Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology , Gothenburg , Sweden.
Int J Radiat Biol. 2014 Sep;90(9):807-15. doi: 10.3109/09553002.2014.942015. Epub 2014 Aug 11.
Cranial radiotherapy is an important tool in the cure of primary brain tumors. Unfortunately, it is associated with late-appearing toxicity to the normal brain tissue, including cognitive impairment, particularly in children. The underlying mechanisms are not fully understood but involve changes in hippocampal neurogenesis. Recent studies report essentially different responses in the juvenile and the adult brain after irradiation, but this has never been verified in a comparative study.
We subjected juvenile (9-day-old) and adult (6-month-old) male rats to a single dose of 6 Gray (Gy) whole brain irradiation and euthanized them 6 hours, 7 days or 4 weeks later. Hippocampal lysates were analyzed for caspase-3 activity (apoptosis) and the expression of cytokines, chemokines and growth factors. Four weeks after irradiation, the number of microglia (expressing ionized calcium-binding adapter molecule 1, Iba-1), activated microglia (expressing cluster of differentiation 68 [CD68]), bromodeoxyuridine (BrdU) incorporation and granule cell layer (GCL) volume were assessed.
The major findings were (i) higher baseline BrdU incorporation (cell proliferation) in juvenile than in adult controls, which explains the increased susceptibility to irradiation and higher level of acute cell death (caspase activity) in juvenile rats, leading to impaired growth and subsequently a smaller dentate gyrus volume 4 weeks after irradiation, (ii) more activated (CD68-positive) microglia in adult compared to juvenile rats, regardless of irradiation, and (iii) differently expressed cytokines and chemokines after cranial irradiation in the juvenile compared to the adult rat hippocampus, indicating a more pro-inflammatory response in adult brains.
We found essentially diverse irradiation reactions in the juvenile compared to the adult hippocampus, indicating different mechanisms involved in degeneration and regeneration after injury. Strategies to ameliorate the cognitive deficits after cranial radiotherapy should therefore likely be adapted to the developmental level of the brain.
颅放射治疗是治疗原发性脑肿瘤的重要手段。不幸的是，它会导致正常脑组织出现迟发性毒性，包括认知障碍，尤其是在儿童中。其潜在机制尚未完全阐明，但涉及海马神经发生的变化。最近的研究报告称，在照射后，幼年和成年大脑的反应本质上不同，但这在比较研究中从未得到验证。
我们将幼年（9 天大）和成年（6 个月大）雄性大鼠接受单次 6 戈瑞（Gy）全脑照射，并在 6 小时、7 天或 4 周后处死。海马裂解物用于分析半胱氨酸天冬氨酸蛋白酶-3 活性（细胞凋亡）和细胞因子、趋化因子和生长因子的表达。照射后 4 周，评估小胶质细胞（表达离子钙结合接头分子 1，Iba-1）、活化小胶质细胞（表达分化簇 68 [CD68]）、溴脱氧尿苷（BrdU）掺入和颗粒细胞层（GCL）体积。
主要发现包括：（i）幼年对照组比成年对照组有更高的基线 BrdU 掺入（细胞增殖），这解释了幼年大鼠对照射的易感性增加和更高水平的急性细胞死亡（半胱氨酸天冬氨酸蛋白酶活性），导致生长受损，随后照射后 4 周时齿状回体积减小，（ii）成年大鼠比幼年大鼠的活化（CD68 阳性）小胶质细胞更多，无论是否照射，以及（iii）幼年和成年大鼠海马照射后表达不同的细胞因子和趋化因子，表明成年大脑中存在更具炎症反应性的反应。
我们发现幼年海马与成年海马相比，照射反应本质上不同，表明损伤后退化和再生涉及不同的机制。因此，改善颅放射治疗后认知障碍的策略可能需要适应大脑的发育水平。
