Inhibition of matirx-metalloproteinases mediates carnosine-neuroprotection during ischemia

Abstract

Despite the increasing global medical burden of ischemic stroke, there is no existing therapeutic option against ischemic stroke. It is urgent to find a new therapeutic candidates or therapeutic targets for ischemic stroke. Matrix-metalloproteinases (MMPs) contribute to deterioration of neuronal damage by breakdown of blood-brain barrier and edema formation during ischemic stroke, and inhibition of MMP activity is known to reduce ischemic brain injury. Our group recently showed that the endogenous dipeptide, carnosine, has a high protective activity against ischemic brain damage, suggesting that carnosine may be a new candidate for stroke treatment. In this study, we investigated whether carnosine regulates the activity of matrix-metalloproteinases (MMPs) and brain edema by in vivo rat stroke models and in vitro enzyme activity assay. Carnosine therapy has significantly reduced neuronal infarct as well as edema in rats with ischemic stroke initiated by permanent occlusion of middle cerebra artery. Inhibitory effect of MMP activation by carnosine were observed in gelatin zymography and western blot of brain hemispheres. In the isolated enzyme assay, carnosine significantly inhibited the activity of MMP-2 and MMP-9 mediated by chelation of zinc, which is essential for the MMP activity. Taken together, we have found that carnosine can inhibit MMP activity, which reduces edema formation and brain damage by reducing the level of co-factor, zinc needed. We believe that our research provides new insights into the carnosine neuroprotection mechanism of ischemic brain injury.