Chronic inflammatory diseases such as periodontitis have been associated with increased risk for various medical conditions including diabetes and cardiovascular disease. Endotoxin (lipopolysaccharide, LPS), derived from gram-negative periodonto-pathogens, can induce the local accumulation of mononuclear cells in the inflammatory lesion, increasing proinflammatory cytokines and matrix metalloproteinases (MMPs). This ultimately results in the destruction of periodontal connective tissues including alveolar bone. Curcumin is the principal dyestuff in the popular Indian spice turmeric and has significant regulatory effects on inflammatory mediators but is characterized by poor solubility and low bioactivity. Recently, we developed a series of chemically modified curcumins (CMCs) with increased solubility and zinc-binding activity, while retaining, or further enhancing, their therapeutic effects. In the current study, we demonstrate that a novel CMC (CMC 2.5: 4-methoxycarbonyl curcumin) has significant inhibitory effects, better than the parent compound curcumin, on proinflammatory cytokines and MMPs in in vitro, in cell culture, and in an animal model of periodontal inflammation. The therapeutic potential of CMC 2.5 and its congeners may help to prevent tissue damage during various chronic inflammatory diseases including periodontitis and may reduce the risks of systemic diseases associated with this local disorder. 1. Introduction Periodontal disease is one of the most common chronic inflammatory diseases encountered in humans. During the pathogenesis of this condition, anaerobic gram-negative periodontal-associated pathogens (e.g., P. gingivalis, T. forsythia) and the lipopolysaccharide (LPS, endotoxin) in their cell walls stimulate the innate and adaptive immune responses in periodontal tissues [1]. Inflammatory cells such as neutrophils and monocytes/macrophages are recruited to the lesion site and generate elevated levels of cytokines and other proinflammatory mediators such as the prostaglandins. The resulting periodontal inflammation upregulates matrix metalloproteinase (MMP) expression and, the activity of the latter, contributes to the destruction and loss of periodontal connective tissues including bone [2]. Curcumin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] is a component of the popular Indian spice turmeric and has been recommended for numerous medical applications [3]. Extensive investigations have led to the conclusion that it is a highly pleiotropic molecule with significant beneficial effects on inflammatory and other
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