<p>Chemically-Modified Curcumin 2.24: A Novel Systemic Therapy for Natural Periodontitis in Dogs</p>

Abstract

Purpose:To determine the effect of a pleiotropic MMP-inhibitor, a novel chemicallymodified curcumin 2.24 (CMC2.24), on the clinical and biological measures of naturallyoccurring periodontitis in the beagle dog. Methods: Eight adult female dogs with generalized periodontitis were distributed into two groups: Placebo and Treatment (n=4/group). After a 1-hr full-mouth scaling and root planing (SRP) at time 0, placebo or CMC2.24 (10mg/kg) capsules were orally administered once/day for 3 months. Various clinical periodontal parameters (e.g., pocket depth, gingival index) were measured at different time periods (0, 1, 2 and 3 months), and gingival crevicular fluid (GCF) samples and gingival tissue biopsies (3-month) were analyzed for cytokines, MMPs and cell-signaling molecules. Standardized radiographs were taken at 0 and 3-month; in addition, peripheral blood monocytes/macrophages from these dogs at 3-month were cultured and analyzed for the pro-, activated-, and total-forms of both MMP-2 and MMP-9. Results: CMC2.24 treatment significantly reduced gingival inflammation (gingival index, GCF flow), pocket depth (PD), and the numbers of pockets (PD≥4mm), compared to placebo. CMC2.24 also significantly reduced MMP-9 and MMP-2 (primarily in the activated-form) in gingival tissue, alveolar bone loss, and reduced GCF IL-1β. Cell-signaling molecules, TLR-2 (but not TLR-4) and p38 MAPK, responded to CMC2.24 in a pattern consistent with reductions in inflammation and collagenolysis. In culture, CMC2.24 had no effect on pro-MMP-9 but essentially completely blocked the conversion of pro-to activated-MMP-9 in systemic blood-derived monocytes/macrophages from these dogs. Conclusion: In the beagle dog model of natural periodontitis, orally administered CMC2.24 (a novel triketonic phenylaminocarbonyl-curcumin) significantly decreased clinical measures of periodontitis as well as pro-inflammatory cytokines, MMPs, and cell-signaling molecules. These and previous studies, using other in vitro and in vivo models, support the clinical potential of CMC2.24 as a novel adjunct to SRP in the treatment of chronic periodontitis.

Novel Chemically Modified Curcumin (CMC) Derivatives Inhibit Tyrosinase Activity and Melanin Synthesis in B16F10 Mouse Melanoma Cells

“…Our group has reported on CMC2.24, a triketonic N -phenylaminocarbonyl derivative of bis-demethoxycurcumin, which exhibits enhanced stability and solubility compared to curcumin and has emerged as a ‘lead compound’ for several pharmacological applications such as treatment of anthrax by inhibition of the metalloprotease, lethal factor [ 21 ], treatment of cancers of the pancreas [ 22 ] and prostate [ 23 ], normalizing wound healing in diabetic rats [ 24 ], reduction in severity of periodontitis and inhibition of alveolar bone resorption associated with the disease in a rat model [ 25 , 26 ]. In addition, CMC2.24 has shown superior anti-inflammatory activity compared to the parent compound curcumin, in inhibiting periodontitis-induced bone resorption in rats via multiple mechanisms [ 27 ], and most recently, for the treatment of natural periodontitis in beagle dogs [ 28 , 29 ]. Other studies have established the pleotropic activities of CMC2.24 in inhibiting matrix metalloproteinases (MMPs) [ 30 ] and nuclear-factor kB (NF-kB), thereby reducing inflammation in models of diabetes-induced periodontitis [ 30 ].…”

A Novel Chemically-Modified Curcumin 2.24: Short-Term Systemic Therapy for Natural Periodontitis in Dogs

“…Interestingly, our results indicated that a short-term/1month protocol, although it did not result in obvious clinical improvement at this early stage, did appear to reduce both pro-and activated-MMP-9 in peripheral blood, which might affect the systemic environment, and also serves as an early and sensitive biomarker that precedes and predicts future clinical changes in oral (and other) inflammatory diseases. In brief, although a 1-month CMC2.24 treatment produced no detectable effect on clinical parameters temporarily, these were indeed observed with longer-term/3-momth therapy (24). At baseline (Figure 2), the levels of activated-MMP-9 in CMC2.24-treated group was 100% greater/higher (p < 0.05) than in the placebogroup.…”

“…It should be noted that the severity of clinical parameters of periodontitis was significantly reduced at the 3-month timeperiod with this regimen of HMT [p < 0.05, data already published (24)].…”

“…Deng et al (24) recently reported a new therapeutic strategy to treat naturally-occurring periodontitis in beagle dogs, involving oral/systemic administration of a novel chemicallymodified curcumin, CMC2.24 (a phenylaminocarbonyl curcumin), for 3-months as a host-response modulator. This pleiotropic therapy, based on (but chemically-modified) a well-known natural product, was designed to reduce pathologic inflammation/collagenolysis in oral and other diseases, and includes enhanced resolution of inflammation and inhibition of bone loss.…”

Does Chemically Modified Curcumin Control the Progression of Periodontitis? A Systematic Review

“…Seven experimental trials involving 162 rats and 8 dogs were concerned in this systematic review over 14-90 days. 10,13,[16][17][18][19][20] Five articles were published in the USA and two studies were conducted in Brazil. Besides, all studies are contemporary, as the oldest of them was published in 2014.…”