A Novel Chemically-Modified Curcumin (CMC2.24) Improves Diabetic Wound-Healing

Objective: To identify a curcumin-derived potent MMP inhibitor and investigate its effectiveness to enhance wound-healing in a diabetic rat model. 

Method: A congener series of five chemically-modified curcumins were assessed in vitro by a fluorogenic substrate assay for their ability to inhibit matrix metalloproteinases. The most potent of these, CMC2.24 was selected for in vivo wound-healing studies in a streptozotocin-induced diabetic rat model, using the dorsal skin defect method (six wounds of 6mm diam. symmetrically located on each rat). Fifteen male Sprague-Dawley rats were distributed into five groups (n=3/group). Group I: non-diabetic healthy rats (control); Group II: diabetic but received no CMC; Groups III and IV: diabetic and their wounds were treated topically with either 1% or 3% of CMC2.24, once daily for seven days (all groups received vehicles daily). Group V: diabetic treated with CMC 2.24 by oral gavage. At sacrifice, granulation tissues, and blood were collected for analysis of MMP-9 activity and glucose content (histology will be discussed elsewhere).

Result: Of the five CMC compounds tested in vitro, CMC2.24 showed the most favorable IC50 against MMP-9 and MMP-13. In vivo topical administration of 1% CMC2.24, to a lesser extent 3% CMC2.24, improved clinically-measured wound healing (p<0.05) and reduced the pathologically-excessive MMP-9 levels in diabetic wounds compared to vehicle-alone (p<0.001). Interestingly the topical treatments had no effect, neither on the levels of the constitutive MMP-2 nor on the severity of the hyperglycemia. 

 

Conclusion: In the in vitro study we identified a potent but selective MMP inhibitor, namely CMC2.24. The compound significantly improved wound healing and attenuated inflammation-induced MMP-9 in the skin of the wounds of diabetic rats. CMC 2.24 therefore has a demonstrated therapeutic potential to resolve inflammation during the healing of diabetic wounds and other inflammatory responses associated with the presence of excessive levels of MMPs.