Liraglutide Ameliorates Inflammation and Oxidative Stress of Periodontitis through Activating Nrf2/HO-1 Signaling Pathway

Abstract

Background and Purpose: Periodontitis was a common inflammatory disease which can lead to bone loss caused by bacterial infection, with the necessity to use local or systemic medication. It has been reported that Liraglutide (Lira) was effective in the treatment of periodontitis. However, its mechanism remains unclear. This study aimed to investigate the dental protective effect and potential mechanisms of Liraglutide on periodontitis rats. Methods: Specific Pathogen Free (SPF)-grade Wistar rats were placed with silk ligatures at the maxillary first molars to induce periodontitis. Rats were administered with different doses of Liraglutide or same volumes of saline (controls group) to investigate whether Lira could alleviate the periodontitis. Meanwhile, adenovirus-encapsulated si-Nrf2 or empty plasmid si-NC (normal control) were administered to investigate whether the protective effect was through the Nrf2/HO-1 signaling pathway. Alveolar bone loss was examined by micro-CT (Computed Tomography). Periodontal tissue paraffin sections were prepared by hematoxylin and eosin (H&E) staining and immunohistochemistry, or tartrate-resistant acid phosphatase (TRAP) staining for osteoclasts. Oxidative stress indicators were assessed by ELISA (Enzyme-Linked Immunosorbent Assay);GLP-1R and Nrf2 mRNA levels were examined by RT-qPCR (Real Time Quantitative PCR), while the expression level of GLP-1R, Nrf2, HO-1, NADH dehydrogenase, Quinone 1 (NQO1), and inflammatory factors such as tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) were measured by western blot. Results: Compared with the control group, the expression level of GLP-1R mRNA TNF-α, IL-1β and IL-6, osteoclast number, and malondialdehyde (MDA) content were significantly higher in the periodontitis group (p < 0.05), whereas the level of glutathione peroxidase (GSH-Px), Nrf2, HO-1 and NQO1 were remarkably lower (p < 0.05). However, these changes could be reversed after the administration of Lira and showed a dose-dependent effect. Moreover, the levels of Nrf2 mRNA, HO-1, NQO1 and GSH-Px were higher in the periodontitis + Lira (H) + si-NC group (p < 0.05) when compared with the periodontitis + solvent + si-NC group, but the levels of MDA, TNF-α, IL-1β and IL-6 were lower (p < 0.05). However, the knockdown of Nrf2 could effectively reverse these changes. Conclusions: Lira could protect periodontal tissues by inhibiting alveolar bone resorption, inflammation and oxidative stress through activation of the Nrf2/HO-1 pathway, which may have therapeutical implications in clinical management of periodontitis.