Department of Radiation Oncology, University of California, Irvine, California.
Department of Neurobiology and Behavior, University of California, Irvine, California.
Cancer Res Commun. 2023 Apr 27;3(4):725-737. doi: 10.1158/2767-9764.CRC-23-0117. eCollection 2023 Apr.
Implementation of ultra-high dose-rate FLASH radiotherapy (FLASH-RT) is rapidly gaining traction as a unique cancer treatment modality able to dramatically minimize normal tissue toxicity while maintaining antitumor efficacy compared with standard-of-care radiotherapy at conventional dose rate (CONV-RT). The resultant improvements in the therapeutic index have sparked intense investigations in pursuit of the underlying mechanisms. As a preamble to clinical translation, we exposed non-tumor-bearing male and female mice to hypofractionated (3 × 10 Gy) whole brain FLASH- and CONV-RT to evaluate differential neurologic responses using a comprehensive panel of functional and molecular outcomes over a 6-month follow-up. In each instance, extensive and rigorous behavioral testing showed FLASH-RT to preserve cognitive indices of learning and memory that corresponded to a similar protection of synaptic plasticity as measured by long-term potentiation (LTP). These beneficial functional outcomes were not found after CONV-RT and were linked to a preservation of synaptic integrity at the molecular (synaptophysin) level and to reductions in neuroinflammation (CD68 microglia) throughout specific brain regions known to be engaged by our selected cognitive tasks (hippocampus, medial prefrontal cortex). Ultrastructural changes in presynaptic/postsynaptic bouton (Bassoon/Homer-1 puncta) within these same regions of the brain were not found to differ in response to dose rate. With this clinically relevant dosing regimen, we provide a mechanistic blueprint from synapse to cognition detailing how FLASH-RT reduces normal tissue complications in the irradiated brain.
Functional preservation of cognition and LTP after hypofractionated FLASH-RT are linked to a protection of synaptic integrity and a reduction in neuroinflammation over protracted after irradiation times.
超高剂量率 FLASH 放射治疗（FLASH-RT）的实施作为一种独特的癌症治疗方式迅速受到关注，与常规剂量率（CONV-RT）的标准放疗相比，它能够显著降低正常组织毒性，同时保持抗肿瘤疗效。治疗指数的提高引发了对潜在机制的深入研究。作为临床转化的前奏，我们对非肿瘤-bearing 的雄性和雌性小鼠进行了分次（3×10 Gy）全脑 FLASH 和 CONV-RT 照射，以在 6 个月的随访中使用功能和分子结果的综合指标评估不同的神经反应。在每种情况下，广泛而严格的行为测试表明，FLASH-RT 可保留学习和记忆的认知指数，这与长时程增强（LTP）测量的突触可塑性相似的保护作用相对应。CONV-RT 后未发现这些有益的功能结果，并且与分子（突触小体蛋白）水平的突触完整性和特定认知任务所涉及的特定脑区的神经炎症（CD68 小胶质细胞）减少有关。在大脑的这些相同区域内，突触前/后囊泡（Bassoon/Homer-1 斑）的超微结构变化在对剂量率的反应中未发现差异。对于这种临床相关的剂量方案，我们从突触到认知提供了一个详细的机制蓝图，说明 FLASH-RT 如何降低照射后大脑的正常组织并发症。
在低分割 FLASH-RT 后认知和 LTP 的功能保留与突触完整性的保护和神经炎症的减少有关，这种减少在照射后时间延长。
