Intensity-and interval-specific repetitive traumatic brain injury can evoke both axonal and microvascular damage

In the experimental setting several investigators have recently reported exacerbations of the burden of axonal damage and other neuropathological changes following repetitive traumatic brain injuries (TBI) that were sustained at intervals from hours to days following the initial insult. These same studies also revealed that prolonging the interval between the first and second insult led to a reduction in the burden of neuropathological changes and/or their complete elimination. Although demonstrating the capability of repetitive TBI to evoke increased axonal and other neuropathological changes, these studies did not address the potential for concomitant microvascular dysfunction or damage, although vascular dysfunction has been implicated in the second-impact syndrome. In this study we revisit the issue of repetitive injury in a well-controlled animal model in which the TBI intensity was bracketed from subthreshold to threshold insults, while the duration of the intervals between the injuries varied. Employing cranial windows to assess vascular reactivity and post-mortem amyloid precursor protein (APP) analysis to determine the burden of axonal change, we recognized that subthreshold injuries, even when administered in repeated fashion over a short time frame, evoked neither axonal nor vascular change. However, with an elevation of insult intensity, repetitive injuries administered within 3-h time frames caused dramatic axonal damage and significant vascular dysfunction bordering on a complete loss of vasoreactivity. If, however, the interval between the repetitive injury was extended to 5 h, the burden of axonal change was reduced, as was the overall magnitude of the ensuing vascular dysfunction. With the extension of the interval between injuries to 10 h, neither axonal nor vascular changes were found. Collectively, these studies reaffirm the existence of significant axonal damage following repetitive TBI administered within a relatively short time frame. Additionally, they also demonstrate that these axonal changes parallel changes in the cerebral microcirculation, which also may have adverse consequences for the injured brain

Evidence for the therapeutic efficacy of either mild hypothermia or oxygen radical scavengers after repetitive mild traumatic brain injury

Repetitive brain injury, particularly that occurring with sporting-related injuries, has recently garnered increased attention in both the clinical and public settings. In the laboratory, we have demonstrated the adverse axonal and vascular consequences of repetitive brain injury and have demonstrated that moderate hypothermia and/or FK506 exerted protective effects after repetitive mild traumatic brain injury (mTBI) when administered within a specific time frame, suggesting a range of therapeutic modalities to prevent a dramatic exacerbation. In this communication, we revisit the utility of targeted therapeutic intervention to seek the minimal level of hypothermia needed to achieve protection while probing the role of oxygen radicals and their therapeutic targeting. Male Sprague-Dawley rats were subjected to repetitive mTBI by impact acceleration injury. Mild hypothermia (35°C, group 2), superoxide dismutase (group 3), and Tempol (group 4) were employed as therapeutic interventions administered 1 h after the repetitive mTBI. To assess vascular function, cerebral vascular reactivity to acetylcholine was evaluated 3 and 4 h after the repetitive mTBI, whereas to detect the burden of axonal damage, amyloid precursor protein (APP) density in the medullospinal junction was measured. Whereas complete impairment of vascular reactivity was observed in group 1 (without intervention), significant preservation of vascular reactivity was found in the other groups. Similarly, whereas remarkable increase in the APP-positive axon was observed in group 1, there were no significant increases in the other groups. Collectively, these findings indicate that even mild hypothermia or the blunting free radical damage, even when performed in a delayed period, is protective in repetitive mTBI

Therapeutic targeting of the axonal and microvascular change associated with repetitive mild traumatic brain injury

Recent interest in mild traumatic brain injury (mTBI) has increased the recognition that repetitive mTBI occurring within the sports and military settings can exacerbate the adverse consequences of the initial injury. While multiple studies have recently reported the pathological, metabolic, and functional changes associated with repetitive mTBI, no consideration has been given to the development of therapeutic approaches to attenuate these abnormalities. In this study, we used the model of repetitive impact acceleration insult previously reported by our laboratory to cause no initial structural and functional changes, yet evoke dramatic change following second insult of the same intensity. Using this model, we employed established neuroprotective agents including FK506 and hypothermia that were administered 1 h after the second insult. Following either therapeutic intervention, changes of cerebral vascular reactivity to acetylcholine were assessed through a cranial window. Following the completion of the vascular studies, the animals were prepared to access the numbers of amyloid precursor protein (APP) positive axons, a marker of axonal damage. Following repetitive injury, cerebral vascular reactivity was dramatically preserved by either therapeutic intervention or the combination thereof compared to control group in which no intervention was employed. Similarly, APP density was significantly lower in the therapeutic intervention group compared in controls. Although the individual use of FK506 or hypothermia exerted significant protection, no additive benefit was found when both therapies were combined. In sum, the current study demonstrates that the exacerbated pathophysiological changes associated with repetitive mTBI can be therapeutically targeted