Experiments were conducted to determine whether a potent, reversible
calpain inhibitor could reduce the cortical ischemic brain damage associated with focal
ischemia in the rat.
AK275 (Z-Leu-Abu-CONH-CH2CH3), the active isomer of the diastereomeric mixture,
CX275, was employed in conjunction with a novel method of perfusing
drug directly onto the infarcted cortical surface. This protocol reduced or eliminated numerous, nonspecific pharmacokinetic, hemodynamic, and other potentially confounding variables that might complicate interpretation of any
drug effect. Focal
ischemia was induced using a variation of the
middle cerebral artery occlusion method. These studies demonstrated a reliable and robust
neuroprotective effect of
AK275 over the concentration range of 10 to 200 microM (perfused supracortically at 4 microliters/h for 21 h). Moreover, a 75% reduction in
infarct volume was observed when initiation of
drug treatment was delayed for 3 h postocclusion. Our data further support an important role of
calpain in
ischemia-induced neuropathology and suggest that
calpain inhibitors may provide a unique and potentially powerful means of treating
stroke and other ischemic brain incidents.