Efficacy of a Novel Pleiotropic MMP-Inhibitor, CMC2.24, in a Long-Term Diabetes Rat Model with Severe Hyperglycemia-Induced Oral Bone Loss.

Abstract

CMC2.24, a novel 4-(phenylaminocarbonyl)-chemically-modified-curcumin, is a pleiotropic MMP-Inhibitor of various inflammatory/collagenolytic diseases including periodontitis. This compound has demonstrated efficacy in host modulation therapy along with improved resolution of inflammation in various study models. The objective of current study is to determine the efficacy of CMC2.24 in reducing the severity of diabetes, and its long-term role as an MMP-inhibitor, in a rat model. Twenty-one adult male Sprague-Dawley rats were randomly distributed into three groups: Normal (N), Diabetic (D) and Diabetic+CMC2.24 (D+2.24). All three groups were orally administered vehicle: carboxymethylcellulose alone (N, D), or CMC2.24 (D+2.24; 30mg/kg/day). Blood was collected at 2-months and 4-months' time-point. At completion, gingival tissue and peritoneal washes were collected/analyzed, and jaws examined for alveolar bone loss by micro-CT. Additionally, sodium hypochlorite(NaClO)-activation of human-recombinant (rh) MMP-9 and its inhibition by treatment with 10μM CMC2.24, Doxycycline, and Curcumin were evaluated. CMC2.24 significantly reduced the levels of lower-molecular-weight active-MMP-9 in plasma. Similar trend of reduced active-MMP-9 was also observed in cell-free peritoneal and pooled gingival extracts. Thus, treatment substantially decreased conversion of pro- to actively destructive proteinase. Normalization of the pro-inflammatory cytokine (IL-1ß, resolvin-RvD1), and diabetes-induced osteoporosis was observed in presence of CMCM2.24. CMC2.24 also exhibited significant anti-oxidant activity by inhibiting the activation of MMP-9 to a lower-molecular-weight (82kDa) pathologically active form. All these systemic and local effects were observed in the absence of reduction in severity of hyperglycemia. CMC2.24 reduced activation of pathologic active-MMP-9, normalized diabetic osteoporosis, and promoted resolution of inflammation but had no effect on the hyperglycemia in diabetic rats. This study also highlights the role of MMP-9 as an early/sensitive biomarker in the absence of change in any other biochemical parameter. CMC2.24 also inhibited significant activation of pro-MMP-9 by NaOCl (oxidant) adding to known mechanisms by which this compound treats collagenolytic/inflammatory diseases including periodontitis.