Caspase pathways, neuronal apoptosis, and CNS injury

Caspases are a family of mammalian proteases related to the ced-3 gene of C aenorhabditis elegans. They mediate many of the morphological and biochemic al features of apoptosis, including structural dismantling of cell bodies a nd nuclei, fragmentation of genomic DNA, destruction of regulatory proteins , and propagation of other pro-apoptotic molecules. Based on their substrat e specificities and DNA sequence homologies, the 14 currently identified ca spases may be divided into three groups: apoptotic initiators, apoptotic ex ecutioners, and inflammatory mediators. Caspases are activated through two principal pathways, known as the "extrinsic pathway," which is initiated by cell surface death receptor ligation, and the intrinsic pathway, which ari ses from mitochondria. Endogenous inhibitors, such as the inhibitors of apo ptosis (IAP) family, modulate caspase activity at various points within the se pathways. Upon activation, caspases appear to play an important role in sequelae of traumatic brain injury, spinal cord injury, and cerebral ischem ia. In addition, they may also play a role in mediating cell death in chron ic neurodegenerative conditions such as Alzheimer's disease, Huntington's d isease, and amyotrophic lateral sclerosis. This article reviews the current literature on the role of caspases in acute and chronic CNS injury, and pr ovides evidence for the potential therapeutic use of caspase inhibitors in the setting of these conditions.