Animals subjected to sublethal transient global ischemia (ischemic preconditioning) exhibit neuroprotection against subsequent global ischemia-induced neuronal death in the hippocampal CA1 (ischemic tolerance). Preconditioning acts on apoptotic signaling cascades to prevent ischemia-induced upregulation of the pro-apoptotic neurotrophin receptor p75 and DNA fragmentation, as assessed by TUNEL staining in CA1 neurons. In contrast, preconditioning does not block ischemia-induced activation of caspase-9 or of caspase-3 (in accordance with H. Tanaka et al., SfN abstract, 2001). Caspase-3 activation has been considered a point of no return in apoptosis These findings indicate that preconditioning acts at a step downstream from caspase-3 activation, but upstream from apoptotic DNA fragmentation to protect CA1 neurons. Studies are underway to determine whether preconditioning prevents activation of DNA fragmentation factor 45 (DFF 45), an important target of activated caspase-3. Caspase-3 cleaves DFF 45 to genera...