The presence of diffuse axonal injury (DAI) is a consistent feature of traumatic brain injury (TBI). DAI is a major cause of poor clinical outcome, with the overall magnitude and distribution of DAI related to increased morbidity following TBI (Adams et al., 2000; Graham et al., 1995; Medana and Esiri, 2003). Traumatic axonal injury (TAI) is becoming increasingly recognized as the most common structural basis of the broad range of persistent disabilities associated with TBI (Graham et al., 1995; Jennett et al., 1975). For these reasons, the overall goal of this dissertation was to extend our understanding of the underlying pathobiology of TAI by first defining using quantitative measures, the heterogeneous response of axons to injury. Utilizing these data, we then extended our understanding of current therapies aimed at attenuating the structural changes that occur in axons following TBI. Finally, we explored the molecular mechanisms that define these changes and investigate the role of Ca2+-mediated changes in traumatic axonal injury specifically involving calpain and caspase.; Previously, TAI was thought to cause intra-axonal changes that consistently lead to local intra-axonal cytoskeletal disruption involving neurofilament compaction (NFC) and impaired axonal transport (IAT). It was assumed that NFC always translated into concomitant upstream IAT, subsequent swelling and bulb formation (Maxwell et al., 1997; Maxwell et al., 2003; Povlishock et al., 1992; Povlishock, 1992; Povlishock, 1993; Povlishock and Christman, 1995; Saatman et al., 1998; Smith et al., 1999). In Chapter 2, we have provided strong evidence in contrary to this belief. Our data reveals that not all traumatically injured axons undergo the traditionally described sequence of axonal demise, involving the focal impairment of AT, swelling, with consequential development of large reactive bulbs culminating in disconnection of the proximal shaft of the axon. Alternatively, the results support that TBI results in multiple populations of morphogically distinct damaged axons that exhibit altered membrane permeability with concomitant dramatic cytoskeletal alterations in the absence of subsequent IAT and bulb formation. We show that in the majority of traumatically injured axons, overt cytoskeletal disruption involving NFC does not typically lead to local IAT (Marmarou et al., 2005; Stone et al., 2001). Our data demonstrates that there appears to be at least two differential axonal responses to injury, one associated with IAT and the other overt cytoskeletal collapse. (Abstract shortened by UMI.)
展开▼
