Inhibition of HMGB1 restores adult hippocampal neurogenesis and spatial learning after adolescent binge alcohol exposure.

Adolescence is a critical neurodevelopmental period during which the hippocampus exhibits heightened vulnerability to environmental insults, including binge alcohol exposure. Adolescent intermittent ethanol (AIE)-a preclinical model of human adolescent binge drinking-induces long-lasting neuroimmune activation and reductions of adult hippocampal neurogenesis, contributing to persistent cognitive impairment. High-mobility group box 1 (HMGB1), a damage-associated molecule released by ethanol, engages Toll-like receptor 4 (TLR4) and activates NFκBp65 signaling, driving prolonged neuroinflammatory cascades. While HMGB1 inhibition represents a promising therapeutic strategy, its capacity to recover AIE-induced neuroimmune and neurogenic pathology remains unclear. Here, we tested whether glycyrrhizic acid-a brain penetrant HMGB1 inhibitor-could ameliorate AIE-induced neuroimmune activation, restore neurogenesis, and improve cognitive function in adulthood. To test this hypothesis, female Wistar rats received AIE (5.0 g/kg, i.g., 2 d on/2 d off) or water control treatment from postnatal day (P)25-P54. From P56-P95, animals received either glycyrrhizic acid (1.0 g/L, p.o.) or water vehicle in drinking water. We report that AIE increased HMGB1-TLR4-pNFκBp65 signaling, astroglial (GFAP) and microglial (CD11b) activation, and cleaved caspase-3 expression while reducing neurogenesis markers DCX and Ki-67 in the adult hippocampus, effects that were restored by post-AIE glycyrrhizic acid treatment. Behaviorally, AIE impaired visible platform performance, increased thigmotaxia, and slowed acquisition of spatial learning on the Morris water maze whereas glycyrrhizic acid normalized all behavioral deficits. Together, these findings identify HMGB1 as a key driver of persistent hippocampal pathology following AIE exposure and demonstrate that targeted HMGB1 inhibition restores neuroimmune homeostasis, neurogenesis, and cognitive function in adulthood.