Signaling of Cell Death and Cell Survival Following Focal Cerebral Ischemia: Life and Death Struggle in the Penumbra

Abstract

Focal ischemia by middle cerebral artery occlusion (MCAO) results in necrosis at the infarct core and activation of complex signal pathways for cell death and cell survival in the penumbra. Recent studies have shown activation of the extrinsic and intrinsic pathways of caspase-mediated cell death, as well as activation of the caspase-independent signaling pathway of apoptosis in several paradigms of focal cerebral ischemia by transient MCAO to adult rats and mice. The extrinsic pathway (cell-death receptor pathway) is initiated by activation of the Fas receptor after binding to the Fas ligand (Fas-L); increased Fas and Fas-L expression has been shown following focal ischemia. Moreover, focal ischemia is greatly reduced in mice expressing mutated (nonfunctional) Fas. Increased expression of caspase-1, -3, -8, and -9, and of cleaved caspase-8, has been observed in the penumbra. Activation of the intrinsic (mitochondrial) pathway following focal ischemia is triggered by Bax translocation to and competition with Bcl-2 and other members of the Bcl-2 family in the mitochondria membrane that is followed by cytochrome c release to the cytosol. Bcl-2 over-expression reduces infarct size. Cytochrome c binds to Apaf-1 and dATP and recruits and cleaves pro-caspase-9 in the apoptosome. Both caspase-8 and caspase-9 activate caspase-3, among other caspases, which in turn cleave several crucial substrates, including the DNA-repairing enzyme poly(ADP-ribose) polymerase (PARP), into fragments of 89 and 28 kDa. Inhibition of caspase-3 reduces the infarct size, further supporting caspase-3 activation following transient MCAO. In addition, caspase-8 cleaves Bid, the truncated form of which has the capacity to translocate to the mitochondria and induce cytochrome c release. The volume of brain infarct is greatly reduced in Bid-deficient mice, thus indicating activation of the mitochondrial pathway by cell-death receptors following focal ischemia. Recent studies have shown the mitochondrial release of other factors; Smac/DIABLO (Smac: second mitochondrial activator of caspases: DIABLO: direct IAP binding protein with low pI) binds to and neutralizes the effects of the X-linked inhibitor of apoptosis (XIAP). Finally, apoptosis-inducing factor (AIF) translocates to the mitochondria and the nucleus following focal ischemia and produces peripheral chromatin condensation and large-scale DNA strands, thus leading to the caspase-independent cell death pathway of apoptosis. Delineation of the pro-apoptotic and pro-survival signals in the penumbra may not only increase understanding of the process but also help to rationalize strategies geared to reducing brain damage targeted at the periphery of the infarct core.

Activation of Proinflammatory Caspases by Cathepsin B in Focal Cerebral Ischemia

“…Activation of proinflammatory caspases, such as caspase-1 and caspase-11, or its human counterpart, caspase-4, in ischemia, has been mainly associated with blood recirculation (Ferrer and Planas, 2003;Kang et al, 2000;Rothwell, 2003). We show here that caspase-11 is also activated in the early stages of infarction, in the absence of reperfusion of the damaged territory, and confirm previous results on caspase-1 (Benchoua et al, 2001).…”

Nuclear–cytoplasmic translocation of BARD1 is linked to its apoptotic activity

“…In the brain, no BARD1 expression can be found normally but maximum BARD1 expression is observed in the regions adjacent to the stroke induced by ischemia (IrmingerFinger et al, 2001), in the penumbra, where apoptosis has been described (Ferrer and Planas, 2003). Immunohistochemisty on mouse brain sections after ischemia demonstrates that the intracellular localization of BARD1 is rather cytoplasmic than nuclear (Figure 1b). )…”

Thinning, movement, and volume loss of residual cortical tissue occurs after stroke in the adult rat as identified by histological and magnetic resonance imaging analysis

“…Ultimately these activators lead to the release of cytochrome c, damage of the mitochondrial membrane, and the activation of caspases. Caspases can activate cytokines (Ferrer and Planas, 2003), exacerbating inflammatory responses in the penumbra, and also metabolize important DNA-repair enzymes (Le et al, 2002). This leads to the destruction of critical genetic information.…”