Bench-to-bedside review: Apoptosis/programmed cell death triggered by traumatic brain injury

Abstract

Apoptosis, or programmed cell death, is a physiological form of cell death that is important for normal embryologic development and cell turnover in adult organisms. Cumulative evidence suggests that apoptosis can also be triggered in tissues without a high rate of cell turnover, including those within the central nervous system (CNS). In fact, a crucial role for apoptosis in delayed neuronal loss after both acute and chronic CNS injury is emerging. In the current review we summarize the growing evidence that apoptosis occurs after traumatic brain injury (TBI), from experimental models to humans. This includes the identification of apoptosis after TBI, initiators of apoptosis, key modulators of apoptosis such as the Bcl-2 family, key executioners of apoptosis such as the caspase family, final pathways of apoptosis, and potential therapeutic interventions for blocking neuronal apoptosis after TBI.

Figure 1

Simplified schematic representation of the initiation and regulation of neuronal apoptosis after traumatic brain injury (TBI). Pathologic mechanisms triggering apoptosis after TBI include ischemia, oxidative stress, energy failure, excitotoxicity (primarily excess glutamate), axonal injury, trophic factor withdrawal, ER stress, and/or death receptor-ligand binding (for example TNF, Fas). Regulation of apoptosis occurs through multiple pathways including kinase-dependent intracellular signaling pathways and Bcl-2 family proteins. Execution of apoptosis involves the caspase cascade and/or release of apoptogenic factors from organelles such as mitochondria and lysosomes. Ultimately DNA fragmentation, cytoskeletal disintegration, and externalization of membrane phosphatidylserine occurs, signaling macrophages and microglia to engulf cellular debris. Potential therapeutic targets discussed in this review are highlighted within the dashed yellow lines. AIF, apoptosis-inducing factor; Apaf-1, apoptotic protease activating factor-1; Bcl, B-cell lymphoma; CAD, caspase-activated deoxyribonuclease; casp, caspase; cyto c, cytochrome c; DISC, death-inducing signaling complex; Endo G, endonuclease G; ER, endoplasmic reticulum; iCAD, inhibitor of CAD; ROS, reactive oxygen species; tBid, truncated Bid; TNF, tumor necrosis factor; TNFR, TNF receptor; TRAF2, TNF receptor associated factor.