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 tensil e strain. Over thee ensuing several hours, injured axons enter a "pathologi cal cascade" of events that lead to secondary axotomy. Use of animal models of traumatic axonal injury (TAI) has allowed description of a number of pa thological changes before axotomy occurs, including structural and function al changes in the axolemma, disorientation, and/or loss of microtubules, ei ther compaction and/or dispersion of neurofilaments together with focal com paction at sites where continuity of the axolemma is lost. Recent literatur e suggests that use of hypothermia may improve behavioral outcomes or reduc e the number/density of injured axons in which axonal transport is altered after TAI. But there is presently no ultrastructural, pathological explanat ion as to how hypothermia may act at the level of the axon to reduce posttr aumatic loss of axoplasmic transport. In this study, we tested the hypothes is that posttraumatic hypothermia may ameliorate (a) alteration of axonal t ransport and (b) early pathological changes in the axonal cytoskeleton prio r to secondary axotomy. We have undertaken a pilot study within 4 h of stre tch injury to adult guinea pig optic nerve axons as a model of TAI and appl ied 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 hypo thermia significantly reduces the number of axons labelled for beta-APP, a marker for disruption of fast axonal transport, and reduces the loss of mic rotubules and compaction of neurofilaments, which occurs in normothermic an imals over the first 4 h after injury.