El-Khatib Sanad M, Vagadia Arya R, Le Anh C D, Baulch Janet E, Ng Ding Quan, Du Mingyu, Johnston Kevin G, Tan Zhiqun, Xu Xiangmin, Chan Alexandre, Acharya Munjal M
Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, USA.
Department of Radiation Oncology, School of Medicine, University of California, Irvine, USA.
Acta Neuropathol Commun. 2024 Dec 18;12(1):190. doi: 10.1186/s40478-024-01906-9.
Cranial radiation therapy (RT) for brain cancers is often associated with the development of radiation-induced cognitive dysfunction (RICD). RICD significantly impacts the quality of life for cancer survivors, highlighting an unmet medical need. Previous human studies revealed a marked reduction in plasma brain-derived neurotrophic factor (BDNF) post-chronic chemotherapy, linking this decline to a substantial cognitive dysfunction among cancer survivors. Moreover, riluzole (RZ)-mediated increased BDNF in vivo in the chemotherapy-exposed mice reversed cognitive decline. RZ is an FDA-approved medication for ALS known to increase BDNF in vivo. In an effort to mitigate the detrimental effects of RT-induced BDNF decline in RICD, we tested the efficacy of RZ in a cranially irradiated (9 Gy) adult mouse model. Notably, RT-exposed mice exhibited significantly reduced hippocampal BDNF, accompanied by increased neuroinflammation, loss of neuronal plasticity-related immediate early gene product, cFos, and synaptic density. Spatial transcriptomic profiling comparing the RT + Vehicle with the RT + RZ group showed gene expression signatures of neuroprotection of hippocampal excitatory neurons post-RZ. RT-exposed mice performed poorly on learning and memory, and memory consolidation tasks. However, irradiated mice receiving RZ (13 mg/kg, drinking water) for 6-7 weeks showed a significant improvement in cognitive function compared to RT-exposed mice receiving vehicle. Dual-immunofluorescence staining, spatial transcriptomics, and biochemical assessment of RZ-treated irradiated brains demonstrated preservation of synaptic integrity and mature neuronal plasticity but not neurogenesis and reduced neuroinflammation concurrent with elevated BDNF levels and transcripts compared to vehicle-treated irradiated brains. In summary, oral administration of RZ represents a viable and translationally feasible neuroprotective approach against RICD.
脑部癌症的颅部放射治疗（RT）通常与放射性认知功能障碍（RICD）的发生有关。RICD对癌症幸存者的生活质量有显著影响，凸显了未满足的医疗需求。先前的人体研究显示，慢性化疗后血浆脑源性神经营养因子（BDNF）显著减少，将这种下降与癌症幸存者的严重认知功能障碍联系起来。此外，利鲁唑（RZ）介导的化疗暴露小鼠体内BDNF增加可逆转认知衰退。RZ是一种经美国食品药品监督管理局（FDA）批准用于肌萎缩侧索硬化症（ALS）的药物，已知其可在体内增加BDNF。为了减轻RT诱导的BDNF下降对RICD的有害影响，我们在成年小鼠颅部照射（9 Gy）模型中测试了RZ的疗效。值得注意的是，接受RT照射的小鼠海马BDNF显著减少，同时神经炎症增加，与神经元可塑性相关的即早基因产物cFos和突触密度丧失。比较RT + 载体组与RT + RZ组的空间转录组分析显示，RZ处理后海马兴奋性神经元具有神经保护的基因表达特征。接受RT照射的小鼠在学习和记忆以及记忆巩固任务中表现不佳。然而，与接受载体的RT照射小鼠相比，接受RZ（13 mg/kg，饮用水）治疗6 - 7周的照射小鼠认知功能有显著改善。与载体处理的照射脑相比，对RZ处理的照射脑进行的双重免疫荧光染色、空间转录组学和生化评估表明，突触完整性和成熟神经元可塑性得以保留，但神经发生未保留，神经炎症减少，同时BDNF水平和转录本升高。总之，口服RZ是一种针对RICD的可行且具有转化可行性的神经保护方法。
