Efeitos anti-inflamatório e antirreabsortivo ósseo da cumarina e da umbeliferona na periodontite via inibição de IL-1β em camundongos

Abstract

Periodontitis is a chronic, inflammatory and multifactorial disease resulting from dysbiosis of the dental biofilm and dysregulation of the host response. This disease has a high prevalence, being considered the main cause of tooth loss in adults. Although there are several treatments for periodontitis, in some patients the response is unsatisfactory, and it is convenient to Search for pharmacological approaches that complement the primary treatment. Coumarins are secondary metabolites found in natural species and exhibit several pharmacological activities, with emphasis on their anti-inflammatory action and, more recently, on bone metabolism. The aim of this dissertation was to verify whether coumarins have pharmacological potential as na adjunct treatment in lytic bone diseases. To this aim, we systematically reviewed the scientific literature to understand the mechanisms of action of coumarins on bone markers. The aim of this dissertation was to evaluate the anti-inflammatory and bone antiresorptive effects of coumarin (CUM) and umbelliferone (UMB) in a ligature-induced alveolar bone resorption model.Groups of male Swiss mice (n=7/each) received i.p. CUM (5, 15 and 45 mg/kg), UMB (15, 45 and 135 mg/kg) or Saline for 7d. As control, naïve animals were used. Alveolar boné resorption (ABR) was evaluated by macroscopy, followed by histomorphometry of the furcation region and expression of tartrate-resistant acid phosphatase (TRAP). The gingiva was evaluated for myeloperoxidase (MPO) activity and IL-1β expression. Systemically, sérum dosages of aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea and creatinine, and daily weighing of the animals were performed. Ligature in Salina animals induced ABR (240%), and increased furcation area (219%) and TRAP expression (932%); in the gingiva, there was an increase in the MPO activity (202%) and expression of IL-1β (883%), compared to naïve. CUM (5, 15 and 45 mg/kg) reduced ABR by 28%, 25% and 22%, respectively, compared to Saline (p<0.05). In the gingiva, CUM (5 mg/kg) reduced MPO by 71.6%, and at doses of 5 and 15 mg/kg CUM reduced IL-1β expression by 62.6% and 53%, respectively, compared to Saline. Systemically, CUM did not change AST, urea, and creatinine levels, however, the two highest doses increased ALT by 100% and 255%, respectively, suggesting hepatotoxic potential. UMB (15, 45 and 135 mg/kg) reduced ABR by 25%, 33% and 25%, respectively, and the highest dose reduced the furcation area by 31%, compared to Saline (p<0.05). Corroborating these findings, UMB (135 mg/kg) decreased TRAP expression. by 48,4%. In the gingiva, UMB (15, 45 and 135 mg/kg) reduced MPO activity by 71%, 76%, 77% and IL-1β expression by 54%, 78%, 50%, respectively, when compared to saline (p<0.05). Systemically, UMB did not change any parameters (p>0.05). In short, with the doses used, CUM and UMB showed anti-inflammatory profiles via inhibition of IL-1β, and bone antiresorptive, with UMB being the best safety standard.