Systemic delivery of carbon monoxide by CORM-401 mitigates inflammation and alveolar bone loss in a rat model of periodontitis

BACKGROUND: Periodontitis is a chronic inflammatory disease characterized by excessive production of pro-inflammatory mediators, oxidative stress, and extracellular matrix degradation, ultimately leading to alveolar bone loss. Carbon monoxide (CO), an endogenous gasotransmitter produced during heme degradation, exhibits anti-inflammatory, antioxidant, and cytoprotective properties. CORM-401, an orally active CO-releasing molecule, can deliver CO systemically with high efficiency, and its ability to regulate energetic metabolism, reduce inflammation, and limit oxidative stress has been documented. However, its potential therapeutic effects in the treatment of periodontal disease have never been investigated. OBJECTIVE: To evaluate whether orally administered CORM-401 attenuates alveolar bone loss and gingival inflammation in a rat model of ligature-induced periodontitis. METHODS: Adult rats were subjected to ligature placement of the first molar to induce periodontitis and treated orally with CORM-401 or vehicle. Alveolar bone loss was quantified by CEJ-BC measurements. Gingival tissues were analyzed for cytokines (TNF-α and IL-1β), nitric oxide metabolites (NOx), and MMP-2 activity. Systemic inflammation was assessed by measuring plasma TNF-α. RESULTS: CORM-401 significantly reduced alveolar bone loss compared with vehicle-treated periodontitis rats. Treatment markedly decreased gingival levels of TNF-α and IL-1β. CORM-401 also reduced gingival NOx accumulation, indicating attenuation of oxidative and proteolytic stress. Plasma TNF-α was lower in CORM-401-treated animals, demonstrating a systemic anti-inflammatory effect. CONCLUSION: Oral administration of CORM-401 effectively mitigates periodontal inflammation and protects against alveolar bone loss in ligature-induced periodontitis. These findings suggest that CO-based pharmacological modulation may represent a promising host-directed therapeutic strategy for controlling periodontal tissue destruction.