Metabolic and histopathological changes in the brain and plasma of rats exposed to fractionated whole-brain irradiation

Abstract

In the present study we investigated the correlation between radiation-induced metabolic and histopathological changes in the brain under experimental conditions. Adult male Wistar rats received fractionated whole-brain irradiation (fWBI) with a total dose of 40 Gy administered in 5 fractions (dose 8 Gy per fraction) once a week on the same day for 5 consecutive weeks. Radiation-induced alteration in plasma and brain metabolites were measured by proton nuclear magnetic resonance (1H NMR)-based metabolomics and proton magnetic resonance spectroscopy (1HMRS). Histopathological changes in the brain were evaluated to determine alteration of neurogenesis and glial cell responses in 2 neurogenic regions: the hippocampal dentate gyrus (DG) and the subventricular zone-olfactory bulb axis (SVZ-OB axis). Evaluation of brain metabolites 15 weeks after irradiation performed with 1H MRS showed a significant decrease in the total N-acetylaspartate to total creatine (tNAA/tCr) ratio in the striatum, hippocampus, and OB, while gamma-aminobutyric acid to tCr (GABA/tCr) ratio in the hippocampus as well as OB and total choline to tCr (tCho/tCr) in striatum and OB. Magnetic resonance imaging (MRI) volumetric analysis showed a significant reduction in total brain volume and atrophy of dorsal hippocampus and OB. 1H NMR in plasma of irradiated animals displayed decreased citrate and increased bile acids. Image analysis of the brain sections 16 weeks after fWBI showed an increase in neurodegeneration and inhibition of neurogenesis. Results showed that fWBI led to metabolic alterations associated with histopathological findings, suggesting a subacute and development of late radiation-induced changes.