Cell death mechanisms and modulation in traumatic brain injury

Cell death after traumatic brain injury (TBI) is a major cause of neurological deficits and mortality. Understanding the mechanisms of delayed post-traumatic cell loss may lead to new therapies that improve outcome. Although TBI induces changes in multiple cell types, mechanisms of neuronal cell death have been the predominant focus. Recent work has emphasized the diversity of neuronal death phenotypes, which have generally been defined by either morphological or molecular changes. This diversity has led to confusing and at times contradictory nomenclature. Here we review the historical basis of proposed definitions of neuronal cell death, with the goal of clarifying critical research questions and implications for therapy in TBI. We believe that both morphological and molecular features must be used to clarify post-traumatic cell death and related therapeutic targets. Further, we underscore that the most effective neuroprotective strategies will need to target multiple pathways to reflect the regional and temporal changes underlying diverse neuronal cell death phenotypes.