A Novel Chemically-modified-curcumin (CMC) Normalizes Wound-healing in Experimental Diabetes

Objectives: Diabetes delays wound-healing and accelerates periodontal breakdown. The current studies demonstrate wound-healing efficacy of a tri-ketonic pleiotropic matrix metalloproteinase-inhibitor (MMP-I), CMC2.24, in a model of severe hyperglycemia in type I diabetic rats.
Methods: CMC2.24 was applied topically to standardized 6mm diameter skin wounds at 0.25%, 1%, and 3% concentrations, or administered systemically (oral intubation; 30mg/kg); controls received vehicles alone, or were administered curcumin. 65 rats, including non-diabetic controls (NDCs), vehicle-treated diabetics (Ds), and CMC2.24- and curcumin-treated Ds were studied for 7, 14 and 30 day time-periods. Wound-closure was assessed by gross and histomorphometric measurements; collagen and MMP-2 /MMP-9 levels were assessed by hydroxyproline measurements and by gelatin zymography/densitometric assays, respectively.
Results: Inducing diabetes in rats by streptozotocin injection reduced wound-closure and re-epithelialization by 50-65% (p<0.001), compared to NDCs, which were both improved by all CMC2.24 (especially 1% topical, and systemic) treatments, significantly better than curcumin. Diabetes increased MMP-9 (leukocyte-type gelatinase) levels which was reduced by 1% topical, and systemic, CMC2.24 more than by other treatments; MMP-2 showed minimal changes. Although the D rats showed re-epithelialization by day 14 (vs. day 7 for NDCs), collagen deposition in these rats remained low over 30 days. NDC rats showed a rapid increase in dermal collagen, while CMC2.24 increased collagen levels in the D rats by 140% (p=0.003) in spite of unaffected hyperglycemia.
Conclusions: Severe type I diabetes dramatically suppressed epithelial and connective tissue wound-healing which was “normalized” either by topical 1% CMC2.24 (significantly better than curcumin), or by oral systemic administration. These data are consistent with previous studies showing efficacy of CMC2.24 in models of periodontitis, osteoarthritis, acute lung disease (ARDS), and cancer.

Supported by Award# A37298 from the Research Foundation, and Center for Advanced Technology, Stony Brook University; Chem-Master Intl., Inc.; and the McClain Laboratories, NY.