Exploiting endogenous anti-apoptotic proteins for novel therapeutic strategies in cerebral ischemia

The acute neuronal degeneration in the ischemic core upon stroke is followed by a second wave of cell demise in the ischemic penumbra and neuroanatomically connected sites. This temporally delayed deleterious event of programmed cell death ('secondary degeneration') often exceeds the initial damage of stroke and, thus, contributes pivotally to significant losses in neurological functions. In fact, it is the injured neurons in these regions around the ischemic core zone that neuropharmacological prevention is targeting to preserve. Clinical and pre-clinical studies have focussed on neuroprotective interventions with caspase inhibitors, but it remains ambiguous whether diminishing or even silencing these aspartate-specific cysteine proteases are in sum beneficial for the clinical outcome. It is often ignored that caspase inhibitors are able to antagonize calpain and cathepsins, thereby protecting the cytoskeleton from damage. Moreover, there is a point of no return, beyond which interfering with caspases cannot rescue the cell, but spoil the obligate and necessary suicide program such that the cellular environment suffers from by-products of necrosis and secondary inflammation. Here we discuss novel alternative strategies to abrogate the death cascade at the level of the genomic response (transcription factors, NF-kappa B, CREB, ICER, HIF), of mitochondrial effectors (cytochrome c, Bcl-2, Smac/DIABLO, HtrA2), and of inhibitor of apoptosis proteins (IAPs). IAPs are the only known endogenous proteins that inhibit specifically and with high affinity the activity of both initiator and effector caspases. Based on compelling biochemical evidence, we argue that patronizing the neuronal endogenous anti-apoptotic machinery could be superior to the pharmacological inhibition of caspases at various levels, with regard to specificity, side effects, and the 'therapeutic window of opportunity'. (C) 2008 Elsevier Ltd. All rights reserved.