GSK-3β 抑制剂可预防小鼠脑辐射坏死。
A GSK-3β inhibitor protects against radiation necrosis in mouse brain.
机构信息
Department of Chemistry, Washington University, St. Louis, Missouri.
Department of Radiology, Washington University, St. Louis, Missouri.
出版信息
Int J Radiat Oncol Biol Phys. 2014 Jul 15;89(4):714-21. doi: 10.1016/j.ijrobp.2014.04.018.
PURPOSE
To quantify the effectiveness of SB415286, a specific inhibitor of GSK-3β, as a neuroprotectant against radiation-induced central nervous system (brain) necrosis in a mouse model.
METHODS AND MATERIALS
Cohorts of mice were treated with SB415286 or dimethyl sulfoxide (DMSO) prior to irradiation with a single 45-Gy fraction targeted to the left hemisphere (brain) using a gamma knife machine. The onset and progression of radiation necrosis (RN) were monitored longitudinally by noninvasive in vivo small-animal magnetic resonance imaging (MRI) beginning 13 weeks postirradiation. MRI-derived necrotic volumes for SB415286- and DMSO-treated mice were compared. MRI results were supported by correlative histology.
RESULTS
Mice treated with SB415286 showed significant protection from radiation-induced necrosis, as determined by in vivo MRI with histologic validation. MRI-derived necrotic volumes were significantly smaller at all postirradiation time points in SB415286-treated animals. Although the irradiated hemispheres of the DMSO-treated mice demonstrated many of the classic histologic features of RN, including fibrinoid vascular necrosis, vascular telangiectasia, hemorrhage, and tissue loss, the irradiated hemispheres of the SB415286-treated mice consistently showed only minimal tissue damage. These studies confirmed that treatment with a GSK-3β inhibitor dramatically reduced delayed time-to-onset necrosis in irradiated brain.
CONCLUSIONS
The unilateral cerebral hemispheric stereotactic radiation surgery mouse model in concert with longitudinal MRI monitoring provided a powerful platform for studying the onset and progression of RN and for developing and testing new neuroprotectants. Effectiveness of SB415286 as a neuroprotectant against necrosis motivates potential clinical trials of it or other GSK-3β inhibitors.
目的
定量评估 GSK-3β 特异性抑制剂 SB415286 对伽玛刀照射所致小鼠中枢神经系统（脑）坏死的神经保护作用。
方法和材料
采用伽玛刀对小鼠左侧大脑半球（脑）进行单次 45Gy 照射，照射前用 SB415286 或二甲基亚砜（DMSO）处理。采用非侵入性小动物活体磁共振成像（MRI），从照射后 13 周开始，对放射坏死（RN）的发生和进展进行纵向监测。比较 SB415286 和 DMSO 处理的小鼠的 MRI 衍生坏死体积。MRI 结果通过相关组织学进行验证。
结果
通过 MRI 与组织学验证发现，用 SB415286 处理的小鼠对放射诱导的坏死具有显著的保护作用。在 SB415286 处理的动物中，所有的 MRI 随访时间点上，MRI 衍生的坏死体积都显著较小。尽管 DMSO 处理的小鼠的照射半球显示出许多 RN 的典型组织学特征，包括纤维蛋白血管坏死、血管扩张、出血和组织丢失，但 SB415286 处理的小鼠的照射半球仅显示出最小的组织损伤。这些研究证实，用 GSK-3β 抑制剂治疗可显著减少照射后大脑坏死的延迟发生时间。
结论
联合使用单侧大脑半球立体定向放射外科小鼠模型和纵向 MRI 监测为研究 RN 的发生和进展以及开发和测试新的神经保护剂提供了一个强大的平台。SB415286 作为一种有效的神经保护剂，对坏死具有保护作用，这激发了对其或其他 GSK-3β 抑制剂进行临床试验的兴趣。
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