Targeting high-mobility group box protein 1 (HMGB1) in pediatric traumatic brain injury: Chronic neuroinflammatory, behavioral, and epileptogenic consequences

Kyria M. Webster, Sandy R. Shultz, Ezgi Ozturk, Larissa K. Dill, Mujun Sun, Pablo Casillas-Espinosa, Nigel C. Jones, Peter J. Crack, Terence J. O'Brien, Bridgette D. Semple

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High mobility group box protein-1 (HMGB1) has been implicated as a key mediator of neuroinflammation and neurodegeneration in a range of neurological conditions including traumatic brain injury (TBI) and epilepsy. To date, however, most studies have examined only acute outcomes, and the adult brain. We have recently demonstrated HMGB1 release after experimental TBI in the pediatric mouse. This study therefore examined the chronic consequences of acute HMGB1 inhibition in the same model, to test the hypothesis that HMGB1 is a pivotal mediator of neuropathological, neurobehavioral, and epilepsy outcomes in pediatric TBI. HMGB1 was inhibited by treatment with 50 mg/kg i.p. Glycyrrhizin (Gly), compared to vehicle controls, commencing 1 h prior to moderate TBI or sham surgery in post-natal day 21 mice. We first demonstrated that Gly reduced brain HMGB1 levels and brain edema at an acute time point of 3 days post-injury. Subsequent analysis over a chronic time course found that pediatric TBI resulted in short-term spatial memory and motor learning deficits alongside an apparent increase in hippocampal microglial reactivity, which was prevented in Gly-treated TBI mice. In contrast, Gly treatment did not reduce the severity of evoked seizures, the proportion of animals exhibiting chronic spontaneous seizure activity, or cortical tissue loss. Together, our findings contribute to a growing appreciation for HMGB1's role in neuropathology and associated behavioral outcomes after TBI. However, further work is needed to fully elucidate the contribution of HMGB1 to epileptogenesis in this context.

Original languageEnglish
Article number112979
Number of pages14
JournalExperimental Neurology
Publication statusPublished - 1 Oct 2019


  • Behavior
  • Glycyrrhizin
  • High-mobility group box protein-1 (HMGB1)
  • Inflammation
  • Neurotrauma
  • Pediatric
  • Post-traumatic epilepsy
  • Seizures
  • Traumatic brain injury

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