Melatonin prevents peri‑implantitis via suppression of TLR4/NF-κB.

Peri‑implantitis, which is characterized by peri‑implant mucositis and alveolar bone resorption, significantly shortens the service life of dental implants. Melatonin is well-known for its anti-inflammatory and osteoprotective activities. Nevertheless, the effects and mechanisms of melatonin to prevent peri‑implantitis remain unknown. In this study, the lipopolysaccharide-induced peri‑implantitis model was established after the titanium implants were osseointegrated, and the rats received daily administrations of melatonin. The gingival fibroblasts and osteoclasts/osteoblasts were also co-cultured to simulate the inflammatory environment in vitro. We found that prophylactic administration of melatonin decreased proinflammatory cytokine levels and osteoclast numbers, attenuated alveolar bone resorption, and reduced the incidence of peri‑implantitis in vivo. Furthermore, melatonin suppressed osteoclastic formation and function in the inflammatory co-culture environment, while melatonin promoted osteoblastic differentiation and function in the in vitro model. Mechanistically, melatonin reduced TLR4 protein levels, and inhibited activation of NF-κB to downregulate the levels of TNF, IL-1β, and IL-6. These data showed that melatonin was a potent agent to prevent peri‑implantitis through inhibiting TLR4/NF-κB signaling. Our findings provide a novel strategy to prevent peri‑implantitis, and expand the applications of melatonin. STATEMENT OF SIGNIFICANCE: Dental implants have become the first choice for restoring partial and full edentulism, but its service life is seriously affected by peri‑implantitis. Exploration of novel and effective approaches to prevent peri‑implantitis is an important and urgent need. In the present study, we have reported for the first time that prophylactic administration of melatonin delayed the occurrence and reduced the incidence of peri‑implantitis by decreasing proinflammatory cytokine levels, inhibiting osteoclastogenesis, and promoting osteogenesis. The study is expected to have an important significance on the prevention of peri‑implantitis.