Necrosis is traditionally considered an externally wrought, unregulated cell death of which there are multiple causes and mechanisms of injury (e.g., excitotoxic swelling, energy failure, toxins, and free radical generation). Generally speaking, changes within the cytoplasm, such as organelle swelling, precede the appearance of nuclear alterations. Other prominent features include cell swelling and plasma membrane rupture (Trump et al. 1965). In contrast, apoptosis, described originally by Kerr and colleagues (Kerr 1971; Kerr et al. 1972), is a mode of cell death characterized by early nuclear changes, notably prominent chromatin condensation (crescent or round shape), while cytoplasmic organelles are still intact. In contrast to necrosis, which results in the release of cellular contents into the surrounding tissue, apoptotic cells condense and are broken up into large, membrane-bound vesicles (apoptotic bodies) for degradation by neighboring cells or phagocytes. The apoptotic morphology has been linked to distinct molecular pathways (e.g., caspase activation) and is a programmed cell death.
Cerebral ischemic injury has been traditionally thought to be necrotic with more recent reports claiming that at least some of it results from apoptosis (Brahma et al. 2009; Cao et al. 2007; Carboni et al. 2005; Hayashi et al. 2005; Nitatori et al. 1995; Ostrowski et al. 2008; Ruan et al. 2003; Zeng and Xu 2000). Some suggest that ischemic injury is neither apoptotic nor necrotic (Sheldon et al. 2001), according to the original meaning of these words. Several names for alternative cell death modes have been coined including oncosis (Majno and Joris 1995), paraptosis (Sperandio et al. 2000), parthanatos (Andrabi et al. 2008; David et al. 2009; Wang et al. 2009), and programmed necrosis (Boujrad et al. 2007). Since apoptosis is the biological counterforce of mitosis, one theoretically expects to find apoptosis in highly mitotic areas such as gut epithelium (Ikeda et al. 1998), but not in post-mitotic brain neurons.
Another potential route of cell death in ischemia is via autophagy, which has been more thoroughly described (Chu 2006; Kroemer and Levine 2008; Levine and Yuan 2005). Autophagy is a normal process for removing cellular constituents, including weak and damaged organelles. Like apoptosis, it is highly regulated, and free radicals play a major role in regulating autophagy, which is increased in injurious processes (Lai et al. 2008). Morphological features include the appearance of multi-membrane structures (autophagosomes) that fuse with lysosomes to form autolysosomes (e.g., mitochondrial autolysosomes). While excessive autophagy can cause cell death, it is important to remember that autophagy is a normal process to recycle cellular waste or to generate amino acids, etc. in times of cellular stress. Accordingly, the appearance of autophagy does not mean the cell has died by autophagy, or even that it has died. Indeed, the ischemic neuroprotection by hypothermia (Colbourne et al. 1999b) can cause, in long term surviving neurons, increased autophagy (see Figures 7-9 in that study). While each 'mode' of cell death described above has unique biochemical features, ultrastructural morphology remains indispensible to help distinguish between them.
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