This review is directed at understanding how neuronal death occurs in two distinct insults, global ischemia and focal ischemia. These are the two principal rodent models for human disease. Cell death occurs by a necrotic pathway characterized by either ischemic/homogenizing cell change or edematous cell change. Death also occurs via an apoptotic-like pathway that is characterized, minimally, by DNA laddering and a dependence on caspase activity and, optimally, by those properties, additional characteristic protein and phospholipid changes, and morphological attributes of apotosis. Death may also occur by autophagocytosis. The cell death process has four major stages. The first, the induction stage, includes several changes initiated by ischemia and reperfusion that are very likely to play major roles in cell death. These include inhibition (and subsequent reactivation) of electron transport, decreased ATP, decreased pH, increased cell Ca2+, release of glutamate, increased arachidonic acid, and also gene activation leading to cytokine synthesis, synthesis of enzymes involved in free radical production, and accumulation of leukocytes. These changes lead to the activation of five damaging events, termed perpetrators. These are the damaging actions of free radicals and their product peroxynitrite, the actions of the Ca2+-dependent protease calpain, the activity of phospholipases, the activity of poly-ADPribose polymerase (PARP), and the activation of the apoptotic pathway. The second stage of cell death involves the long-term changes in macromolecules or key metabolites that are caused by the perpetrators. The third stage of cell death involves long-term damaging effects of these macromolecular and metabolite changes, and of some of the induction processes, on critical cell functions and structures that lead to the defined end stages of cell, damage. These targeted functions and structures include the plasmalemma, the mitochondria, the cytoskeleton, protein synthesis, and kinase activities. The fourth stage is the progression to the morphological and biochemical end stages of cell death. Of these four stages, the last two are the least well understood. Quite little is known of how the perpetrators affect the structures and functions and whether and how each of these changes contribute to cell death. According to this description, the key step in ischemic cell death is adequate activation of the perpetrators, and thus a major unifying thread of the review is a consideration of how the changes occurring during and after ischemia, including gene activation and synthesis of new proteins, conspire to produce damaging levels of free radicals and peroxynitrite, to activate calpain and other Ca2+-driven processes that are damaging, and to initiate the apoptotic process. Although it is not fully established for all cases, the major driving force for the necrotic cell death process, and very possibly the other processes, appears to be the generation of free radicals and peroxynitrite. Effects of a large number of damaging changes can be explained on the basis of their ability to generate free radicals in early or late stages of damage. Several important issues are defined for future study. These include determining the triggers for apoptosis and autophagocytosis and establishing greater confidence in most of the cellular changes that are hypothesized to be involved in cell death. A very important outstanding issue is identifying the critical functional and structural changes caused by the perpetrators of cell death. These changes are responsible for cell death, and their identity and mechanisms of action are almost completely unknown.
