HMGB1 a-Box Reverses Brain Edema and Deterioration of Neurological Function in a Traumatic Brain Injury Mouse Model

Abstract

Background/Aims: Traumatic brain injury (TBI) is a complex neurological injury in young adults lacking effective treatment. Emerging evidences suggest that inflammation contributes to the secondary brain injury following TBI, including breakdown of the blood brain barrier (BBB), subsequent edema and neurological deterioration. High mobility group box-1 (HMGB1) has been identified as a key cytokine in the inflammation reaction following TBI. Here, we investigated the therapeutic efficacy of HMGB1 A-box fragment, an antagonist competing with full-length HMGB1 for receptor binding, against TBI. Methods: TBI was induced by controlled cortical impact (CCI) in adult male mice. HMGB1 A-box fragment was given intravenously at 2 mg/kg/day for 3 days after CCI. HMGB1 A-box-treated CCI mice were compared with saline-treated CCI mice and sham mice in terms of BBB disruption evaluated by Evan’s blue extravasation, brain edema by brain water content, cell death by propidium iodide staining, inflammation by Western blot and ELISA assay for cytokine productions, as well as neurological functions by the modified Neurological Severity Score, wire grip and beam walking tests. Results: HMGB1 A-box reversed brain damages in the mice following TBI. It significantly reduced brain edema by protecting integrity of the BBB, ameliorated cell degeneration, and decreased expression of pro-inflammatory cytokines released in injured brain after TBI. These cellular and molecular effects were accompanied by improved behavioral performance in TBI mice. Notably, HMGB1 A-box blocked IL-1β-induced HMGB1 release, and preferentially attenuated TLR4, Myd88 and P65 in astrocyte cultures. Conclusion: Our data suggest that HMGB1 is involved in CCI-induced TBI, which can be inhibited by HMGB1 A-box fragment. Therefore, HMGB1 A-box fragment may have therapeutic potential for the secondary brain damages in TBI.

High mobility group box 1 (HMGB1) as a novel frontier in epileptogenesis: from pathogenesis to therapeutic approaches

“…Structural analysis of HMGB1 revealed two DNA binding domains (box A and box B) and a negatively charged C‐terminal (Ulloa and Messmer ; Yang et al . ). Box A contains the antagonistic site of box B, and demonstrates anti‐inflammatory properties in both in vivo and in vitro models of inflammation (Girard ).…”

“…The precise understanding of basic HMGB1 chemistry is crucial to understanding its function, as it is composed of different boxes with specific binding sites resulting in different activities. Structural analysis of HMGB1 revealed two DNA binding domains (box A and box B) and a negatively charged C-terminal (Ulloa and Messmer 2006;Yang et al 2018). Box A contains the antagonistic site of box B, and demonstrates anti-inflammatory properties in both in vivo and in vitro models of inflammation (Girard 2007).…”

HMGB1: A Common Biomarker and Potential Target for TBI, Neuroinflammation, Epilepsy, and Cognitive Dysfunction

“…In addition, neuroinflammatory processes mainly mediated by activated microglia and astrocytes are crucial for the initiation and progression of TBI ( Li D. et al, 2017 ). TBI induces a series of events including BBB breakdown, brain edema, upregulation of tight junction proteins (TJPs), expression of inflammation related molecules ( Yang et al, 2018 ). TLR4 has been linked with TBI where TLR4 mediates glial phagocytic activity and inflammatory cytokines production ( Jiang et al, 2018 ) and plays an important role in inflammatory response and brain injury ( Fang et al, 2013 ).…”

“…High mobility group box 1 A-box fragment, an antagonist competing with HMGB1 for receptor binding, significantly ameliorated the BBB breakdown and brain edema induced by controlled cortical impact (CCI), and these effects were associated with the decrease in expressions of inflammation-related factors as well as improved neurological functions ( Yang et al, 2018 ). Ethyl pyruvate ( Table 1 ) ( Su et al, 2011 ) and omega-3 polyunsaturated fatty acid supplementation ( Chen et al, 2017b ) has demonstrated its effectiveness against TBI via inhibition of the HMGB1/TLR4/NF-κB pathway.…”

High Mobility Group Protein 1 and Dickkopf-Related Protein 1 in Schizophrenia and Treatment-Resistant Schizophrenia: Associations with Interleukin-6, Symptom Domains, and Neurocognitive Impairments

“…48 On the other hand, HMGB1-specific antibodies protect against lethal endotoxaemia 20 and preserve BBB integrity thereby attenuating glial activation, oxidative stress and elevated inflammatory gene expression, including IL-6, damage to hippocampal neurons, neuronal degeneration, and brain damage. 49,50 Furthermore, blocking of HMGB1 signaling improves neuroprotection in neurodegenerative disorders. 51 Clinical studies show that sepsis survivors have permanent cognitive deficits, which are probably mediated via elevated HMGB1 levels.…”