| 黄国栋,罗鸣,屈晓飞,程彦磊,蔡茜,董晓荣,伍钢.电离辐射抑制海马区神经发生与放射性脑损伤认知损害的关系[J].中华放射医学与防护杂志,2013,33(2):113-118,123 |
| 电离辐射抑制海马区神经发生与放射性脑损伤认知损害的关系 |
| Relationship between impaired hippocampal neurogenesis and cognitive dysfunction induced by cranial radiation therapy |
| 投稿时间：2012-09-19 |
| DOI：10.3760/cma.j.issn.0254-5098.2013.02.001 |
| 中文关键词: 放射性脑损伤 海马 神经发生 小胶质细胞 炎性反应 |
| 英文关键词:Irradiation-induced brain injury Hippocampus Neurogenesis Microglia Inflammation |
| 基金项目:国家自然科学基金(30800283, 81172595);中国博士后科学基金(201104440);中国博士后科学基金面上项目(20100480905) |
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| 中文摘要: |
| 目的 研究放疗后海马区神经发生与小鼠放射性脑损伤认知损害的关系。方法 10 d龄C57BL/6J小鼠24只给予10 Gy 6MV X射线全脑照射,Morris水迷宫实验检测放射性脑损伤模型的建立。在照射后不同时间点(0.5、3、6、12、24、48、72 h,1、2、4、8、16、24周),取脑组织标本进行HE染色,观察海马区神经细胞的病理变化。免疫组织化学染色双皮质蛋白(DCX)、增殖细胞核抗原(PCNA)标记海马区神经发生水平,ED1标记小胶质细胞激活情况,TUNEL标记海马区神经细胞凋亡情况。采用Real-time PCR法检测脑组织TNF-α、IL-1β表达水平的变化;酶联免疫吸附法(ELISA)检测照射后不同时间点血浆TNF-α水平的变化。结果 照射后急性期表现为间质水肿,炎性细胞浸润,海马区齿状回神经细胞逐渐出现变性、坏死、凋亡,慢性期间质水肿消退,炎性细胞减少,海马齿状回出现细胞再生呈极性分布。受照后各时间点,DCX阳性细胞和PCNA阳性细胞较对照组均有不同程度减少(F=4.9~12.5,5.2~15.7,P<0.05),受照后ED1阳性细胞较对照组增多(F=20.8, P<0.05)。TUNEL标记凋亡神经元在放疗后6 h可见,于48 h达到峰值(F=15.1, P<0.05);照射后0.5 h,γ-H2AX焦点形成达到高峰(F=18.4, P<0.05),后逐渐减少。照射后脑组织TNF-α和IL-1β表达较对照组均有所增加(t=16.3、12.7,P<0.05);血浆 TNF-α照射后3 h开始升高,至1周达到峰值(F=10.5, P<0.05),随后逐渐降低。Morris水迷宫实验照射组和对照组相比,照后1、2、3 d两者差异无统计学意义,但随着时间的延长,4、5、6 d照射组躲避潜伏期较对照组延长(F=7.01、8.17、4.22, P<0.05)。结论 10 Gy全脑照射后,建立放射性脑损伤模型,发现海马区神经发生受到抑制和小胶质细胞激活可能是小鼠放射性脑损伤认知损害产生的原因之一。 |
| 英文摘要: |
| Objective To investigate the changes of hippocampal neurogenesis and cognitive dysfunction induced by cranial radiation therapy. Methods C57BL/6J mice aged 10 d were subjected to 10 Gy whole brain irradiation with 6 MV X-rays to develop irradiation-induced brain injury model. Morris water maze was designed to estimate spatial learning and memory. At different time post irradiation, brain tissue was removed to stain with hematoxylin-eosin for the pathological results.DCX and PCNA immunohistochemical staining was used to mark the level of neurogenesis in the hippocampus, and ED1 immunohistochemical staining to mark the activation of microglia. The TUNEL assay was used to assess the apoptotic neuron death in situ in the hippocampus. Real-time PCR was supplied to inspect the expression of TNF-α and IL-1β mRNA. Enzyme Linked Immunosorbent Assay (ELISA) was tested for the concentration of TNF-α in the plasma.Results Pathological studies demonstrated that radiation could induce interstitial edema, inflammatory cell infiltration, cell degeneration, necrosis, apoptosis in the acute phase, edema subsiding, reduction of inflammatory cells, and cytothesis in the dentate gyrus of the hippocampus. IHC studies revealed that, at different time post irradiation, the number of DCX-positive cells and PCNA-positive cells decreased(F=4.9-12.5,5.2-15.7,P<0.05) but ED1-positive cells increased significantly (F=20.8, P<0.05). TUNEL-positive cells began to appear in the dentate gyrus of hippocampus 6 h post-irradiation, and its number reached to the highest level at 48 h post-irradiation (F=15.1, P<0.05). The formation of γ-H2AX foci got at the top 0.5 h post-irradiation (F=18.4, P<0.05) and then decreased. After irradiation, the expressions of TNF-α and IL-1β mRNA in the the irradiated group was higher than those of the control group (t=16.3,12.7, P<0.05). The concentration of TNF-α in the plasma of the irradiated group was higer than that in the control group 3 h post-irradiation, and maximized at 1 week post-irradiation (F=10.5, P<0.05). Morris water maze tests showed that the latency had no significant differences between the irradiated group and the control group at 1, 2, 3 d post-irradiation, but the latency in the irradiated group was longer than that in the control group with a significant differences at 4, 5, 6 d post-irradiation (F=7.01, 8.17, 4.22, P<0.05).Conclusions Irradiation-induced cognitive dysfunction may be caused by microglial activation and suppression in hippocampal neurogenesis following cranial radiation therapy. |
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