Neuroprotective Effects of Ultra-High Dose Rate FLASH Bragg Peak Proton Irradiation.

PURPOSE: To investigate brain tissue response to ultra-high dose rate (uHDR, FLASH) and standard dose rate (SDR) proton irradiations in the Bragg peak region. METHODS AND MATERIALS: Active scanning uHDR delivery was established for proton beams for investigation of dose rate effects between clinical SDR and uHDR at ∼10 Gy in the Bragg peak region (dose-averaged linear energy transfer [LET(D)] ranging from 4.5 to 10.2 keV µm(-1) ). Radiation- induced injury of neuronal tissue was assessed by studying the DNA double strand break repair kinetics surrogated by nuclear γH2AX staining (radiation induced foci [RIF]), microvascular density and structural integrity (MVD, CD31+ endothelium), and inflammatory microenvironmental response (CD68+ microglia/macrophages and high mobility group box protein 1[HMGB]) in healthy C57BL/6 mouse brains. RESULTS: Averaged dose rates achieved were 0.17 Gy/s (SDR) and 120 Gy/s (uHDR). The fraction of RIF-positive cells increased after SDR ∼10-fold, whereas a significantly lower fraction of RIF-positive cells was found after uHDR versus SDR (∼2 fold, P < .0001). Moreover, uHDR substantially preserved the microvascular architecture and reduced microglia/macrophage regulated associated inflammation as compared with SDR. CONCLUSIONS: The feasibility of uHDR raster scanning proton irradiation is demonstrated to elicit FLASH sparing neuroprotective effects compared to SDR in a preclinical in vivo model.