Excessive matrix metalloproteinase activity in diabetes: Inhibition by tetracycline analogues with zinc reactivity

Diabetes mellitus in rats is characterized by excessive activity of several matrix metalloproteinases (MMPs), notably collagenase(s) and gelarinase(s) , in skin, gingiva. acid other tissues. A number of tetracyclines (TCs), bo th antimicrobial compounds as well as chemically modified non-antimicrobial TC analogues (CMTs) are known to possess potent inhibitory activity agains t these enzymes. Three conventional antimicrobial TCs and six CMTs were use d in this study. In vitro, doxycycline was shown to possess higher inhibito ry capacity (i.e. lower IC50) against diabetic rat skin collagenase than ei ther minocycline or tetracycline HCl. Addition of excess zinc partially rev ersed the proteinase inhibition by TCs. In vivo, using rats made diabetic w ith streptozotocin (STZ), oral administration of various TCs led to decreas ed weight loss and substantial reductions in the activity of both skin coll agenase and skin gelatinase (primarily MMP-9, 92 kDa) without affecting blo od glucose. Using an in vitro spectrophotometric technique, the Zn++ reacti vity of several CMT5 was assessed and found to be positively related to the potency of these compounds as MMP inhibitors. One particular CMT (CMT-5, p yrazole analogue), which is neither antimicrobial nor capable of binding me tal cations, did nor inhibit the MMPs. TCs have potential utility in manage ment of diabetic complications mediated by excessive activity of MMPs.