Late Side Effects in Normal Mouse Brain Tissue After Proton Irradiation

Theresa Suckert; Elke Beyreuther; Johannes Müller; Behnam Azadegan; Matthias Meinhardt; Felix Raschke; Elisabeth Bodenstein; Cläre von Neubeck; Armin Lühr; Mechthild Krause; Antje Dietrich

doi:10.3389/fonc.2020.598360

Late Side Effects in Normal Mouse Brain Tissue After Proton Irradiation

Front Oncol. 2021 Jan 11:10:598360. doi: 10.3389/fonc.2020.598360. eCollection 2020.

Authors

Theresa Suckert^{1

2}, Elke Beyreuther^{2

3}, Johannes Müller^{2

4}, Behnam Azadegan^{2

5}, Matthias Meinhardt⁶, Felix Raschke^{2

4}, Elisabeth Bodenstein², Cläre von Neubeck^{1

2

7}, Armin Lühr^{1

2

4

8}, Mechthild Krause^{1

2

4

9

10}, Antje Dietrich^{1

2}

Affiliations

¹ German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
² OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
³ Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiation Physics, Dresden, Germany.
⁴ Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology - OncoRay, Dresden, Germany.
⁵ Department of Physics, Hakim Sabzevari University, Sabzevar, Iran.
⁶ Neuropathology, Institute of Pathology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.
⁷ Department of Particle Therapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
⁸ Department of Medical Physics and Radiotherapy, Faculty of Physics, TU Dortmund University, Dortmund, Germany.
⁹ National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany.
¹⁰ Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Abstract

Radiation-induced late side effects such as cognitive decline and normal tissue complications can severely affect quality of life and outcome in long-term survivors of brain tumors. Proton therapy offers a favorable depth-dose deposition with the potential to spare tumor-surrounding normal tissue, thus potentially reducing such side effects. In this study, we describe a preclinical model to reveal underlying biological mechanisms caused by precise high-dose proton irradiation of a brain subvolume. We studied the dose- and time-dependent radiation response of mouse brain tissue, using a high-precision image-guided proton irradiation setup for small animals established at the University Proton Therapy Dresden (UPTD). The right hippocampal area of ten C57BL/6 and ten C3H/He mice was irradiated. Both strains contained four groups (n_irradiated = 3, n_control = 1) treated with increasing doses (0 Gy, 45 Gy, 65 Gy or 85 Gy and 0 Gy, 40 Gy, 60 Gy or 80 Gy, respectively). Follow-up examinations were performed for up to six months, including longitudinal monitoring of general health status and regular contrast-enhanced magnetic resonance imaging (MRI) of mouse brains. These findings were related to comprehensive histological analysis. In all mice of the highest dose group, first symptoms of blood-brain barrier (BBB) damage appeared one week after irradiation, while a dose-dependent delay in onset was observed for lower doses. MRI contrast agent leakage occurred in the irradiated brain areas and was progressive in the higher dose groups. Mouse health status and survival corresponded to the extent of contrast agent leakage. Histological analysis revealed tissue changes such as vessel abnormalities, gliosis, and granule cell dispersion, which also partly affected the non-irradiated contralateral hippocampus in the higher dose groups. All observed effects depended strongly on the prescribed radiation dose and the outcome, i.e. survival, image changes, and tissue alterations, were very consistent within an experimental dose cohort. The derived dose-response model will determine endpoint-specific dose levels for future experiments and may support generating clinical hypotheses on brain toxicity after proton therapy.

Keywords: blood–brain barrier (BBB); brain irradiation; brain tissue toxicity; late side effects; magnetic resonance imaging (MRI); preclinical mouse model; proton therapy; radiation dose modeling.