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Cited by 311Advanced Glycation End Products researchNeuroinflammation and Neurodegeneration MechanismsTraumatic Brain Injury and Neurovascular Disturbances

The DOI matches its Crossref record; 164 of the 166 references it cites were found in a registry or an index.

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

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Paudel, Yam Nath, Shaikh, Mohd. Farooq, Chakraborti, Ayanabha, Kumari, Yatinesh, Aledo-Serrano, Ángel, Aleksovska, Katina, Alvim, Marina Koutsodontis Machado, Othman, Iekhsan·2018·Frontiers in Neuroscience
DOI 10.3389/fnins.2018.00628PMC PMC6142787
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Abstract

High mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein released by glia and neurons upon inflammasome activation and activates receptor for advanced glycation end products (RAGE) and toll-like receptor (TLR) 4 on the target cells. HMGB1/TLR4 axis is a key initiator of neuroinflammation. In recent days, more attention has been paid to HMGB1 due to its contribution in traumatic brain injury (TBI), neuroinflammatory conditions, epileptogenesis, and cognitive impairments and has emerged as a novel target for those conditions. Nevertheless, HMGB1 has not been portrayed as a common prognostic biomarker for these HMGB1 mediated pathologies. The current review discusses the contribution of HMGB1/TLR4/RAGE signaling in several brain injury, neuroinflammation mediated disorders, epileptogenesis and cognitive dysfunctions and in the light of available evidence, argued the possibilities of HMGB1 as a common viable biomarker of the above mentioned neurological dysfunctions. Furthermore, the review also addresses the result of preclinical studies focused on HMGB1 targeted therapy by the HMGB1 antagonist in several ranges of HMGB1 mediated conditions and noted an encouraging result. These findings suggest HMGB1 as a potential candidate to be a common biomarker of TBI, neuroinflammation, epileptogenesis, and cognitive dysfunctions which can be used for early prediction and progression of those neurological diseases. Future study should explore toward the translational implication of HMGB1 which can open the windows of opportunities for the development of innovative therapeutics that could prevent several associated HMGB1 mediated pathologies discussed herein.

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Crossref · 10.3389/fnins.2018.00628

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FIGURE 1 Interlinkage of HMGB1 with TBI, neuroinflammation, epilepsy and cognitive dysfunction. The HMGB1 contributes to the pathogenesis of TBI, neuroinflammation, epilepsy, and cognitive dysfunction through a putative mechanism outlined in this figure.
FIGURE 1 Interlinkage of HMGB1 with TBI, neuroinflammation, epilepsy and cognitive dysfunction. The HMGB1 contributes to the pathogenesis of TBI, neuroinflammation, epilepsy, and cognitive dysfunction through a putative mechanism outlined in this figure.CC BY · PubMed Central
FIGURE 2 Mechanism of HMGB1 release via brain injury. HMGB1 translocation results from brain injuries and epileptogenesis. Dying cells, neurons and glia are responsible for the release of extracellular HMGB1 which can be partially oxidized. Neuronal excitability is enhanced via the mediation of pro-inflammatory activities through the activation of TLR4 signaling by disulphide HMGB1. The stabilization of HMGB1 in its disulphide form is promoted by the generation of ROS. HMGB1 via activating receptors RAGE and TLR4 leads to neuronal cell loss, neuroinflammation, epilepsy, and cognitive dysfunction (Ravizza et al., 2017).
FIGURE 2 Mechanism of HMGB1 release via brain injury. HMGB1 translocation results from brain injuries and epileptogenesis. Dying cells, neurons and glia are responsible for the release of extracellular HMGB1 which can be partially oxidized. Neuronal excitability is enhanced via the mediation of pro-inflammatory activities through the activation of TLR4 signaling by disulphide HMGB1. The stabilization of HMGB1 in its disulphide form is promoted by the generation of ROS. HMGB1 via activating receptors RAGE and TLR4 leads to neuronal cell loss, neuroinflammation, epilepsy, and cognitive dysfunction (Ravizza et al., 2017).CC BY · PubMed Central
FIGURE 3 Array of factors contributing to epileptogenesis. Much is unknown about the precise mechanism of epileptogenesis making it difficult to design and develop new therapies. But there is an increased understanding that brain injury, BBB disruption, neurodegeneration, oxidative stress, epigenetic DNA modification and pathology of amygdala contribute and aggravate the epileptogenesis.
FIGURE 3 Array of factors contributing to epileptogenesis. Much is unknown about the precise mechanism of epileptogenesis making it difficult to design and develop new therapies. But there is an increased understanding that brain injury, BBB disruption, neurodegeneration, oxidative stress, epigenetic DNA modification and pathology of amygdala contribute and aggravate the epileptogenesis.CC BY · PubMed Central
FIGURE 4 HMGB1/TLR4/RAGE signaling in epilepsy. HMGB1 released from glia and neuronal cells in the CNS, activates its main receptor (TLR4 and RAGE) and contributes to epileptogenesis possibly via BBB disruption and activation of neuroinflammatory pathways.
FIGURE 4 HMGB1/TLR4/RAGE signaling in epilepsy. HMGB1 released from glia and neuronal cells in the CNS, activates its main receptor (TLR4 and RAGE) and contributes to epileptogenesis possibly via BBB disruption and activation of neuroinflammatory pathways.CC BY · PubMed Central

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  1. Mohamed, 2017, Biochemical and apoptotic biomarkers as indicators of time elapsed since death in experimentally induced traumatic brain injury., SM J. Forensic Res. Criminol., 1

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Authors
Paudel, Y. N., Shaikh, M. F., Chakraborti, A., Kumari, Y., Aledo-Serrano, Á., Aleksovska, K., Alvim, M. K. M., & Othman, I.
Affiliations
  • Monash University Malaysia (MY)
  • University of Alabama at Birmingham (US)
  • Ss. Cyril and Methodius University in Skopje (MK)
  • Universidade Estadual de Campinas (UNICAMP) (BR)
Corresponding author
Shaikh, Mohd. Farooq
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2018-09-11
Volume
12
Pages
628-628
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2018.00628
PMC
PMC6142787
OpenAlex
W2889849480
Cited by
311
References
166
Citations by year
2026: 38 · 2025: 29 · 2024: 36 · 2023: 33 · 2022: 56 · 2021: 45 · 2020: 53 · 2019: 19 · 2018: 2
FWCI
3.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Monash University Research Portal (Monash University) (submittedVersion, cc-by)
  • Charles Sturt University Research Output (CRO) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Monash University
  • Monash University Malaysia
  • Jaypee University of Information Technology
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
Keywords
HMGB1, traumatic brain injury, neuroinflammation, epileptogenesis, cognitive impairment, TLR4, RAGE, inflammasome, prognostic factors, neuroinflammatory disorders

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