Targeting Active Microglia Alleviates Distal Edge of Proton Radiation-induced Neural Damage.

Purpose: Proton therapy (PT) has distinct advantages in its ability to precisely target tumors while avoiding adjacent normal tissues. However, the distal edge effects of PT constrain its application. This study investigated the brain tissue response in the distal edge regions of protons and compared it with the effect of photons.

Methods And Materials: The occurrence of damage from photons and at the distal edge of protons was investigated in a murine model. Bragg peak treatment plans for murine models were optimized. Hematoxylin and eosin and immunofluorescence staining were performed along the distal margin. In addition, the approximate distance from the Bragg peak to the neuronal damage sites was calculated. Furthermore, a small-molecule inhibitor was studied for its ability to inhibit microglia activation.

Results: The distal edge brain injury murine model was successfully established. Reactive gliosis and granulovacuolar neuronal degeneration were observed in the right hemisphere of the brain in the proton irradiation group. Neuronal injuries were observed at multiple locations (the frontal lobe, thalamus, and cerebral cortex) along the distal border, but no injured neurons were detected along vertical photon irradiation exposed areas. Meanwhile, severe neural damage was seen with horizontal photon irradiation. At the distal edge of the Bragg peak (0.4633 ± 0.01856 cm), microglia with abnormal morphology accumulated. IBA1 and CD68 staining revealed activated microglia at the corresponding neuronal damage sites, indicating their involvement in irradiation-induced damage. Activated microglia were not observed with vertical photon irradiation, whereas many activated microglia were observed with horizontal photon irradiation. Moreover, asparagine endopeptidase inhibitors administered via intraperitoneal injection significantly reduced active microglia in the thalamus and cerebral cortex and alleviated brain damage.

Conclusions: This study demonstrated that proton radiation induces neuronal damage and accumulation of activated microglia at the distal edge. Targeting activated microglia may play a protective role in distal edge injury from radiation.