Mechanisms underlying hypoxia-induced neuronal apoptosis

In vivo models of cerebral hypoxia-ischemia have shown that neuronal death may occur via necrosis or apoptosis. Necrosis is, in general, a rapidly occ urring form of cell death that has been attributed, in part, to alterations in ionic homeostasis. In contrast, apoptosis is a delayed form of cell dea th that occurs as the result of activation of a genetic program. In the pas t decade, we have learned considerably about the mechanisms underlying apop totic neuronal death following cerebral hypoxia-ischemia. With this growth in knowledge, we are coming to the realization that apoptosis and necrosis, although morphologically distinct, are likely part of a continuum of cell death with similar operative mechanisms. For example, following hypoxia-isc hemia, excitatory amino acid release and alterations in ionic homeostasis c ontribute to both necrotic and apoptotic neuronal death. However, apoptosis is distinguished from necrosis in that gene activation is the predominant mechanism regulating cell survival. Following hypoxic-ischemic episodes in the brain: genes that promote as well as inhibit apoptosis are activated. I t is the balance in the expression of pro- and anti-apoptotic genes that li kely determines the fate of neurons exposed to hypoxia. The balance in expr ession of pro- and anti-apoptotic genes may also account for the regional d ifferences in vulnerability to hypoxic insults. In this review, we will exa mine the known mechanisms underlying apoptosis in neurons exposed to hypoxi a and hypoxia-ischemia. (C) 2000 Elsevier Science Ltd. All rights reserved.