Axonal cytoskeletal responses to nondisruptive axonal injury and the short-term effects of posttraumatic hypothermia.
In human diffuse axonal injury (DAI), axons are exposed to transient tensile strain. Over the ensuing several hours, injured axons enter a "pathological cascade" of events that lead to secondary axotomy. Use of animal models of traumatic axonal injury (TAI) has allowed description of a number of pathological changes before axotomy occurs, including structural and functional changes in the axolemma, disorientation, and/or loss of microtubules, either compaction and/or dispersion of neurofilaments together with focal compaction at sites where continuity of the axolemma is lost. Recent literature suggests that use of hypothermia may improve behavioral outcomes or reduce the number/density of injured axons in which axonal transport is altered after TAI. But there is presently no ultrastructural, pathological explanation as to how hypothermia may act at the level of the axon to reduce posttraumatic loss of axoplasmic transport. In this study, we tested the hypothesis that posttraumatic hypothermia may ameliorate (a) alteration of axonal transport and (b) early pathological changes in the axonal cytoskeleton prior to secondary axotomy. We have undertaken a pilot study within 4 h of stretch injury to adult guinea pig optic nerve axons as a model of TAI and applied stereological techniques to assess differences in pathology in animals either maintained at 37.5 degrees C or cooled to 32-32.5 degrees C for 2 or 4 h after injury. We provide quantitative evidence that posttraumatic hypothermia significantly reduces the number of axons labelled for beta-APP, a marker for disruption of fast axonal transport, and reduces the loss of microtubules and compaction of neurofilaments, which occurs in normothermic animals over the first 4 h after injury.
Maxwell
W L
WL
Laboratory of Human Anatomy, Institute of Biomedical and Life Sciences, University of Glasgow, United Kingdom. W.Maxwell@bio.gla.ac.uk
Donnelly
S
S
Sun
X
X
Fenton
T
T
Puri
N
N
Graham
D I
DI
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D003599:Cytoskeleton / Q000502:physiology* / Q000648:ultrastructure; D006168:Guinea Pigs; D007036:Hypothermia, Induced; D007150:Immunohistochemistry; D008854:Microscopy, Electron; D008870:Microtubules / Q000648:ultrastructure; D020221:Optic Nerve Injuries / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D013997:Time Factors
D016564:Amyloid beta-Protein Precursor