Ischemic Preconditioning: Neuronal Survival in the Face of Caspase-3 Activation

Abstract

Apoptosis is an evolutionarily conserved process critical to tissue development and tissue homeostasis in eukaryotic organisms and, when dysregulated, causes inappropriate cell death. Global ischemia is a neuronal insult that induces delayed cell death with many features of apoptosis. Ischemic preconditioning affords robust protection of CA1 neurons against a subsequent severe ischemic challenge. The molecular mechanisms underlying ischemic tolerance are unclear. Here we show that ischemia induces pronounced caspase-3 activity in naive neurons that die and in preconditioned neurons that survive. Preconditioning intervenes downstream of proteolytic processing and activation of caspase-3 (a protease implicated in the execution of apoptosis) and upstream of the caspase-3 target caspase-activated DNase (CAD, a deoxyribonuclease that catalyzes DNA fragmentation) to arrest neuronal death. We further show that global ischemia promotes expression of the pro-survival inhibitor-of-apoptosis (IAP) family member cIAP, but unleashes Smac/DIABLO (second mitochondria-derived activator of caspases/direct IAP-binding protein with low pI), a factor that neutralizes the protective actions of IAPs and promotes neuronal death. Preconditioning blocks the mitochondrial release of Smac/DIABLO, but not the ischemiainduced upregulation of IAPs. In the absence of Smac/DIABLO, cIAP halts the caspase death cascade and arrests neuronal death. These findings suggest that preconditioning preserves the integrity of the mitochondrial membrane, enabling neurons to survive in the face of caspase activation.

Adenoviral expression of XIAP antisense RNA induces apoptosis in glioma cells and suppresses the growth of xenografts in nude mice

“…XIAP was proposed to be expressed by neurons and a sub-population of oligodendrocytes. 41 Global ischemia promoted the expression of cIAP2 42 and loss of XIAP expression was linked to neuronal loss in an animal model of motor neuron disease. 43 The clinical perspective of IAP antisense gene therapy depends on the differential requirement for IAP as survival factors in normal versus neoplastic cells.…”

Caspase‐3 activation in astrocytes following postnatal excitotoxic damage correlates with cytoskeletal remodeling but not with cell death or proliferation

“…Although the preponderance of data has emerged from work in the immune system and peripheral organs, several studies have also suggested non-apoptotic roles of caspase-3 in the CNS. Under physiological conditions, caspase-3 has been implicated in neuronal cytoskeletal changes (Rohn et al, 2004), in synaptic remodeling (Dash et al, 2000;Shimohama et al, 2001), in neuronal survival associated with preconditioning (Garnier et al 2003;McLaughlin et al, 2003;Tanaka et al, 2004), in the differentiation of cerebellar Bergmann glial cells (Oomman et al, 2004(Oomman et al, , 2005(Oomman et al, , 2006, and as a marker of astroglial subpopulations (Noyan-Ashraf et al, 2005). Accordingly, following excitotoxic damage in the neonatal brain we have demonstrated that presence of cleaved caspase-3 in nitrated reactive astrocytes in the absence of cell death (Acarin et al, 2005).…”

“…In addition, caspase-3 activation and substrate cleavage has been reported in the absence of cell death in gerbil hypoxia (Garnier et al, 2004) and in ischemic tolerance where neuronal caspase-3 is essential for the neuroprotective effect of preconditioning (Garnier et al 2003;McLaughlin et al, 2003;Tanaka et al, 2004). Furthermore, other studies have also demonstrated a role of caspase-3 in the maturation of cerebellar granular cells during development (Oomman et al, 2004) and the differentiation of neural progenitor cells in the olfactory bulb (Fernando et al, 2005;Yan et al, 2001).…”

Epigenetic Mechanisms in Cerebral Ischemia

“…HSP70, regarded as one of the key mediators of cell survival pathways, is known to interact with apoptotic protease-activating factor 1 (APAF) and apoptosis-inducing factor (AIF). 5 Under ischemic conditions, HSP70 is expressed, 105,106 however, its transcription is highly increased after treatment with diverse HDACi. 46,47,53,76,77,107 This increase seems to depend on the AKT pathway and the transcription factor SP1, of which HSP70 constitutes a target.…”