In the above passages, we have focused upon the contemporary appreciation of the cellular and subcellular changes involved in diffuse axonal injury. Importantly, all these changes were believed to be ongoing only in myelinated nerve fiber populations with no involvement of unmyelinated axons that, in general, have received virtually no consideration either in the context of TBI (Jafari et al., 1998) or, for that matter, any other CNS disorder. Recently, however, this perception was changed by work conducted by Reeves et al. (2005) who, through the use of electrophysiological methods, provided compelling evidence for unmyelin-ated nerve fiber damage and dysfunction within the corpus callosum of traumatically brain-injured animals. Using an analysis of compound action potentials by examining two specific wave forms that can be independently related to either myelin-ated or unmyelinated axons populations, Reeves and colleagues showed significant and sustained depression of the compound action potentials associated with the unmyelinated axon population. These electrophysiological studies were accompanied by routine morphological analysis using electron microscopy. Although these studies were preliminary, they suggested that the morphological progression of unmyelinated fiber change observed was quite dissimilar from that described above for myelinated axons. This potential difference is also partially supported by excellent in vitro studies that have examined non-myelinated neurites subjected to mechanical strains that ultimately led to local axonal beading and disconnection (Wolf et al., 2001; Iwata et al., 2004). In this pathology, however, no evidence of overt axolemmal change or axolemmal disruption was discerned. Rather, the depolarization associated with this injury evoked sodium influx, the activation of voltage gated calcium channels and the concomitant activation of sodium/calcium exchangers, all of which contributed to local intraaxonal calcium overloading (Wolf et al., 2001). These calcium-mediated changes, comparable with some of the changes described in myelinated axons, were linked with the activation of proteases. These, in turn, contributed to subsequent proteolysis of its NaCh subunit to promote a persistent elevation in intracellular calcium, fueling additional pathological changes through many of the pathways addressed above (Iwata et al., 2004). While these changes obviously remain to be confirmed in vivo, they are intriguing and speak to yet another, different form of cellular and subcellular change that, in this case, involves a potential channelopathy as major player in the ensuing unmyelinated axonal perturbation.
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