Late effects of radiation on the central nervous system: Role of vascular endothelial damage and glial stem cell survival
Late effects of radiation on the central nervous system: Role of vascular endothelial damage and glial stem cell survival
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DOI：
10.1667/rr3597.1
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发表时间：
2006-09-01
影响因子：
3.4
通讯作者：
van der Kogel, Albert J.
中科院分区：
文献类型：
--
作者：
Coderre, Jeffrey A.;Morris, Gerard M.;van der Kogel, Albert J.
在本研究中使用的大鼠脊髓的血管系统的选择性照射，这是专门设计来解决的问题，无论是内皮细胞或胶质祖细胞，是负责在中枢神经系统中的晚期白色物质坏死的目标。血管内皮的选择性照射是通过腹膜内（ip）给予硼化合物BSH（Na 2B 12 H11 SH），然后用热中子局部照射来实现的。已知血脑屏障将BSH从CNS实质中排除。在ip注射BSH后30分钟，血液中的硼浓度为100 μ g B-10/g，而CNS实质中的硼浓度低于硼分析系统的检测限，< 1 μ g B-10/g。O2 A（少突胶质细胞2型星形胶质细胞）胶质祖细胞存活的离体克隆形成测定在照射后1周和脊髓中白色物质坏死导致脊髓病之前的潜伏期期间的不同时间进行。单独4.5戈伊热中子照射后一周（约为产生50%放射性脊髓病发病率所需剂量的三分之一），平均神经胶质祖细胞存活分数为0.03。与BSH的热中子照射后的胶质祖细胞的存活分数为0.46，具有可比性的效果。在BSH存在下照射后高水平的胶质祖细胞存活清楚地反映了由于血脑屏障完全排除BSH而递送至实质的较低剂量。胶质祖细胞在被称为BPA（p-二羟基硼基-苯丙氨酸）的硼化合物的存在下用热中子照射后的中间反应，再次对于代表辐射诱导的脊髓病的ED 50的三分之一的剂量，反映了在照射时该化合物在血液和CNS实质之间的硼-10的差异分配，其穿过血脑屏障。在放射性脊髓病发展之前的4-5个月潜伏期内，由于选择性白色物质坏死，在放射后1周观察到的胶质祖细胞存活率的巨大差异在放射性脊髓病发展之前也得以维持，在放射性脊髓病的发生率较高的剂量照射后。胶质祖细胞的生存率与对照值相似，在100天后照射剂量的热中子在BSH的存在下，显着大于ED 100，脊髓病的发病前不久的正常时间。与此相反，胶质祖细胞存活率低于1%的控制水平照射后，与15戈伊的热中子单独。该剂量的热中子代表脊髓病的近似ED 90 -100。对等效剂量X射线（ED 90：23戈伊）辐照的反应介于这两个极端之间，因为在BPA存在的情况下，它对热中子的反应略低，相当于辐射性脊髓病的近似ED 60。从这些研究中得出的结论是，在剂量水平下进行的辐射诱导的脊髓病作为白色物质坏死的结果，是在胶质祖细胞存活率中观察到的巨大差异与实质中的剂量分布直接相关。这些观察结果清楚地表明，作为导致白色物质坏死的主要事件，剂量对血管内皮的相对重要性。(c)2006年，辐射研究协会。
Selective irradiation of the vasculature of the rat spinal cord was used in this study, which was designed specifically to address the question as to whether it is the endothelial cell or the glial progenitor cell that is the target responsible for late white matter necrosis in the CNS. Selective irradiation of the vascular endothelium was achieved by the intraperitoneal (ip) administration of a boron compound known as BSH (Na2B12H11SH), followed by local irradiation with thermal neutrons. The blood-brain barrier is known to exclude BSH from the CNS parenchyma. Thirty minutes after the ip injection of BSH, the boron concentration in blood was 100 mu g B-10/g, while that in the CNS parenchyma was below the detection limit of the boron analysis system, < 1 mu g B-10/g. An ex vivo clonogenic assay of the O2A (oligodendrocyte-type 2 astrocyte) glial progenitor cell survival was performed I week after irradiation and at various times during the latent period before white matter necrosis in the spinal cord resulted in myelopathy. One week after 4.5 Gy of thermal neutron irradiation alone (approximately one-third of the dose required to produce a 50% incidence of radiation myelopathy), the average glial progenitor cell surviving fraction was 0.03. The surviving fraction of glial progenitor cells after a thermal neutron irradiation with BSH for a comparable effect was 0.46. The high level of glial progenitor cell survival after irradiation in the presence of BSH clearly reflects the lower dose delivered to the parenchyma due to the complete exclusion of BSH by the blood-brain barrier. The intermediate response of glial progenitor cells after irradiation with thermal neutrons in the presence of a boron compound known as BPA (p-dihydroxyboryl-phenylalanine), again for a dose that represents one-third the ED50 for radiation-induced myelopathy, reflects the differential partition of boron-10 between blood and CNS parenchyma for this compound, which crosses the blood-brain barrier, at the time of irradiation. The large differences in glial progenitor survival seen 1 week after irradiation were also maintained during the 4-5-month latent period before the development of radiation myelopathy, due to selective white matter necrosis, after irradiation with doses that would produce a high incidence of radiation myelopathy. Glial progenitor survival was similar to control values at 100 days after irradiation with a dose of thermal neutrons in the presence of BSH, significantly greater than the ED100, shortly before the normal time of onset of myelopathy. In contrast, glial progenitor survival was less than 1% of control levels after irradiation with 15 Gy of thermal neutrons alone. This dose of thermal neutrons represents the approximate ED90-100 for myelopathy. The response to irradiation with an equivalent dose of X rays (ED90: 23 Gy) was intermediate between these extremes as it was to thermal neutrons in the presence of BPA at a slightly lower dose equivalent to the approximate ED60 for radiation myelopathy. The conclusions from these studies, performed at dose levels approximately iso-effective for radiation-induced myelopathy as a consequence of white matter necrosis, were that the large differences observed in glial progenitor survival were directly related to the dose distribution in the parenchyma.These observations clearly indicate the relative importance of the dose to the vascular endothelium as the primary event leading to white atter necrosis. (c) 2006 by Radiation Research Society.