Novel MMP inhibitor has potential for treatment of stroke.

The use of new and selective inhibitors of matrix metalloproteinases (MMPs) may have significant therapeutic potential in stroke patients, report US researchers. The role of MMPs, and MMP-9 in particular, has been suggested in the pathogenesis of neurological disorders, but efforts to inhibit MMP activity have been largely unsuccessful in human clinical trials, says study author Stuart A Lipton (The Burnham Institute, La Jolla, CA, USA). “They failed because of side-effects”, he says, “but we have developed a totally new way of inhibiting MMPs.” Previous research has shown that concentrations of both MMP-9 and MMP-2 are high after a stroke. Attempts to ameliorate MMPmediated brain damage in human clinical trials have been unsuccessful because of low specificity and high toxicity. Lipton and colleagues developed a thiirane gelatinase inhibitor, called SB-3CT, which is highly specific for MMP-9 and MMP-2 (J Neurosci 2005; 25: 6401–18). “The drug is activated by the catalytic side of MMPs”, says Lipton. “So when MMP activity increases, the drug is increasingly activated to inhibit the activity.” “Not only is the drug very specific for these two MMPs, which will eliminate many of the side-effects, but also it is very particular, in that it inhibits pathological activity far more than normal activity”, he adds. “That is why we think that this class of drugs has a great deal of potential.” In a mouse model of stroke, mice that received SB-3CT seemed to be protected from brain damage, compared with mice that did not receive the treatment. In the mice treated with SB3CT, MMP-9 activity significantly declined whereas no changes were noted in the activity of other MMPs. Brain damage in the treated mice was only 30% of that in the controls. In addition, tissue plasminogen activator (tPA), the only treatment approved for stroke in the USA, is also neurotoxic, and part of that effect is mediated by activating MMPs. We may be able to use this drug to offset the side effects of tPA, explains Lipton. This paper replicates research that has already been published by several groups, comments Eng H Lo (Harvard University, Cambridge, MA, USA). “Our lab has shown that the main complication of the only FDA-approved stroke therapy is caused by tPAtriggered MMP-9 upregulation. MMP inhibitors can reduce this dreaded complication of tPA for stroke therapy.”