This application seeks continued support for a proposal that has focused on the diffuse neuronal, axonal, synaptic and vascular responses to traumatic brain injury (TBI). The focus of the previous application centered on the pathogenesis of traumatic axonal injury, grounded on the belief that TBI caused progressive, focal changes within the axon cylinder, resulting in impaired axonal transport, swelling and delayed disconnection. Various therapeutic approaches were shown protective, with success achieved with the use of the immunophilin ligands, cyclosporin A and FK506, and hypothermic intervention. It was posited that impaired axonal transport, swelling and disconnection constituted the full repertoire of axonal change post TBI. More recent studies, however, have demonstrated that this premise was oversimplistic, with TBI evoking other forms of axonal change involving focal intraaxonal cytoskeletal collapse and disconnection, independent of axonal swelling. Although it was assumed these pathologies occurred only in myelinated axons, unmyelinated axonal injury was also recently identified. In recognition of this now diverse axonal pathology, the current application seeks to critically revisit the specific pathogenesis of the above described diverse axonal pathologies and their specific therapeutic modulation. Discrete brain loci from TBI rats and mice will be followed to identify potential focal alterations in axolemmal permeability to extracellular tracers, together with focal intraaxonal markers of impaired transport, cysteine protease activity and calpain activation. Routine fluorescence microscopy will be used for qualitative and quantitative analyses, together with confocal microscopy, with subsequent computer-assisted EM analysis of the axonal segments showing specific tracer/immunoreactive change. These intraaxonal responses will be explored under normal, traumatic conditions as well as experimental modification of intracranial pressure (ICP). In terms of these complex intraaxonal pathologies and their potential ICP modification, hypothermia and immunophilin ligands will be used to determine their precise effects upon the specific types of TBI-induced axonal change. Lastly, these studies will be interfaced with parallel electrophysiological assessment of compound action potentials from the same brain regions. Collectively, these studies should provide information of both therapeutic and mechanistic importance, which should have relevance to several ongoing clinical trials.
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