Objective: To develop poly-enolic zinc-binding compounds (“PEZBINs”) which can inhibit matrix metalloproteinases (MMPs) and cytokines in periodontal and other collagen-destructive and inflammatory diseases; tetracyclines in non-antimicrobial (ie., low) doses also inhibit these mediators, and are approved for systemic administration to patients with chronic inflammatory periodontal and skin diseases, but in higher doses can produce side-effects.
Methods: Having previously demonstrated that the β-diketone zinc-binding site of tetra-phenolic/tetracyclines (e.g., doxycycline) is important for their host-modulating therapeutic efficacy, we recently synthesized a series of simpler bi-phenolic 1,3-diketo analogues (ie., bis-aroyl methanes, and chemically-modified curcumins e.g., methoxycarbonyl curcumin, MCC) and tested their efficacy as inhibitors of: (a) human MMP-8 (collagenase-2) activity in vitro; (b) cytokine production by human monocytes exposed to endotoxin in cell culture; and (c) MMP-8 and MMP-9 (gelatinase B) in vivo in a rat model of streptozotocin-induced diabetes.
Results: Of nine PEZBINs tested in vitro, MCC was the most potent inhibitor of MMP-8 activity with an IC50 similar to that of 1,10 phenanthroline (a standard Zn++ chelator/MMP inhibitor). MCC (2-10µM) in cell culture also inhibited the production of the cytokines, IL-1β, TNF∂, IL-6 and MCP-1 by 63%, 41%, 74% and 30%, respectively, by non-cytotoxic mechanisms including inhibition of the activation/phosphorylation of NFkB. In vivo, oral administration of MCC to diabetic rats appeared to reduce pathologically-elevated MMP levels in plasma and gingiva and adverse events seen in the untreated diabetics, but had no effect on the severity of hyperglycemia.
Conclusion: Simple enolic zinc-binding compounds may be useful therapeutically in diseases such as periodontitis characterized by elevated levels of MMPs and pro-inflammatory cytokines.
Grant support from The Center for Advanced Biotechnology/Stony Brook University,(NYSTAR grant #A43273), Chem. Master Intl., and the Academy of Finland, Helsinki Univ. Central Hospital Res. Foundation.
Division:
IADR/PER General Session
Meeting:
2010 IADR/PER General Session (Barcelona, Spain)
Location:
Barcelona, Spain
Year:
2010
Final Presentation ID:
1182
Abstract Category|Abstract Category(s):
Periodontal Research - Therapy
Authors
Golub, Lorne M.
( State University of New York @ Stony Brook, Stony Brook, NY, USA
)
Hambardjieva, Elana
( State University of New York @ Stony Brook, Stony Brook, NY, USA
)
Zhang, Yu
( State University of New York @ Stony Brook, Stony Brook, NY, USA
)
Johnson, Francis
( State University of New York @ Stony Brook, Stony Brook, NY, USA
)
Lee, Hsi-ming
( State University of New York @ Stony Brook, Stony Brook, NY, USA
)
Zhang, Yazhou
( State University of New York @ Stony Brook, Stony Brook, NY, USA
)
London, Lucille
( State University of New York @ Stony Brook, Stony Brook, NY, USA
)
Grewal, Jasvir
( State University of New York @ Stony Brook, Stony Brook, NY, USA
)
Grewal, Suman
( State University of New York @ Stony Brook, Stony Brook, NY, USA
)
Gu, Ying
( State University of New York - Stony Brook, Stony Brook, NY, USA
)
Sorsa, Timo
( University of Helsinki, Helsinki, N/A, Finland
)
Tervahartiala, T.
( University of Helsinki, Helsinki, N/A, Finland
)
SESSION INFORMATION
Poster Session
New Therapeutics to Treat Periodontal Diseases, in vitro and Animal Studies
07/15/2010