POSTISCHEMIC ADMINISTRATION OF AK275, A CALPAIN INHIBITOR, PROVIDES SUBSTANTIAL PROTECTION AGAINST FOCAL ISCHEMIC BRAIN-DAMAGE

Experiments were conducted to determine whether a potent, reversible c alpain inhibitor could reduce the cortical ischemic brain damage assoc iated with focal ischemia in the rat. AK275 (Z-Leu-Abu-CONH-CH2CH3), t he active isomer of the diastereomeric mixture, CX275, was employed in conjunction with a novel method of perfusing drug directly onto the i nfarcted cortical surface. This protocol reduced or eliminated numerou s, nonspecific pharmacokinetic, hemodynamic, and other potentially con founding variables that might complicate interpretation of any drug ef fect. Focal ischemia was induced using a variation of the middle cereb ral artery occlusion method. These studies demonstrated a reliable and robust neuroprotective effect of AK275 over the concentration range o f 10 to 200 mu M (perfused supracortically at 4 mu l/h for 21 h). More over, a 75% reduction in infarct volume was observed when initiation o f drug treatment was delayed for 3 h postocclusion. Our data further s upport an important role of calpain in ischemia-induced neuropathology and suggest that calpain inhibitors may provide a unique and potentia lly powerful means of treating stroke and other ischemic brain inciden ts.