Abstract

Purpose

Harmful effects of ionizing radiation on the Central Nervous System (CNS) are a concerning outcome in the field of cancer radiotherapy and form a major risk for deep space exploration. Both acute and chronic CNS irradiation induce a complex network of molecular and cellular alterations including DNA damage, oxidative stress, cell death and systemic inflammation, leading to changes in neuronal structure and synaptic plasticity with behavioral and cognitive consequences in animal models. Due to this complexity, countermeasure or therapeutic approaches to reduce the harmful effects of ionizing radiation include a wide range of protective and mitigative strategies, which merit a thorough comparative analysis.

Materials and methods

We reviewed current approaches for developing countermeasures to both targeted and non-targeted effects of ionizing radiation on the CNS from the molecular and cellular to the behavioral level.

Results

We focus on countermeasures that aim to mitigate the four main detrimental actions of radiation on CNS: DNA damage, free radical formation and oxidative stress, cell death, and harmful systemic responses including tissue death and neuroinflammation. We propose a comprehensive review of CNS radiation countermeasures reported for the full range of irradiation types (photons and particles, low and high linear energy transfer) and doses (from a fraction of gray to several tens of gray, fractionated and unfractionated), with a particular interest for exposure conditions relevant to deep-space environment and radiotherapy. Our review reveals the importance of combined strategies that increase DNA protection and repair, reduce free radical formation and increase their elimination, limit inflammation and improve cell viability, limit tissue damage and increase repair and plasticity.

Conclusions

The majority of therapeutic approaches to protect the CNS from ionizing radiation have been limited to acute high dose and high dose rate gamma irradiation, and few are translatable from animal models to potential human application due to harmful side effects and lack of blood-brain barrier permeability that precludes peripheral administration. Therefore, a promising research direction would be to focus on practical applicability and effectiveness in a wider range of irradiation paradigms, from fractionated therapeutic to deep space radiation. In addition to discovering novel therapeutics, it would be worth maximizing the benefits and reducing side effects of those that already exist. Finally, we suggest that novel cellular and tissue models for developing and testing countermeasures in the context of other impairments might also be applied to the field of CNS responses to ionizing radiation.

中文翻译：

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电离辐射对中枢神经系统的风险以及细胞和啮齿动物模型中的对策

摘要

目的

电离辐射对中枢神经系统 (CNS) 的有害影响是癌症放射治疗领域的一个令人担忧的结果，是深空探索的主要风险。急性和慢性中枢神经系统照射都会诱导复杂的分子和细胞改变网络，包括 DNA 损伤、氧化应激、细胞死亡和全身炎症，从而导致神经元结构和突触可塑性的变化以及动物模型中的行为和认知后果。由于这种复杂性，减少电离辐射有害影响的对策或治疗方法包括广泛的保护和缓解策略，值得进行彻底的比较分析。

材料和方法

我们回顾了目前从分子和细胞到行为水平制定针对电离辐射对 CNS 的靶向和非靶向影响的对策的方法。

结果

我们专注于旨在减轻辐射对 CNS 的四种主要有害作用的对策：DNA 损伤、自由基形成和氧化应激、细胞死亡和有害的全身反应，包括组织死亡和神经炎症。我们建议对针对所有辐照类型（光子和粒子、低和高线性能量转移）和剂量（从几分之一灰度到几十灰度、分级和未分级）报告的中枢神经系统辐射对策进行全面审查，对与深空环境和放射治疗相关的暴露条件特别感兴趣。我们的审查揭示了增加 DNA 保护和修复、减少自由基形成并增加其消除、限制炎症和提高细胞活力的综合策略的重要性，

结论

大多数保护中枢神经系统免受电离辐射的治疗方法仅限于急性高剂量和高剂量率伽马辐射，由于有害的副作用和缺乏血脑屏障通透性，很少能从动物模型转化为潜在的人类应用这排除了外围管理。因此，一个有前途的研究方向将集中在更广泛的辐射范式中的实际适用性和有效性，从分次治疗到深空辐射。除了发现新的治疗方法外，将现有疗法的益处最大化并减少副作用也是值得的。最后，