Late Side Effects in Normal Mouse Brain Tissue After Proton Irradiation

Area of Science:

• Neuroscience
• Radiation Oncology
• Preclinical Research

Background:

• Late side effects of radiation, including cognitive decline and normal tissue complications, significantly impact brain tumor survivors.
• Proton therapy's precise dose deposition offers potential for sparing surrounding normal tissue, possibly reducing these adverse effects.

Purpose of the Study:

• To establish a preclinical model for investigating the biological mechanisms of high-dose proton irradiation in specific brain regions.
• To analyze the dose- and time-dependent effects of proton therapy on mouse brain tissue and the blood-brain barrier.

Main Methods:

• Utilized a high-precision image-guided proton irradiation setup for small animals.
• Irradiated the right hippocampal area of C57BL/6 and C3H/He mice with varying doses (up to 85 Gy).
• Conducted longitudinal monitoring including MRI and histological analysis for up to six months post-irradiation.

Main Results:

• Observed dose-dependent blood-brain barrier (BBB) damage, evidenced by contrast agent leakage, appearing as early as one week post-irradiation in high-dose groups.
• Mouse health status and survival correlated with the extent of BBB damage.
• Histological analysis revealed radiation-induced tissue alterations, including vessel abnormalities and gliosis, with some effects noted in the contralateral hippocampus at higher doses.

Conclusions:

• Proton irradiation induces dose-dependent BBB damage and tissue alterations in the mouse brain.
• The observed effects are consistent within dose cohorts, supporting the development of a dose-response model.
• This preclinical model and derived data can inform clinical hypotheses regarding brain toxicity after proton therapy.