Programmed cell death in cerebral ischemia

Programmed cell death (PCD) is an ordered and tightly controlled set of cha nges in gene expression and protein activity that results in neuronal cell death during brain development. This article reviews the molecular pathways by which PCD is executed in mammalian cells and the potential relation of these pathways to pathologic neuronal cell death. Whereas the classical pat terns of apoptotic morphologic change often do not appear in the brain afte r ischemia, there is emerging biochemical and pharmacologic evidence sugges ting a role for PCD in ischemic brain injury. The most convincing evidence for the induction of PCD after ischemia includes the altered expression and activity in the ischemic brain of deduced key death-regulatory genes. Furt hermore, studies have shown that alterations in the activity of these gene products by peptide inhibitors, viral vector-mediated gene transfer. antise nse oligonucleotides, or transgenic mouse techniques determine, at least in part, whether ischemic neurons live or die after stroke. These studies pro vide strong support for the hypothesis that PCD contributes to neuronal cel l death caused by ischemic injury. However, many questions remain regarding the precise pathways that initiate, sense, and transmit cell death signals in ischemic neurons and the molecular mechanisms by which neuronal cell de ath is executed at different stages of ischemic injury. Elucidation of thes e pathways and mechanisms may lead to the development of novel therapeutic strategies for brain injury after stroke and related neurologic disorders.