Received for publication March 24, 2006.
Revised May 5, 2006.
Accepted for publication May 15, 2006.

SELECTIVE INHIBITION OF PLASMA KALLIKREIN PROTECTS BRAIN FROM REPERFUSION INJURY

Abstract

We have studied the effect of DX-88, a selective recombinant inhibitor of human plasma kallikrein in transient or permanent focal brain ischemia (with or without reperfusion, respectively) induced in C57Bl/6 mice. In transient ischemia, DX-88 induced a dose-dependent reduction of ischemic volume that, at the dose of 30 µg/mouse, reached 49% of the volume of saline-treated mice. At the same dose, DX-88 was also able to reduce brain swelling to 32%. Twenty-four hours after ischemia, mice treated with DX-88 had significantly lower general and focal deficit score. Fluoro-Jade staining, a marker for neuronal degeneration, showed that DX-88-treated mice had a reduction in the number of degenerating cells, compared to saline-treated mice. Seven days after transient ischemia DX-88 protective effect, was still present. On the contrary, DX-88 was not able to reduce the ischemic volume in the permanent occlusion model. This study shows that DX-88 has a strong neuroprotective effect in the early phases of brain ischemia preventing reperfusion injury and indicates that inhibition of plasma kallikrein may be a useful tool in the strategy aimed at reducing the detrimental effects linked to reperfusion.

Key words: C1-Inhibitor, cerebral ischemia, inflammation, kallikrein, oedema, reperfusion