Cytoskeletal derangements following traumatic brain injury: cellular mechanisms and therapeutical implications

Traumatic brain injury is the leading cause of mortality and morbidity among young adults. While recent studies in humans and experimental models of traumatic brain injury have well established a role for necrosis in traumatic cell damage, accumulating evidence now suggests that apoptosis may also be a prominent contributor. However, the precise mechanisms leading to neuronal and glial degeneration after traumatic brain injury are still poorly understood. During the study period of the research project P12287-MED funded by the Austrian Science Fund from November 1997 to November 2001 the Innsbruck Neurotrauma Research Laboratory has devoted considerable effort to investigating the contribution of different proteases to apoptotic cell degeneration following experimental traumatic brain injury in vivo. For example, studies of the funded research project have provided first evidence that Fas receptor and Fas ligand mediated mechanisms leading to apoptosis occur after traumatic brain injury in vivo and that the initiator caspase-8 is upregulated and processed in neurons and glia after traumatic brain injury in vivo. Further, it has been shown that brain trauma leads to the activation of the effector caspase-3. These results were the first to systematically examine the execution of the extrinsic apoptotic pathway after experimental brain trauma in vivo. Importantly, the generated data suggest a contributory role of activated caspase-8 and activated caspase-3 in traumatically induced neuronal and glial apoptotic degeneration. In summary, the conducted studies have advanced the understanding of CNS cell degeneration after experimental TBI and lay the necessary foundation for potential novel therapeutic interventions and, eventually, the improved management of the traumatically injured patient, so that the mortality, morbidity, and cost associated with CNS injury can be minimized.