A Novel Chemically-modified-curcumin (CMC2.24) Resolves Systemic Inflammation in Diabetic Rats

Objectives: To determine whether a novel triketonic CMC2.24 (in contrast to diketonic curcumin), a pleiotropic matrix metalloproteinase-inhibitor (pMMP-I) modulates the abnormal inflammatory response in peritoneal exudates (PEs) of diabetic rats.
Methods: Nineteen adult rats were made diabetic by I.V. injection of streptozotocin; non-diabetic rats (N; n=9) served as controls. Half of the diabetics (blood glucose > 500mg/dl) were orally administered CMC2.24 (30mg/kg) once per day for 3 weeks; untreated diabetics (D) and N rats received vehicle alone. PEs were collected at time=0 (resident macrophages), and at day 4 and day 6 after peritoneal thioglycolate injection. The PE macrophages were counted (hemocytometer); matrix metalloproteinases (MMPs) in the cell-free exudates (CFEs) were analyzed by densitometric analysis of gelatin zymograms, and cytokines analyzed by ELISA.
Results: The PE macrophages at day 0, 4 and 6 days after thioglycolate injection in the D rats appeared to be increased compared to the N rats, MMP-9 (including the homo- and hetero-dimer) levels in the CFEs of D rats were increased 420% (p<0.05) at time=0, compared to N rats; MMP-2 levels showed minimal changes. At day 4 and 6, again MMP-9 was significantly increased (p<0.05) in the D rats vs N rats, however CMC2.24 treatment of the diabetics “normalized” this MMP. Regarding cytokine analysis, proinflammatory IL-6 appeared increased, while pro-resolvin IL-10 was decreased, in the D rat PEs compared to N, and both appeared to be “normalized” by CMC2.24 treatment.
Conclusions: Diabetes in rats modulates inflammatory cell activity in peritoneal exudates, and these abnormalities appear to be “normalized” by oral administration of CMC2.24. Based on the dynamics of the inflammatory response with time, and its prolongation by severe hyperglycemia, and “normalization” by this novel compound, we conclude that CMC2.24 exhibits “resolvin-like” activity in addition to pleiotropic-inhibition of MMPs.