The impact of high and low dose ionising radiation on the central nervous system

Abstract

Responses of the central nervous system (CNS) to stressors and injuries, such as ionising radiation, are modulated by the concomitant responses of the brains innate immune effector cells, microglia. Exposure to high doses of ionising radiation in brain tissue leads to the expression and release of biochemical mediators of 'neuroinflammation', such as pro-inflammatory cytokines and reactive oxygen species (ROS), leading to tissue destruction. Contrastingly, low dose ionising radiation may reduce vulnerability to subsequent exposure of ionising radiation, largely through the stimulation of adaptive responses, such as antioxidant defences. These disparate responses may be reflective of non-linear differential microglial activation at low and high doses, manifesting as an anti-inflammatory or pro-inflammatory functional state. Biomarkers of pathology in the brain, such as the mitochondrial Translocator Protein 18kDa (TSPO), have facilitated in vivo characterisation of microglial activation and 'neuroinflammation' in many pathological states of the CNS, though the exact function of TSPO in these responses remains elusive. Based on the known responsiveness of TSPO expression to a wide range of noxious stimuli, we discuss TSPO as a potential biomarker of radiation-induced effects.

Keywords: Antioxidants; Ionizing radiation; Microglia; Neuroinflammation; Reactive oxygen species (ROS); Translocator Protein (TSPO).

Graphical abstract

Fig. 1

Publications trends using the SCOPUS database. ‘Ionising radiation’ and ‘microglia’ yields fewer results (49) than ‘ionising radiation’ and ‘brain’ search terms (2330). The lack of research between 1964 and 1997 is significant, and the striking increase in literature in the last 2 decades may coincide with the emergence of the concept of ‘neuroinflammation’ as a prolific research field within neuroscience. Even fewer results are yielded for ‘low dose ionising radiation’ (328), and fewer yet when ‘microglia’ is included (6), representing the paucity of studies on this topic. The second wave of publications on ‘low dose ionising radiation’ and ‘brain’ starting at the beginning of the 1970s may be as a result of the heightened use of medical radiation technologies and the consequent clinical exposure of patients to low doses.

Fig. 2

Radiation exposure compromises the integrity of the blood-brain barrier (BBB). Adapted from , . (A) Normal compartmental separation of the CNS from the peripheral immune system represents an intact BBB. Compartmental separation may not be compromised following low dose radiation exposure. (B) High dose irradiation can induce damage and apoptosis of endothelial cells, resulting in the infiltration of peripheral macrophages (as indicated by red arrows), disturbing the normal compartmental separation between the CNS and the peripheral immune system. High doses can also induce microglial activation (cells in red), responsible for the brains innate immune response.

Fig. 3

Ionising radiation and the cellular and molecular mediators of responses in the CNS. (A) Low dose ionising radiation may confer neuroprotection by decreasing neuroinflammation, increasing antioxidant levels and neutralising oxidative stress. (B) High dose ionising radiation provokes a neuroinflammatory response via activated microglia (cells in red), pro-inflammatory cytokines and reactive oxygen species (ROS) which can have deleterious effects on cell functioning and survival. The role of TSPO in modulating ROS may also implicate this protein in redox balance after ionising radiation at different doses. Adapted from , .