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

Abstract

Jie Deng,1 Lorne M Golub,1 Hsi-Ming Lee,1 Michael C Lin,1 Heta Dinesh Bhatt,1 Hou-Lin Hong,2 Francis Johnson,3 Joseph Scaduto,4 Thomas Zimmerman,5 Ying Gu6 1Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY 11794, USA; 2Department of Public Health, School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; 3Department of Chemistry and Pharmacological Sciences, School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; 4Traverse Biosciences, Inc., Stony Brook, NY 11790, USA; 5Division of Laboratory Animal Resources (DLAR) at Stony Brook, Stony Brook University, Stony Brook, NY 11794, USA; 6Department of General Dentistry, School of Dental Medicine, Stony Brook University, Stony Brook, NY 11794, USACorrespondence: Jie DengDepartment of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY 11794, USATel [phone]Fax [phone]Email [email protected]: 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

Keywords

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