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

Abstract

Purpose

To determine the effect of a pleiotropic MMP-inhibitor, a novel chemically-modified curcumin 2.24 (CMC2.24), on the clinical and biological measures of naturally-occurring 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.

Keywords:

• periodontitis
• bone loss
• chemically modified curcumin
• matrix metalloproteinases
• host-modulation therapy

Acknowledgments

This study was funded by NIDCR/NIH grant R42DE024946 and Traverse BioSciences, Inc. Authors would like to thank Rachel Kogan (Department of Biology, Stony Brook University, New York, USA), Akshani Patel (Department of Biology, Stony Brook University, New York, USA), Tyler Francisco (Department of Psychology, Stony Brook University, New York, USA), and Kai-Xi Lin (Department of Pharmacology, Stony Brook University, New York, USA) for their assistances to the dog study.

Disclosure

Lorne M. Golub is listed as an inventor on several related patents and these have been fully assigned to his institution, Stony Brook University, The State University of New York (SUNY). In the past, he received grants from Stony Brook University, Johnson & Johnson Dental Care Inc., Collagenex Pharma, Inc., and from NY State Diabetes Assoc., but not during the conduct of the study. In addition, Dr. Lorne M. Golub also provided consulting in the past for Johnson & Johnson Dental care Inc., and Collagernex Pharma Inc. Francis Johnson is also listed as an inventor on several related patents which have been fully assigned to Stony Brook University and to Chem-Master Int., Inc., on a shared basis. In addition, both Lorne M. Golub and Francis Johnson are minor shareholders in Traverse Biosciences, Inc., and Joseph Scaduto is the president and major shareholder in Traverse Biosciences Inc. They received grants from NIH/NIDCR (Phase II STTR Award 2R42DE024946-02) and from Traverse Biosciences Inc. Also, Traverse Biosciences Inc. has exclusively licensed patents from the Research Foundation for the State University of New York (RF/SUNY) covering the structure and use of the chemically-modified curcumins for the purpose of commercialization in human and animal health. The authors report no other conflicts of interest in this work.