Radiation-induced injury of CNS is a dynamic and complex process. Based on a time sequence and clinical symptoms, it can be classified into three phases. Acute reactions, which usually occur within minutes to days after radiation, are often associated with increased intracranial pressure, possibly due to acute vasogenic edema. Patients may experience a wide range of symptoms, including nausea, headache, vomiting, drowsiness, fever, and worsening neurological symptoms. Early delayed reactions after irradiation, which typically take several weeks to months for symptoms to develop, are often due to demyelination of surrounding structures. Some symptoms of this type of neurologic damage can include headache, lethargy, transitory cognitive impairment, and worsening of lateralizing signs. The third type, late, delayed reactions, may not appear for months or years after radiation. Late delayed neurologic damage may include radiation necrosis, cerebral atrophy, leukoencephalo/vasculopathy, and mild to moderate cognitive changes (Sundgren and Cao, 2009; Katsura et al., 2021). However, their clinical impact is high because they are progressive and irreversible. During clinical treatment, tissue near the radiation field is often exposed to lower doses of radiation. The radiation, therefore, affects directly irradiated cells and non-irradiated neighbors (Marín et al., 2015; Tang et al., 2023). This phenomenon, known as the radiation-induced bystander effect, can trigger mutations, cell-killing, changes in signal transduction, genomic instability, malignant transformation, and increased survival in non-irradiated cells (Marín et al., 2015).

In the clinical treatment of metastases of the brain and spinal cord, mainly fractionated radiotherapeutic modalities are used to spare normal tissue around the tumor. However, dose fractionation does not produce a sparing effect for adjacent cells receiving bystander signals from irradiated ones. The bystander effect can have profound clinical implications for health risks after low radiation exposure, depending on the distance from the radiation field (Marín et al., 2015).

Radiation-induced changes may impact neural functions (i.e., cognitive functions) and neural responses, which should be considered within the broader context of somatic effects (i.e., visceral organ-specific effects, peripheral blood, immune, endocrine system, etc.) (Schindler et al., 2008). The development of neurocognitive deficits after irradiation is associated with impaired hippocampal activity, which also affects the ability to produce new neurons. The subgranular zone (SGZ) in the hippocampal dentate gyrus (DG) and the anterior subventricular zone (SVZa) in the wall of the lateral ventricles (LV) are the source of neurogenesis and neuroregeneration in the brain of adult mammals (Doetsch et al., 1997; Bicker et al., 2017; Christian et al., 2020). From the SVZa, newly formed neurons travel along the migration route – the rostral migratory stream (RMS) to their destination, to the olfactory bulb (OB) (Kaneko et al., 2017).

Our study investigated the bystander effect caused by a gradual decrease of the dose fraction/total dose applied to the spinal cord and its effect on selected brain areas. Manifestation of the radiation-induced bystander effect was investigated in neurogenic (SVZa, hippocampal DG) and the adjacent regions (corpus striatum, OB) using in vivo measurement of metabolites (proton magnetic resonance spectroscopy; 1H MRS). Our aim was also to compare in vivo short-term and long-term radiation effects at the level of brain metabolites and its possible neuroprotective outcome. After sacrifice, we detected changes in the distribution of cell types using immunohistochemical staining and image analysis of brain sections. We correlated brain metabolite data with changes in circulating metabolites in plasma using proton nuclear resonance (1H NMR). Changes in plasma metabolites reflect the state of the whole organism and form the basis for tissue response and regeneration after fractionated irradiation. In addition, disruption of the blood-brain barrier (BBB) causes metabolites to pass from the bloodstream into the brain tissue, affecting it (Kadry et al., 2020).