Delayed administration of alpha-difluoromethylornithine prevents hippocampus-dependent cognitive impairment after single and combined injury in mice.
Delayed administration of alpha-difluoromethylornithine prevents hippocampus-dependent cognitive impairment after single and combined injury in mice.
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DOI：
10.1667/rr13753.1
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发表时间：
2014-11
影响因子：
3.4
通讯作者：
Fike JR
中科院分区：
文献类型：
--
作者：
Allen AR;Eilertson K;Sharma S;Baure J;Allen B;Leu D;Rosi S;Raber J;Huang TT;Fike JR
由于放射性恐怖主义和军事情况而造成的辐射照射对平民人口构成持续的威胁。在不受控制的辐射事件中，可能会涉及其他类型的损伤，包括创伤。虽然辐射复合损伤被认为是一个具有重大意义的领域，但总体而言，关于辐射与其他形式损伤之间相互作用的基本机制，或何种对策可有效缓解这种变化的信息仍然很少。本研究的目的是确定如果在暴露后24小时开始给药，二氟甲基鸟氨酸（DFMO）是否可以减少单一或联合损伤的不良反应。8周龄C57 BL/J6成年雄性小鼠接受4戈伊的137 Cs全身照射。照射后立即使用受控皮质撞击系统诱导单侧创伤性脑损伤。辐射后44天，在Morris水迷宫中测试动物的视皮层依赖性认知表现。在认知测试之后，动物被安乐死，并且它们的大脑被快速冷冻用于海马齿状回中的神经炎症（活化的小胶质细胞）和神经发生的生物化学评估。我们的数据表明，单一和复合损伤引起不同程度的视神经依赖性认知功能障碍，当给予24小时后创伤，DFMO治疗改善这些影响。包括神经发生和激活的小胶质细胞数量在内的细胞变化通常与认知变化无关。进一步的分析还显示，与媒介物处理的动物相比，DFMO增加了抗氧化剂硫氧还蛋白1和过氧化物氧还蛋白3的海马蛋白水平。虽然DFMO治疗后认知改善的机制尚不清楚，但这些结果构成了进一步开发DFMO作为改善创伤和放射联合损伤个体认知功能障碍风险的对策的基础。
Radiation exposure due to radiological terrorism and military circumstances are a continuing threat for the civilian population. In an uncontrolled radiation event, it is likely that there will be other types of injury involved, including trauma. While radiation combined injury is recognized as an area of great significance, overall there is a paucity of information regarding the mechanisms underlying the interactions between irradiation and other forms of injury, or what countermeasures might be effective in ameliorating such changes. The objective of this study was to determine if difluoromethylornithine (DFMO) could reduce the adverse effects of single or combined injury if administered beginning 24 h after exposure. Eight-week-old C57BL/J6 young-adult male mice received whole-body cesium-137 (137Cs) irradiation with 4 Gy. Immediately after irradiation, unilateral traumatic brain injury was induced using a controlled cortical impact system. Forty-four days postirradiation, animals were tested for hippocampus-dependent cognitive performance in the Morris water maze. After cognitive testing, animals were euthanized and their brains snap frozen for immunohisto-chemical assessment of neuroinflammation (activated microglia) and neurogenesis in the hippocampal dentate gyrus. Our data show that single and combined injuries induced variable degrees of hippocampus-dependent cognitive dysfunction, and when given 24 h post trauma, DFMO treatment ameliorated those effects. Cellular changes including neuro-genesis and numbers of activated microglia were generally not associated with the cognitive changes. Further analyses also revealed that DFMO increased hippocampal protein levels of the antioxidants thioredoxin 1 and peroxiredoxin 3 compared to vehicle treated animals. While the mechanisms responsible for the improvement in cognition after DFMO treatment are not yet clear, these results constitute a basis for further development of DFMO as a countermeasure for ameliorating the of risks for cognitive dysfunction in individuals subjected to trauma and radiation combined injury.