Ischemic neurons die acutely by osmotically driven rupture of cellular and subcellular membranes by a process called necrosis, but may also die in a delayed manner, dependent on the activation of a family of cysteine proteases named caspases. Caspases are synthesized as inactive proenzymes containing three subunits, an N-terminal prodomain, a large (∼20 kDa) and a small subunit (∼10 kDa), which form heterotetromers on cleavage and activation. Family members show a near absolute specificity for cleavage at the N-terminal of aspartate residues. At least 14 caspases have been identified to date, designated 1 to 14. Caspases −1, −2, −3, −7, −8 and −9 are constitutively expressed in the brain. In the spinal cord, caspases −2, −3 and −8 are constitutively expressed. Caspases −1, −4 and −5 (caspase-1 family members) promote cytokine maturation and mediate inflammation whereas caspases −2, −3, −6, −7, −8 and −9 (caspase-3 family members) promote apoptotic cell death. On activation, caspase-11, which is found only in mice, promotes both cytokine maturation and apoptosis.
In this review, we will briefly summarize the evidence implicating caspases in cerebral and spinal cord ischemia. Caspase-driven cell death may have important therapeutic implications for ischemia as well as for other acute and chronic central nervous system (CNS) conditions in which cell death is prominent.