Maintenance of Tight Junction Integrity in the Absence of Vascular Dilation in the Brain of Mice Exposed to Ultra-High-Dose-Rate FLASH Irradiation.

摘要: Persistent vasculature abnormalities contribute to an altered CNS microenvironment that further compromises the integrity of blood-brain barrier and exposes brain a host neurotoxic conditions. Standard radiation therapy at conventional (CONV) dose rate elicits short-term damage by disrupting supportive cells, volume tight junction proteins. While current clinical applications cranial radiotherapy use fractionation reduce normal tissue damage, these treatments still cause significant complications. escalation enhances treatment radiation-resistant tumors, methods subvert are clearly needed. In this regard, we have recently developed new modality irradiation based on ultra-high-dose-rate FLASH does not induce classical pathogenic patterns caused CONV irradiation. previous work, optimized physical parameters required minimize toxicity (i.e., FLASH, instantaneous intra-pulse rate, 6.9 · 106 Gy/s, mean 2,500 Gy/s), which then used in study determine effect barrier. Both early (24 h, one week) late (one month) timepoints postirradiation were investigated using C57Bl/6J female mice exposed whole-brain delivered single doses 25 Gy 10 Gy, respectively, (0.09 Gy/s) or (>106 Gy/s). majority changes found day minimal, was levels apoptosis neurogenic regions time. At week month postirradiation, vascular dilation, well described sign alteration, while minimized effects. These results positively correlated with temporally coincident immunostaining vasodilator eNOS colocalized vasculature, suggestive possible dysregulation blood flow latter times. Overall expression proteins, occludin claudin-5, significantly reduced after irradiation, remained unchanged FLASH-irradiated brains four weeks postirradiation. Our data confirm that, compared isodoses known elicit detrimental effects, vasculature. now provide first evidence preserves microvasculature brain, may prove beneficial cognition allowing for better tumor control clinic.