Plasma kallikrein inhibitor DX-88 protects against brain ischemia|[sol]|reperfusion injury

We have investigated the involvement of the kinin system in ischemia/reperfusion brain injury in mice by using the new specific plasma kallikrein inhibitor DX-88 (Dyax Corp., Cambridge, MA). We first analysed whether DX-88 was able to cross the blood-brain barrier and found that thirty minutes after treatment with 30g/mouse iv, a marked inhibitory activity was present in cerebrospinal fluid. Ischemia was induced by occlusion of the middle cerebral artery, using a 6-0 monofilament. At the end of the 30 min ischemic period, the filament was removed and reperfusion allowed. Mice received DX-88 iv at the beginning of the ischemic period or at the end of it (ie at reperfusion), or 1 h after the beginning of the ischemic period. Twenty four hours after ischemia, neurological deficits and infarct size were evaluated. While saline treated mice showed stable scores, those who received of DX-88 at the beginning of the ischemic period had significantly reduced general (by 37.5%) and focal (by 50.0%) deficits scores. In these mice the ischemic volume was also significantly reduced by 50.9%. When given at reperfusion, DX-88 was similarly effective in improving general (by 38% ) and focal (by 50.1% ) deficits scores as well as the ischemic volume that was reduced by 58%. The inhibitor lost its neuroprotective action when administrated 1 h after the beginning of the ischemic period. This study shows that: i) this specific kallikrein inhibitor can rapidly cross the intact blood-brain barrier and thus possibly reach brain tissue in its active form; ii) it has a marked neuroprotective effect indicating an important role of kallikrein in brain ischemia/reperfusion injury.