Apoptotic and Necrotic Death Mechanisms Are Concomitantly Activated in the Same Cell After Cerebral Ischemia

Abstract

Background and Purpose-Both necrotic and apoptotic cell death mechanisms are activated after cerebral ischemia.However, whether they are concomitantly active in the same cell or in discrete cell populations is not known. Methods-We investigated activation of both pathways at the cellular level in mice brains subjected to transient or permanent focal ischemia. Results-Four hours after ischemia, diffuse cathepsin-B spillage into cytoplasm, suggesting lysosomal leakage, was observed within neurons immunoreactive for the active form of caspase-3 (p20). Ischemic neurons with a leaky plasma membrane (positive for propidium iodide) were colabeled with caspase-cleaved actin fragment and exhibited TUNEL-positive nuclei having apoptotic morphology. At 72 hours, up to 27% of cells with caspase activity displayed morphological features suggestive of secondary necrosis. Conclusions-These data, demonstrating an early and concurrent increase in caspase-3 and cathepsin-B activities followed by appearance of caspase-cleavage products, DNA fragmentation, and membrane disintegration, suggest that subroutines of necrotic and apoptotic cell death are concomitantly activated in ischemic neurons and that the dominant cell death phenotype is determined by the relative speed of each process.

Normobaric Hyperoxia Delays Perfusion/Diffusion Mismatch Evolution, Reduces Infarct Volume, and Differentially Affects Neuronal Cell Death Pathways after Suture Middle Cerebral Artery Occlusion in Rats

“…In general, necrosis predominates in the severely stressed core area, whereas neuronal apoptosis is concentrated in the less severely inflicted border zone of the ischemic territory (Unal-Cevik et al, 2004), and it may be argued that peripheral areas of the ischemic lesion may benefit the most from NBO therapy. Indeed, in this study, a significant cytoprotective effect (i.e., decreased selective neuronal death) in the ischemic penumbra but not the core was observed as indicated by ISEL staining.…”

Caspase-independent pathways of hair cell death induced by kanamycin in vivo

“…The coexistence of multiple cell death mechanisms in the same tissue is not uncommon and may even occur in the same cell population. 38 A most painstaking morphological day-by-day evaluation of kanamycin ototoxicity 39 suggested the occurrence of both apoptotic and necrotic features. Following chronic aminoglycoside treatment Nakagawa et al 40 did not see apoptotic labels at the primary site of aminoglycoside toxicity, namely the basal turn of the cochlea.…”

Cortical Fluoro-Jade Staining and Blunted Adrenomedullary Response to Hypoglycemia after Noncoma Hypoglycemia in Rats

“…We did not detect labeled cells after hypoglycemic insult by using immunohistochemical probes of caspase and calpain pathways. However, these do not represent the only modes of neuron death as cathepsins are also implicated in neuron death, for example, after cerebral ischemia (Seyfried et al, 1997;Hill et al, 1997;Ü nal-Çevik et al, 2004). Because the number of dying cells is small in this model, it is not likely that methods for quantifying neuron loss (such as Nissl staining) will detect significant depletion of neurons.…”