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Abstract

Cerebral ischemia initiates a program of cell death known as apoptosis. Early steps in these death promoting events are the release of cytochrome c from the mitochondria and activation of caspase-9. The purpose of this report is to determine if the administration of a specific caspase-9 inhibitor, Z-Leu-Glu(Ome)-His-Asp(Ome)-FMK x TFA (Z-LEHD-FMK) would attenuate apoptosis and the resultant brain injury after ischemia. Adult Wistar rats underwent 3 h of temporary middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion. An intraventricular injection of 4.8 microg of Z-LEHD-FMK was given 15-min postreperfusion. Administration of the caspase-9 inhibitor, Z-LEHD-FMK, to the experimental group (n = 12) reduced total infarction volume by 49% (p < 0.05) and improved neurological outcome by 63% (p < 0.01) as compared to the control group (n = 12). Western blot analysis of animals that underwent ischemia-reperfusion showed the appearance of the active form of caspase-9. Inhibition of caspase-9, the apical caspase in cytochrome-c-dependent apoptosis, is an effective intervention to attenuate neurological injury after focal ischemia.

p53 activation and mitochondria-mediated pathway are involved during hanging death-induced neuronal cell apoptosis in dentate gyrus region of the rat brain

“…In the present study, HD increased number of Bax positive neuronal cells and cytochrome c concentration in a time-dependent manner during initial period (1–6 h) as compare to their respective CD groups. Similarly, an increase of cytochrome c concentration and neuronal cell apoptosis have been reported during global brain ischemia induced by other methods (Mouw et al 2002; Krajewski et al 1999; Plesnila 2004). Taken together, these data suggest that HD induced p53 activation, overexpression of Bax protein and increased cytochrome c concentration during HD-induced neuronal cell apoptosis.…”

“…The increased cytosolic cytochrome c level initiates apoptotic signals in neuronal cells (Endo et al 2006) but the downstream pathway after global brain ischemia remains to be elucidated. However, few studies indicate that the cytochrome c binds to apoptotic factor-1 (Apaf-1) leading to the recruitment and activation of procaspase-9 (Krajewski et al 1999; Mouw et al 2002; Plesnila 2004). As a result, procaspase-9 auto processes and cleaves the procaspase-3 (Namura et al 1998; Ferrer et al 2003; Chan 2004).…”

Carbon Monoxide Modulates Fas/Fas Ligand, Caspases, and Bcl-2 Family Proteins via the p38α Mitogen-activated Protein Kinase Pathway during Ischemia-Reperfusion Lung Injury

“…There is significant evidence for the pivotal role of apoptosis in the pathogenesis of I-R organ injury (6,7,22). Strategies to attenuate I-R-induced apoptosis will expand the currently limited therapeutic options.…”

“…There is increasing evidence that apoptosis plays an important role in the pathogenesis of I-R injury in a variety of organs such as brain (1), heart (2), kidney (3), liver (4), and lung (5). More importantly, inhibiting apoptosis during I-R injury is associated with improved survival and organ function (6,7). Unlike necrosis, apoptosis is a regulated cell death process involving specific pathways and cellular components.…”

Mitochondrial Mechanisms of Neuroglobin’s Neuroprotection

“…For example, specific inhibitors for caspase-3 and caspase-9 ameliorated brain tissue loss and improved neurological outcomes in rat or mice stroke models [93–95]. It is reasonable to assume that a strategy targeting upstream regulators of mitochondria-mediated cell death pathway would provide better neuroprotection than targeting downstream regulators.…”