As noted above, there is currently no direct evidence for the involvement of programmed necrosis in neuronal death. However, indirect evidence suggests that at least some of the necrotic phenotypes observed in dying neurons might turn to be programmatic rather than accidental. Before discussing this evidence, it has to be stressed that clear distinction of programmed necrosis among other types of programmed cell death outcomes is further complicated by the fact that even apoptosis, triggered by pathological insults in adult neurons, can display some clearly necrotic features. The related morphologies seen in acutely injured neurons have been designated as atypical, hybrid cell death phenotypes because they present the characteristics of both apoptosis and necrosis in the single neuron (Unal-Cevik et al. 2004).
Among these atypical morphologies, absent or mild chromatin aggregation in irregular or reticular forms has been reported (Fukuda and Yamamoto 1999; Oo et al. 1996; Stadelmann et al. 1998; Liu et al. 2004; Strosznajder and Gajkowska 2006). In many instances, these morphologies are reminiscent of necrosis seen in DNA damage-triggered cell death in neuroblastoma cell lines (Daugas et al. 2000).
Moreover, some biochemical findings reveal the involvement of calpains (proteases implicated in programmed necrosis) in acute neuronal injury. Thus, it has been shown that there is calpain activation in a rat model of acute neurodegeneration such as status epilepticus (Araujo et al. 2005). In addition, the aberrant expression (or impaired activity) of calpains has been related with neuronal injuries seen in ischemia and strokes (Goll et al. 2003; Saez et al. 2006; Cao et al. 2007).
Finally, recent evidence points to the existence of a Bax-sensitive component of DNA damage-induced AIF translocation in campothecin treated neurons (Cheung et al. 2005). Furthermore, AIF-mediated DNA fragmentation in campothecin-induced cell death is TUNEL positive (Cheung et al. 2005), as is programmed necrosis in MEFs (Moubarak et al. 2007). The existence of a Bax-positive component of DNA-damage-induced AIF translocation combined with its TUNEL-positivity (Cheung et al. 2005), further suggests that programmed necrosis, similar to that characterized in MEFs (Moubarak et al. 2007), can be induced in neurons.
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