Ischemic neuronal death in the rat hippocampus: the calpain-calpastatin-caspase hypothesis

Inappropriate imbalances between proteases and protease inhibitors are known to occur under cerebral ischemia and neurodegenerative processes, and could be contributors to various diseases that are characterized by excessive (ischemia, AIDS) or inadequate (cancer, autoimmunity) cell death. For instance, calpain is activated in various necrotic and apoptotic conditions, whereas caspase-3 is only activated in neuronal apoptosis. Caspases and calpains are cysteine proteases that require proteolytic cleavage for activation. The substrates cleaved by caspases include cytoskeletal and associated proteins, kinases, members of the Bcl-2 family of apoptosis-related proteins, presenilins, and DNA-modulating enzymes. Calpain substrates include cytoskeletal and associated proteins, kinases and phosphatases, membrane receptors and transporters, and steroid receptors. This article provides a review of the properties of caspases and calpains, their roles in cell death pathways following cerebral ischemia, and the substrates upon which they act. Because calpain inhibitors and caspase inhibitors appear to protect brain tissue by distinct mechanisms in cerebral ischemia, the possible therapeutic interactions between these drugs in a well-defined rodent model of global ischemia are briefly discussed and documented. (C) 2003 Elsevier Science (USA). All rights reserved.