PROLONGED THERAPEUTIC WINDOW FOR ISCHEMIC BRAIN-DAMAGE CAUSED BY DELAYED CASPASE ACTIVATION

Apoptotic cell death is prominent in neurodegenerative disorders, such as Alzheimer's disease and Huntington's disease? and is found in cere bral ischemia. Using a murine model of delayed cell death, we determin ed that cleavage of zDEVD-amino-4-trifluoromethyl coumarin (zDEVD-afc) in brain homogenate, a measure of caspase activation, increased initi ally 9 hours after brief (30 minutes) middle cerebral artery occlusion along with caspase-3p20 immunoreactive cleavage product as determined by immunoblotting. zDEVD-afc cleavage activity was blocked by pretrea tment or posttreatment with the caspase-inhibitor Asp(OMe)-Glu(OMe)-Va l-Asp(OMe)-fluoromethyl-ketone (zDEVD-fmk), and ischemic damage was re duced when the drug was injected up to 9 hours after reperfusion. The protection was long lasting (21 days). Hence, the period before caspas e activation defined the therapeutic opportunity for this neuroprotect ive agent after mild ischemic brain injury. Prolonged protection after caspase inhibition plus the extended treatment window may be especial ly relevant to the treatment of neurodegenerative disorders.