Focal axonal injury: the early axonal response to stretch

Abstract

The development of a model for axonal injury in the optic nerve of the guinea pig has allowed analysis of early morphological changes within damaged axons. We provide evidence that the initial site of damage after stretch is the nodes of Ranvier, some of which develop 'nodal blebs'. The development of nodel blebs is correlated with the loss of subaxolemmal density, disruption of the neurofilament cytoskeleton and aggregation of membranous profiles of smooth endoplasmic reticulum. Nodal blebs are numerous 15 min after injury but less so at later survivals. The glial-axonal junction is intact at early survivals in damaged nodes. Marked accumulation of membranous organelles occurs in the paranodal and internodal regions adjacent to damaged nodes between two and six hours and is correlated with disruption of the myelin sheath. Axotomy and the formation of degeneration bulbs occurs between 24 and 72 h. The area of axonal injury is invaded by phagocytic cells by 72 h and large numbers of myelin figures occur within the neuropil until 14 days. The results are compared with those of other studies of diffuse axonal injury and other neuropathies. The time course of axonal changes is more rapid than during Wallerian degeneration. Our data from longer surviving animals is exactly comparable with published data. We are confident that the principal site of axonal injury is the node of Ranvier. We suggest that damage at the node results in disruption of axonal transport, which in turn leads to a cascade of events, culminating in axotomy between 24 and 72 h after the initial insult.

Wallerian-like axonal degeneration in the optic nerve after excitotoxic retinal insult: an ultrastructural study

“…In response to excitotoxic perikaryal injury, this study found nodal changes in the form of bleb formation and abnormal accumulation of organelles in the paranodal region with no obvious myelin terminal loop retraction as early changes. These changes resembled the response observed after non-disruptive stretch injury, where accumulation of membranous organelles in the paranodal and internodal regions preceeded the nodal bleb formation related with loss of axolemmal undercoating [60]. …”

Electron tomographic analysis of cytoskeletal cross-bridges in the paranodal region of the node of Ranvier in peripheral nerves

“…Equally compelling support for an axo-glial integration of function is provided by the disruption of the myelin structure or maintenance of the glial cell in Charcot-Marie-Tooth disease, a set of human hereditary neuropathies (Bergoffen et al, 1993;Martini, 2001), causing changes in axonal morphology and nerve impulse conduction. Pathological conditions in peripheral neuropathies are also found when constituent proteins of the node of Ranvier malfunction (Bergoffen et al, 1993;Griffin et al, 1996;Rasband et al, 2003;Sima, 1993), are deficiently expressed (Bhat et al, 2001;Boyle et al, 2001;Sherman et al, 2005;Weber et al, 1999) or after axonal ischemic injury (Waxman et al, 1992) and trauma (Maxwell et al, 1991).…”

Therapy Development for Diffuse Axonal Injury

“…39,78,79 Owing, in part, to the isolated nature of the white matter injury, these models have proven very useful in evaluating ultrastructural changes in axons after trauma as well as identifying pathological chemical cascades that may represent important therapeutic targets. 34,39,47,[78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93] These models, however, are not widely used or practical for high-throughput therapy evaluation. Nonetheless, they represent a potential stepwise bridge between in vitro and in vivo therapy development.…”