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PL-01A PRECLINICAL JUVENILE RAT MODEL OF BRAIN INJURY AFTER FRACTIONATED WHOLE BRAIN IRRADIATION

机译:PL-01A分割全脑照射后脑损伤的临床前少年大鼠模型

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摘要

BACKGROUND: Late effects of radiotherapy in survivors of pediatric brain tumors are life-long and debilitating. We describe the behavior and imaging characteristics of a rat model given fractionated whole brain radiation equivalent to doses used to treat children with high-risk medulloblastoma. METHODS: One month-old Fischer rats were given 9 fractions of either 0 or 3 Gray (Gy). A third group was given eight 3Gy fractions followed by a single 10Gy “top off” to serve as a positive control. The 27Gy dose is biologically equivalent to 36Gy given to children. The open-field exploration task and the elevated plus maze were performed at 4 months post-irradiation. Declarative memory was tested by novel object recognition at 4- and 7-months post-irradiation. Magnetic resonance imaging, including diffusion tensor imaging (DTI) and spectroscopy (MRS), was obtained at baseline, 4-, and 7-months post-irradiation. RESULTS: 4 months post-irradiation, there were no differences in the open-field exploration task among the groups. Both the 27Gy (p = 0.002) and 34Gy (p = 0.04) groups demonstrated less exploration of the open arms of the elevated plus maze. There were no differences in novel object recognition at 4 months, but both irradiated groups demonstrated deficits by 7 months post-irradiation (p27 = 0.02, p34 = 0.02). Fractional anisotropy of the corpus callosum at 7 months post-irradiation was decreased only in the 34Gy group (p = 0.02) and not in the 27Gy group. N-acetyl aspartate remained higher than controls at 7-months post-irradiation in both hippocampus (p27 < 0.01, p34 < 0.03) and corpus callosum (p27 < 0.08, p34 < 0.04). CONCLUSIONS: This model of a juvenile rat given fractionated, clinically-relevant doses of radiation displays cognitive deficits described in survivors of medulloblastoma who have received radiotherapy. Imaging characteristics indicate a potential disruption of the normal developmental myelination by MRS that correlates with memory deficits and may be useful for evaluating novel therapeutic strategies of radiation mitigation.
机译:背景:放疗对小儿脑瘤幸存者的晚期作用是终生且使人衰弱的。我们描述了大鼠模型的行为和影像学特征,该模型具有全脑放射线等效的剂量,等同于用于治疗高危髓母细胞瘤儿童的剂量。方法:给一个月大的Fischer大鼠提供9份0或3份Gray(Gy)分数。第三组给予8个3Gy馏分,然后单次添加10Gy作为“阳性对照”。 27Gy剂量在生物学上等同于给予儿童的36Gy。野外探索任务和高架迷宫在照射后4个月进行。声明性记忆是在照射后4个月和7个月通过新颖的物体识别测试的。在基线后,照射后4个月和7个月获得磁共振成像,包括扩散张量成像(DTI)和光谱学(MRS)。结果:照射后4个月,各组之间的野外勘探任务没有差异。 27Gy(p = 0.002)和34Gy(p = 0.04)组都显示出对高架迷宫的张开臂​​的探索较少。在4个月时,新物体的识别没有差异,但是两个辐照组在辐照后7个月都显示出缺陷(p27 = 0.02,p34 = 0.02)。辐照后7个月(体的分数各向异性仅在34Gy组(p = 0.02)中降低,而在27Gy组中没有降低。照射后7个月,海马(p27 <0.01,p34 <0.03)和call体(p27 <0.08,p34 <0.04)的N-乙酰天门冬氨酸含量仍然高于对照组。结论:该模型的幼鼠接受了分次的,与临床有关的放射剂量,显示出接受放疗的髓母细胞瘤幸存者中描述的认知缺陷。成像特征表明,MRS可能破坏正常发育的髓鞘形成,与记忆缺陷相关,可用于评估减轻辐射的新治疗策略。

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