceará, Brazil. 3. School of Medicine, Federal University of Ceará, Sobral, Ceará, Brazil. 4. Postgraduate Program in Odontology, School of Odontology, Federal University of Ceará, Fortaleza, Ceará, Brazil. 5. Postgraduate Program in Chemistry, Federal University of Ceará, Fortaleza, Ceará, Brazil. 6. Department of Morphology, School of Medicine, Postgraduate Program in Morphological Science, Federal University of Ceará, Fortaleza, Ceará, Brazil. 7. School of Medicine, University Center INTA - UNINTA, Sobral, Ceará, Brazil. 8. Department of Pathology and Legal Medicine, Medical School, Federal University of Ceará, Fortaleza, Ceará, Brazil. 9. Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, Ceará, Brazil. 10. Postgraduate Program in Health Sciences, Federal University of Ceará, Sobral, Ceará, Brazil. mirna@ufc.br. 11. School of Medicine, Federal University of Ceará, Sobral, Ceará, Brazil. mirna@ufc.br. 12. Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, Ceará, Brazil. mirna@ufc.br.
Abstract
OBJETIVE: This study aimed to evaluate the anti-resorptive activity of a semi-synthetic coumarin derivative from Platymiscium floribundum, named 6,7-dimethoxy-3-nitrocoumarin. MATERIAL AND METHODS: Molecular docking studies were performed to test the binding performance of the derivative against targets associated with alveolar bone loss (TNF-α, IL-1β, and catalase) and a target considered an antioxidant defense (HO-1) during periodontitis. Periodontitis was induced by placing a nylon ligature around the second molars. The rats received for 11 days 6,7-dimethoxy-3-nitrocoumarin (0.01, 0.1, or 1 mg/kg) or vehicle. We investigated by RT-qPCR analysis (TNF-α, IL-1β, and HO-1 mRNA expression levels) and by colorimetric assay (catalase activity) the mechanism of action mediated by 6,7-dimethoxy-3-nitrocoumarin. The in vivo toxicity of 6,7-dimethoxy-3-nitrocoumarin was evaluated. RESULTS: 6,7-Dimethoxy-3-nitrocoumarin (0.1 or 1 mg/kg) reduced alveolar bone loss (1.05 ± 0.24), when compared to vehicle-treated group (3.05 ± 0.30). The interactions of 6,7-dimethoxy-3-nitrocoumarin and the four targets (TNF-α, IL-1β, catalase, and HO-1) showed firm bonds above 6.0 kcal/mol. 6,7-dimethoxy-3-nitrocoumarin (1 mg/kg) lowered mRNA expression levels of TNF-α (2.33 ± 0.56) and IL-1β (19.87 ± 2.9), while it increased both the mRNA expression levels of HO-1 (43.40 ± 1.05) and the catalase activity (46.42 ± 4.59), when compared to vehicle-treated group (46.29 ± 8.43; 37.83 ± 4.38; 1.58 ± 0.11; 8.93 ± 1.86, respectively). The animals did not show any signs of toxicity. CONCLUSION: 6,7-Dimethoxy-3-nitrocoumarin decreased inflammatory bone loss in the ligature-induced periodontitis in rats, and the activation of the HO-1 pathway may contribute, at least partially, to its protective effects by reducing TNF-α and IL-1β mRNA levels and increasing catalase activity. CLINICAL RELEVANCE: 6,7-Dimethoxy-3-nitrocumarin could be used as an adjunct to subgingival instrumentation during active and supportive periodontal treatment.
OBJETIVE: This study aimed to evaluate the anti-resorptive activity of a semi-synthetic coumarin derivative from Platymiscium floribundum, named 6,7-dimethoxy-3-nitrocoumarin. MATERIAL AND METHODS: Molecular docking studies were performed to test the binding performance of the derivative against targets associated with alveolar bone loss (TNF-α, IL-1β, and catalase) and a target considered an antioxidant defense (HO-1) during periodontitis. Periodontitis was induced by placing a nylon ligature around the second molars. The rats received for 11 days 6,7-dimethoxy-3-nitrocoumarin (0.01, 0.1, or 1 mg/kg) or vehicle. We investigated by RT-qPCR analysis (TNF-α, IL-1β, and HO-1 mRNA expression levels) and by colorimetric assay (catalase activity) the mechanism of action mediated by 6,7-dimethoxy-3-nitrocoumarin. The in vivo toxicity of 6,7-dimethoxy-3-nitrocoumarin was evaluated. RESULTS: 6,7-Dimethoxy-3-nitrocoumarin (0.1 or 1 mg/kg) reduced alveolar bone loss (1.05 ± 0.24), when compared to vehicle-treated group (3.05 ± 0.30). The interactions of 6,7-dimethoxy-3-nitrocoumarin and the four targets (TNF-α, IL-1β, catalase, and HO-1) showed firm bonds above 6.0 kcal/mol. 6,7-dimethoxy-3-nitrocoumarin (1 mg/kg) lowered mRNA expression levels of TNF-α (2.33 ± 0.56) and IL-1β (19.87 ± 2.9), while it increased both the mRNA expression levels of HO-1 (43.40 ± 1.05) and the catalase activity (46.42 ± 4.59), when compared to vehicle-treated group (46.29 ± 8.43; 37.83 ± 4.38; 1.58 ± 0.11; 8.93 ± 1.86, respectively). The animals did not show any signs of toxicity. CONCLUSION: 6,7-Dimethoxy-3-nitrocoumarin decreased inflammatory bone loss in the ligature-induced periodontitis in rats, and the activation of the HO-1 pathway may contribute, at least partially, to its protective effects by reducing TNF-α and IL-1β mRNA levels and increasing catalase activity. CLINICAL RELEVANCE: 6,7-Dimethoxy-3-nitrocumarin could be used as an adjunct to subgingival instrumentation during active and supportive periodontal treatment.
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Authors: Alrieta H Teixeira; Jordânia M de Oliveira Freire; Luzia H T de Sousa; Antônia T Parente; Nayara A de Sousa; Angela M C Arriaga; Francisca R Lopes da Silva; Iracema M Melo; Igor I Castro da Silva; Karuza M A Pereira; Paula Goes; José J do Nascimento Costa; Gerardo Cristino-Filho; Vicente de Paulo T Pinto; Hellíada V Chaves; Mirna M Bezerra Journal: Front Physiol Date: 2017-12-01 Impact factor: 4.566