Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.
PLoS One. 2012;7(1):e31094. doi: 10.1371/journal.pone.0031094. Epub 2012 Jan 27.
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.
在放射恐怖主义情景、自然灾害或核战场上暴露于不受控制的辐射下，可能会同时叠加其他类型的损伤，如创伤。在中枢神经系统中，涉及辐射和创伤性脑损伤的辐射复合损伤（RCI）可能具有多方面的特征。这可能涉及与认知表现相关的细胞和分子变化，包括神经发生和可塑性相关即时早期基因 Arc 的表达变化。由于创伤性刺激会引发多胺代谢的特征性早期增加，我们假设使用多胺抑制剂α-二氟甲基鸟氨酸（DFMO）治疗会减轻单一或复合损伤对海马体结构和功能的不良影响。使用 Morris 水迷宫对海马体依赖的认知障碍进行量化，结果表明 DFMO 可有效逆转所有损伤后，特别是创伤性脑损伤后的认知障碍。Arc 蛋白表达也出现了类似的结果，但神经发生没有。鉴于多胺已被发现可调节大脑中的炎症反应，我们还评估了总激活和新生激活小胶质细胞的数量，并发现新生细胞数量减少。虽然 DFMO 治疗后认知改善的机制尚不清楚，但本研究提供了关于 DFMO 作为单一或复合损伤不良影响的潜在对策的新的、令人信服的数据。
