https://orcid.org/0000-0003-3306-1806
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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.
Acknowledgements
The authors thank the two reviewers for providing helpful comments and suggestions to improve this manuscript.
Disclosure statement
No potential conflict of interest is reported by the author(s).
Additional information
Funding
Notes on contributors
Eloise Pariset
Eloise Pariset, Ph.D., is a Postdoctoral Research Fellow in the Space Biosciences Research Branch at NASA Ames Research Center, Mountain View, CA.
Sherina Malkani
Sherina Malkani is a former Research Associate in the Space Biosciences Research Branch at NASA Ames Research Center, Mountain View, CA, and is currently a PhD student at Rice University, Houston, TX.
Egle Cekanaviciute
Egle Cekanaviciute, Ph.D., is a Research Scientist in the Space Biosciences Research Branch at NASA Ames Research Center, Mountain View, CA.
Sylvain V. Costes
Sylvain V. Costes, Ph.D., is a Senior Research Scientist in the Space Biosciences Research Branch at NASA Ames Research Center, Mountain View, CA, and the Project Manager for NASA GeneLab space omics database.