Conclusion

It is currently reasonably certain that not one, but a myriad of different cell death outcomes contribute to neuronal demise in the course of acute neuronal injuries. It is moreover generally accepted that these different death outcomes include both accidental (uncontrolled) and programmed (thus obviously controlled) modalities. It is also reasonably certain that excitotoxic cell death, induced by excessive release and accumulation of the excitatory neurotransmitter glutamate, represents a common determinant of various acute (and chronic) neurodegenerations. However, it is also clear that excitotoxicity cannot be considered as a synonym for acute neuronal injury, and that other factors (local accumulation of immune cells, release of the relevant signalling mediators by these cells, etc.) do contribute to brain damage in vivo.

This being said, it remains true that excitotoxicity is probably the main pathological component of the acute neuronal injury. A great amount of experimental evidence supports the view that excitotoxic neuronal death actually corresponds to a mixture of different cell death phenotypes, although the existence of excitotoxic cell death, stricto sensu, as a single entity corresponding to a peculiar form of cell death has also been proposed (Kroemer et al. 2005). However, to date there is no convincing experimental data to support the latter hypothesis. By contrast, as discussed here, different PCD modalities have been demonstrated to take part in neuronal demise in the course of acute injuries. These include caspase-independent phenotypes such as apoptosis-like and autophagic PCD and, probably to a lesser extent, caspase-dependent apoptosis.

In addition, the involvement of nonprogrammed cell death such as necrosis has been repeatedly and convincingly demonstrated by a number of morphological studies. In recent years, a novel concept has begun to emerge concerning necrosis in general. According to this new concept, at least part of the cell death outcomes that appear necrotic at the ultrastructural level might in fact be the end-point of a death programme designated as programmed necrosis. Although not yet tested, the assumption is that programmed necrosis also occurs in neurons. Morphological evidence (e.g. the absence of pronounced chromatin condensation) and biochemical (e.g. involvement of the effectors demonstrated to mediate programmed necrosis in cell lines such as Bax, calpain, AIF, and PARP-1) is in agreement with this assumption. Future studies are now required to assess them experimentally in different models of acute neuronal injuries. The task is very difficult to accomplish because the biochemical pathways underlying programmed necrosis remain poorly understood. This means that we have to work backwards from the described necrotic morphologies and attempt to discover and ascribe effectors responsible for the phenotypic expression to each of these morphologies seen in the acute neuronal injuries. It is very probable that the programmed necrosis that we have recently described in non-neuronal cells (Moubarak et al. 2007) will be unravelled in neurons dying in the course of acute injuries. It is moreover reasonable to postulate that this particular phenotype of programmed necrosis represents only the tip of the iceberg, as it was for caspase-dependent apoptosis, considered upon its discovery as the sole existing PCD. The efforts similar to those made in understanding molecular mechanisms of apoptosis at the time of its re-discovery by Kerr, Wylie, and Curie (Kerr et al. 1972) should now be oriented towards understanding the molecular mechanisms of programmed necrosis in general, and those occurring in neurons in particular. The goal is ambitious, but our hope is that the invested efforts will bring results as exciting as those obtained in the field of apoptosis. The understanding of the mechanisms of programmed necrosis would have a great impact not only in the domain of neurodegeneration, but probably in the fields of cancer and developmental diseases as well.

Acknowledgments We apologize to colleagues whose original work we could not cite owing to limitations of space. The authors wish to thank Marcela Segade for invaluable help. Our research is supported by institutional grants from Institut Pasteur and CNRS and by specific grants from Ligue Contre le Cancer and Association pour la Recherche sur le Cancer (ARC; contract n° 4043) to Santos A. Susin and joint INSERM/FRSQ cooperation programme to Slavica Krantic (France) and Remi Quirion (Canada).

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