Early HMGB1 Inhibition Reduces Hippocampal Injury During Adolescence in a Young Mouse Model of Radiation-Induced Brain Injury.

Radiotherapy is a primary treatment for childhood malignant brain tumors. However, it often leads to radiation-induced brain injury (RIBI), which significantly impairs neurodevelopment in pediatric patients. Effective treatment for this complication remains limited. Given the established link between RIBI-associated neuroinflammation and HMGB1, we investigated the neuroprotective potential of early HMGB1 inhibition in a young mouse model. Four-week-old male C57BL/6 mice received a single 10 Gy whole-brain irradiation and were divided into Sham + PBS, Rad + PBS, and Rad + glycyrrhizin (GL, 10 mg/kg for 14 days post-irradiation) groups. Immunofluorescence showed that irradiation significantly triggered nuclear-to-cytoplasmic translocation of HMGB1 in hippocampus 7 days post-irradiation. Preliminary data suggests that GL administration abrogates increases in HMGB1 expression and translocation as well as of the key inflammatory receptors TLRs and RAGE. Immunofluorescence and Nissl staining confirmed that GL treatment inhibited microglial activation and mitigated neuronal loss 14 days post-irradiation. Critically, behavioral assessment via the Morris water maze 8 weeks post-irradiation showed that this early intervention significantly improved spatial learning and memory deficits. Complementary preliminary in vitro experiments demonstrate irradiation-associated increases in microglia-derived inflammatory mediators and corresponding changes in neuronal MAP2 staining following exposure to microglia-conditioned media, with altered cytokine profiles observed in the presence of GL. Collectively, our results demonstrate that early pharmacological blockade of the HMGB1 pathway alleviates microglial activation and hippocampal damage, offering a potential new treatment target for pediatric RIBI. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10571-026-01683-0.