Abstract
Exposure to uncontrolled irradiation in a radiologic terrorism scenario, a natural disaster or a nuclear battlefield, will likely be concomitantly superimposed on other types of injury, such as trauma. In the central nervous system, radiation combined injury (RCI) involving irradiation and traumatic brain injury may have a multifaceted character. This may entail cellular and molecular changes that are associated with cognitive performance, including changes in neurogenesis and the expression of the plasticity-related immediate early gene Arc. Because traumatic stimuli initiate a characteristic early increase in polyamine metabolism, we hypothesized that treatment with the polyamine inhibitor alpha-difluoromethylornithine (DFMO) would reduce the adverse effects of single or combined injury on hippocampus structure and function. Hippocampal dependent cognitive impairments were quantified with the Morris water maze and showed that DFMO effectively reversed cognitive impairments after all injuries, particularly traumatic brain injury. Similar results were seen with respect to the expression of Arc protein, but not neurogenesis. Given that polyamines have been found to modulate inflammatory responses in the brain we also assessed the numbers of total and newly born activated microglia, and found reduced numbers of newly born cells. While the mechanisms responsible for the improvement in cognition after DFMO treatment are not yet clear, the present study provides new and compelling data regarding the potential use of DFMO as a potential countermeasure against the adverse effects of single or combined injury.
Highlights
Uncontrolled exposure to radiation presents challenges unlike those encountered in a clinical situation, i.e. radiotherapy
The results of this study showed that: a) single and combined injuries induced variable degrees of hippocampus-dependent cognitive dysfunction and DFMO treatment ameliorated those effects; b) measurements of the plasticity-related immediately early gene Arc were consistent with the cognitive findings; and c) neurogenesis per se may not be a critical factor in the changes in cognitive performance with or without DFMO
Given there are virtually no data available addressing the concept of combined radiation and traumatic brain injury and how factors associated with long term behavioral performance are affected in such a scenario, the present study provides new and compelling data regarding the potential use of DFMO in this context
Summary
Uncontrolled exposure to radiation presents challenges unlike those encountered in a clinical situation, i.e. radiotherapy. Radiation effects might be complicated by other types of injury (trauma, burns, infection, etc.) that either occur at the time of irradiation or at some time thereafter. While laboratory and some human data are available regarding whole body radiation exposure alone [2], there is a paucity of information regarding the magnitudes and mechanisms underlying the interactions between irradiation and other forms of injury, in the central nervous system (CNS), or if the resultant damage can be prevented or ameliorated. In the CNS, severe tissue injury generally occurs only after exposure to high radiation doses [3]. One type of injury that can be induced by relatively low doses of irradiation, and that may be exacerbated in a RCI scenario, is cognitive injury or deficits in behavioral performance. While the mechanisms responsible for such changes are not well understood, they are likely multifactorial and may involve altered neurogenesis [8,15,16,17,18] and the expression of the plasticity-related behaviorally-induced immediate early gene Arc (activity-regulated cytoskeleton-associated protein) [19,20]
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