Post-Acute Alterations in the Axonal Cytoskeleton after Traumatic Axonal Injury

Abstract

All previous analyses of axonal responses to traumatic axonal injury (TAI) have described the ultrastructure of changes in the cytoskeleton and axolemma within 6 h of injury. In the present study we tested the hypothesis that there are, in addition, ultrastructural pathological changes up to 1 week after injury. TAI was induced in the adult guinea pig optic nerve of nine animals. Three animals were killed at either 4 h, 24 h, or 7 days (d) after injury. Quantitative analysis of the number or proportion of axons within 0.5-micro m-wide bins showed an increase in the number of axons with a diameter of less than 0.5 micro m at 4 h, 24 h, and 7 d, the presence of lucent axons at 24 h and 7 d and that the highest number of injured axons occurred about half way along the length of the nerve. A spectrum of pathological changes occurred in injured fibers-pathology of mitochondria; dissociation of myelin lamellae but little damage to the axon; loss of linear register of the axonal cytoskeleton; differential responses between microtubules (MT) and neurofilaments (NF) in different sizes of axon; two different sites of compaction of NF; loss of both NF (with an increase in their spacing) and MT (with a reduction in their spacing); replacement of the axoplasm by a flocculent precipitate; and an increased length of the nodal gap. These provide the first ultrastructural evidence for Wallerian degeneration of nerve fibers in an animal model of TAI.

Therapy Development for Diffuse Axonal Injury

“…31,61 A similar focal loss of microtubules in injured axons has also been found after optic nerve stretch injury in the guinea pig as well as rat TBI models. 47,87,158,159 With the complete loss of microtubules, axonal transport is totally derailed, triggering unmitigated accumulation of the cargoes. In turn, the resulting swelling can lead to disconnection and degeneration.…”

Mechanical and cellular processes driving cervical myelopathy

“…Numerous studies have reproducibly demonstrated that axonal injury frequently occurs at sites of maximal mechanical stress and occurs as a series of recognized events: Myelin stretch injury, altered axolemmal permeability, calcium entry, cytoskeletal collapse, compaction of neurofilaments and microtubules, disruption of anterograde axonal transport, accumulation of organelles, axon retraction, bulb formation, and secondary axotomy [11,53,54] . There is clearly support for the contention that myelopathy increases in the presence of abnormal or excessive motion in the neck [55][56][57] .…”

Chronic Traumatic Encephalopathy as a Consequence of Repetitive Sports Head Injury: A Review

“…Disinhibition occurs as more frontal lobe involvement develops and degeneration in temporoparietal and occipital cortex results in visuospatial symptoms. Finally, in the late stages, degeneration of the substantia nigra causes Parkinsonian symptoms [7,[16][17].…”

“…CTE caused by repetitive mTBI continues to progress decades after the injuries have stopped indicating that once the cascades are initiated, they continue to execute their effects, and that, the longer the individual lives, the worse the symptoms [7,16]. The severity threshold of the brain injury that can initiate these progressive chronic neurodegenerative changes, as well as the frequency are still unknown.…”