Discovery of Harlequin (Hq) mice bearing a mutation in AIF gene, which results in 80% reduction of the normal AIF expression (Klein et al. 2002), brought a valuable model to study the involvement of AIF in neuronal cell death. Thus, the fact that decreased expression of AIF in Hq mice confers neuroprotection to cortical neurons exposed to glutamate in vitro provided a direct evidence for the causal involvement of apoptosis-like, AIF-dependent PCD in neuronal death, with obvious implications for the acute neuronal injuries (Cheung et al. 2005). Currently, it is, however, clear that AIF-mediated neuronal death by apoptosis-like PCD can be triggered concomi-tantly with classical apoptosis (see discussion in section "Excitotoxic Neuronal Death and Programmed Necrosis in Acute Injuries"). Indeed, ceramide, which accumulates in neurons in a variety of acute (and chronic) neurodegenerative processes, has the capacity to induce the mitochondrial release of AIF in conjunction with other, classical apoptosis-associated mitochondrial proteins (cytochrome c, Omi/HtrA2, or Smac/ DIABLO) (Stoica et al. 2005). This complexity makes it difficult to clearly distinguish between caspase-dependent and -independent PCD outcomes in this particular paradigm, and also more broadly highlights the difficulties in accurately establishing the PCD phenotype(s) involved in response to a majority of cell death triggers.
Glutamate-induced PCD in cortical and CGN neurons has been defined as apoptosis-like PCD based on its insensitivity to caspase inhibitors and AIF translocation to the nucleus (Cheung et al. 2005; Wang et al. 2004). Such apoptosis-like PCD involves mainly the NMDA type of glutamate receptors since NMDA antagonist (MK-801) has the capacity to inhibit it, at last in vitro (Cheung et al. 2005; Wang et al. 2004). Similarly, trophic factors like hepatocyte growth factor (HCG), capable of preventing NMDA- (Ishihara et al. 2005) or glutamate-induced AIF nuclear translocation (Niimura et al. 2006), also prevent neuronal death. Most importantly, both glutamate- and NMDA-triggered apoptosis-like PCD appears Bax-independent (in contrast to caspase-dependent apoptosis), since genetic ablation of Bax does not confer neuroprotection (Cheung et al. 2005; Miller et al. 1997; Dargusch et al. 2001). Such Bax-independence is an important finding as it provides a clear-cut criterion to distinguish between apoptosis and apoptosis-like PCD, at least in this particular model of neuronal death.
In addition to these in vitro data, excitotoxic neuronal death of an apoptosis-like type via NMDA receptor activation has been convincingly demonstrated in vivo in the following acute neuronal injuries: traumatic brain injury in rat (Zhang et al. 2002), ischemia in rat and mice (Zhu et al. 2003, 2006, 2007; Cao et al. 2003b) and stroke (Plesnila et al. 2004).
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