Mechanisms underlying cell death have been categorized under two broad processes, namely passive or active (the latter also referred to as ‘programmed’ or ‘regulated cell death’) (1). As summarized by Galluzzi et al.32, the former commonly results from exposure to external events such as excessive temperatures, shear forces and/or pressures, and reflects mechanical disassembly of cellular constituents not involving molecular machinery. This cellular response is referred to as necrosis, and as stated by Edinger and Thompson33, is the end result of a bioenergetic catastrophe to a level incompatible with cell survival. Disruption of the plasma membrane induces cellular contents to escape to the extracellular space, evoking an inflammatory response. Apoptosis was the initial example of regulated cell death, involving a genetically programmed cell death that does not evoke a secondary inflammatory response. Now recognized are an array of regulated cell death processes, i.e., involving molecular mechanisms, many of which have now been demonstrated to contribute to OL death in experimental or in vitro models, and are being implicated in the MS disease process (Fig. 1). This category now also includes injury mechanisms that result in the features of cell necrosis described above.
