Background and Purpose The mitochondrial-signaling pathway has been implicated in the pathogenesis of neuronal cell death resulting from ischemic brain injury.This signaling pathway is initiated by cytochrome c release and subsequent activation of apoptotic protease activating factor-1 (Apaf-1),leading to the activation of caspase-9 and caspase-3.The objective of the current study was to determine whether inhibition of the mitochondrial-signaling pathway either at the mitochondrial level or at the level of Apaf-1 activation could confer long term neuroprotection against CA1 neuronal loss and cognitive dysfunction after transient global ischemia.Methods Transient global cerebral ischemia was induced in adult male rats for 15 min using the 4-vessel occlusion method.Anti-apoptotic treatment was achieved by i.c.v.