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. 2020 Feb 10:12:47-60.
doi: 10.2147/JEP.S236792. eCollection 2020.

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

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 Gu  6
Affiliations

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

Jie Deng et al. J Exp Pharmacol. .

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: bone loss; chemically modified curcumin; host-modulation therapy; matrix metalloproteinases; periodontitis.

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Conflict of interest statement

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.

Figures

Figure 1
Figure 1
Structures of doxycycline, chemically modified tetracycline-3 (CMT-3), curcumin, and a chemically modified curcumin, CMC2.24. All these bi- and tetra-phenolic compounds possess the cation-binding β-diketone moiety at the C-4 position (as "circled" and illustrated on the right top) (note that the highlighted tri-phenolic CMC2.24 is also tri-ketonic as "circled" on the right bottom while the other compounds are di-ketonic).
Figure 2
Figure 2
Schema describing the longitudinal protocol.
Figure 3
Figure 3
The effects of orally administered CMC2.24 or placebo on numbers of severely inflamed gingival sites (GI≥2) at each time point (baseline, 1, 2, and 3 months). Grey bar: Placebo group; black bar: CMC2.24 treatment group. Each value represents the mean (139–183 sites/per group) ± S.E.M. *Indicates p<0.05, values at each time period compared to its own baseline.
Figure 4
Figure 4
The effects of orally administered CMC2.24 or placebo on probing depth (PD) in dogs during a three-month protocol. Grey bar: Placebo group; black bar: CMC2.24 treatment group. (A) Pockets with baseline (time=0) probing depth≥4mm in posterior tooth sites were monitored at 1, 2, and 3 months. Each value represents the mean (90–144 sites/per group) ± S.E.M. ***Indicates p<0.001, values at each time period compared to its own baseline; ###Indicates p<0.001, values compared to placebo at each time period. (B) Number of pockets with PD ≥ 4mm were measured for baseline, 1, 2, and 3-month time period. Each value represents the mean (35–238 sites/per group) ± S.E.M. *Indicates p<0.05, values at each time period compared to its own baseline; #Indicates p<0.05, values compared to placebo at each time period.
Figure 5
Figure 5
The distance (mm) from cementoenamel junction (CEJ) to alveolar bone crest (ABC) was measured by radiography for CMC2.24 and placebo groups at baseline and 3 months. (A) Arrows in circles indicate the distance of alveolar bone loss. (B) Grey bar: Placebo group; black bar: CMC2.24 treatment group. Each value represents the mean (79–104 sites/per group) ± S.E.M. ###Indicates p<0.001, values compared to placebo at 3-month time period.
Figure 6
Figure 6
The effects of orally administered CMC2.24 or placebo on clinical and biochemical measurements of GCF in dogs during a three-month protocol. Grey bar: Placebo Group; black bar: CMC2.24 Treatment Group. (A). Each value represents the Mean (25–29 sites/per group) ± S.E.M. *Indicates p<0.05, values at 3-month time period compared to its own baseline; #Indicates p<0.05, values compared to placebo at 3 months. (B). IL-1β levels (pg/mL) in GCF were also measured at baseline, 1, 2, and 3 months. Each value represents the mean (n=4/group) ± S.E.M. *Indicates p<0.05, values at each time period compared to its own baseline; #Indicates p<0.05, values compared to placebo at each time period.
Figure 7
Figure 7
The effects of orally administered CMC2.24 or placebo on MMP-9 and MMP-2 in gingival extracts measured by gelatin zymography at three months. Grey bar: Placebo group; black bar: CMC2.24 treatment group. Each value represents the mean (n=4 samples/group) ± S.E.M. (A) Pro-, activated-, and total-MMP-9 in gingival extracts were measured by gelatin zymography at three months. ## and ###Indicate p<0.005 and p<0.001, respectively, values compared to placebo at 3-month time period. (B) Pro-, activated-, and total-MMP-2 in gingival extracts were measured by gelatin zymography at three months. #Indicates p<0.05, values also compared to placebo at 3-month time period.
Figure 8
Figure 8
The effects of orally administered CMC2.24 or placebo on cell-signaling molecules in gingival extracts were measured by Western blot at three months. Grey bar: Placebo group; black bar: CMC2.24 treatment group. Each value represents the mean (n=4 samples/group) ± S.E.M. (A) TLR-2 in gingival extracts. #Indicates p<0.05, values compared to placebo at 3-month time period. (B) p38 MAPK in gingival extracts. #Indicates p<0.05, values compared to placebo at 3-month time period.
Figure 9
Figure 9
The effects of orally administered CMC2.24 or placebo on pro-, activated-, and total-MMP-9 in blood-derived monocyte/macrophage culture (ex-vivo) were detected by gelatin zymography at three months. Grey bar: Placebo group; black bar: CMC2.24 treatment group. Each value represents the mean (n=4/group) ± S.E.M. #Indicates p<0.05, values compared to placebo at 3-month time period.
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