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.