Exploring the Toxicity and Antiresorptive Activity of a Diterpene from Egletes viscosa (L.) less. in Mice: in silico and in vivo Studies

Abstract

Egletes viscosa (macela) is known for its gastroprotective properties in traditional medicine in Brazil. Herein, we evaluated the toxicity and antiresorptive activity of 12-acetoxyhawtriwaic acid lactone (12-AHAL), a diterpene obtained from E. viscosa. 12-AHAL has been demonstrated to have biological effects which might be important during periodontitis, a bone disorder. Molecular docking studies analyzed ADMT-Tox properties of 12-AHAL and evaluated its binding performance against targets associated with bone loss. Periodontitis was induced by a ligature around the mandibular first molars. The mice received (gavage) 12-AHAL (12.5; 25; 50 mg/kg) for 14d. Bone loss was assessed through morphometric and histometric analysis. Picrosirius Red staining was performed in mandible sections. We investigated in gingival tissues by RT-qPCR RANK-L/OPG and catalase mRNA expression levels, and by colorimetric assay catalase and superoxide dismutase-SOD activities. The in vivo toxicity of 12-AHAL was evaluated. In silico assays suggested good oral bioavailability and hepatotoxicity, and the interactions of 12-AHAL with RANKL/OPG and catalase showed firm bonds. In in vivo experiments, 12-AHAL reduced bone loss. Although 12-AHAL (25 or 50 mg/kg) produced liver and renal toxicity, 12-AHAL (12.5 mg/kg) showed no signs of toxicity, increased collagen type I, reduced RANK-L mRNA levels and increased OPG and catalase mRNA levels, and enhanced catalase and SOD activities. 12-AHAL (12.5 mg/kg) was safe and had anti-resorptive effects during periodontitis in mice, showing antioxidant activity with the involvement of the RANK-L/OPG pathway. These findings point to a novel application for E. viscosa and highlights the need for cautious utilization of medicinal plants.