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

• Published in: Experimental neurology Vol. 320; p. 112979
• Main Authors: Webster, Kyria M., Shultz, Sandy R., Ozturk, Ezgi, Dill, Larissa K., Sun, Mujun, Casillas-Espinosa, Pablo, Jones, Nigel C., Crack, Peter J., O'Brien, Terence J., Semple, Bridgette D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2019
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Behavior; Brain Injuries, Traumatic - complications; Brain Injuries, Traumatic - metabolism; Brain Injuries, Traumatic - pathology; Glycyrrhizic Acid - pharmacology; Glycyrrhizin; High-mobility group box protein-1 (HMGB1); HMGB1 Protein - metabolism; Inflammation; Male; Mice; Mice, Inbred C57BL; Neurotrauma; Pediatric; Post-traumatic epilepsy; Seizures; Seizures - etiology; Traumatic brain injury; Glycyrrhizin; Traumatic brain injury; Inflammation; Behavior; High-mobility group box protein-1 (HMGB1); Pediatric; Post-traumatic epilepsy; Seizures; Neurotrauma
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2019.112979

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. •High mobility group box protein-1 (HMGB1) is implicated in epileptogenesis•Previous findings showed HMGB1 release after traumatic brain injury in young mice•Glycyrrhizin inhibits HMGB1 and reduces acute post-injury edema•Glycyrrhizin ameliorated some cognitive deficits but did not affect seizures•Findings do not support a crucial role for HMGB1 in post-traumatic epilepsy