Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Traumatic axonal injury (TAI) is associated with TBI and significantly contributes to its morbidity and mortality. Recent observations have demonstrated that TAI is not caused by the immediate rupture of the axon at the moment of injury. Rather it is the result of a slowly evolving sequence of pathological events leading to axonal disconnection thereby offering the potential for therapeutic intervention. Recent data from our lab suggests that calcium- indticed, calpain-mediated proteolytic modification of axolemmal permeability and the resultant calcium overload of damaged axonal segments are pivotally involved in the mitochondrial damage associated with TAI and they are also responsible for the enzymatic modification and disruption of the axonal cytoskeleton that leads to the halt of the axoplasmic transport, axonal swelling and disconnection. The goal of this application is to clarify the role of calpain-mediated proteolytic changes in the pathogenesis of the axolemmal/axonal damage while also evaluating the efficacy of therapeutic interventions targeting calpain activation, in TAI to disrupt the pathological cascade that leads to axonal disconnection. Using a well-characterized rodent model of inertial impact we will test whether the systemic administration of calpain-inhibitors prevents the axolemmal permeability changes precluding the uptake of horseradish peroxidase and fluorescent tracers. Utilizing different lightand electron microscopic double labeling approaches we also assess, whether calpain-inhibitors prevents downstream events associated with TAI such as the activation of the caspase death cascade and the accumulation of beta amyloid precursor protein, a marker of axonal disconnection caused by cytoskeletal alterations. Using immunohistochemistry and immunoblot-techniques assisted by digital image analysis and statistical data-comparison we will compare the relative efficacy of a cell-permeable selective calpain inhibitor in the prevention of calpain- and caspase-mediated breakdown of the structural protein spectrin, a constituent of the subaxolemmal network while also assessing the motor/behavioral effects of such interventions. Not only should the work proposed lead to better understanding of the pathobiology of traumatically induced axonal injury but also may prove helpful for designing more rational and effective therapeutic interventions for traumatic brain injury and axonal damage.
| Tamas, Andrea; Zsombok, Andrea; Farkas, Orsolya et al. (2006) Postinjury administration of pituitary adenylate cyclase activating polypeptide (PACAP) attenuates traumatically induced axonal injury in rats. J Neurotrauma 23:686-95 |
| Buki, A; Povlishock, J T (2006) All roads lead to disconnection?--Traumatic axonal injury revisited. Acta Neurochir (Wien) 148:181-93; discussion 193-4 |
| Buki, A; Farkas, O; Doczi, T et al. (2003) Preinjury administration of the calpain inhibitor MDL-28170 attenuates traumatically induced axonal injury. J Neurotrauma 20:261-8 |
