High mobility group box-1 (HMGB1) is a non-histone, DNA-binding nuclear protein belonging to the family of damage-associated molecular patterns (DAMPs). HMGB1 has been reported to play an important role during epileptogenesis although the mechanisms of its actions are still not clear. Many hypotheses have been suggested especially about the relationship between HMGB1 and inflammation responses and blood-brain barrier disruption during epileptogenesis. In this review, we will mainly discuss the role of HMGB1 in epileptogenesis

Fu, Li

Nishibori, Masahiro

Okayama University Scientific Achievement Repository

E pilepsy is a severe neurological disorder charac-terized by spontaneous and recurrent seizures,  affecting about 1% of the general population of all ages and races in the world.  However,  the mechanisms of epileptogenesis remain unknown.  Epilepsy is often refractory to pharmacological treatment [1].  For exam-ple,  about one third of patients are resistant to anti- epileptic drugs (AEDs) [2 , 3].  Additionally,  current AEDs relieve symptoms rather than interfere with the causal mechanisms of the disease,  and therefore do not cure the disorder.  Thus,  the development of a novel anti-epileptic therapeutic is crucial.  Usually,  most patients do not realize that they have epilepsy until they start experiencing seizures.  Clinical trial designs for novel therapeutics against epileptogenesis are hampered by the lack of non-invasive biomarkers that allow for the early identification of patients at high risk of developing epilepsy.Relationship between Central Nervous System (CNS) Disorders and InflammationIn recent years,  it has been suggested that neuroin-flammatory processes play an important role in CNS disorders.  Thus,  the selective targeting of CNS inflam-mation might be a viable strategy for interfering with the progression of neurodegenerative disorders [4].  Translational and clinical evidence support the possibil-ity that neuroinflammatory mediators are implicated in seizures and epileptogenesis [5 , 6],  putting forth the hypothesis that inflammation in the brain contributes to the generation of seizures as well as to cell damage and death.  In turn,  these inflammatory processes trigger further seizures via the activation of inflammatory pathways [7].  Thus,  inflammation can have a causative role as well as a consequential one in regards to epilep-togenesis [7].High-mobility group box 1 (HMGB1) protein is a non-histone,  DNA-binding nuclear protein belonging to the family of damage-associated molecular patterns (DAMPs) [8].  Under normal conditions,  HMGB1 plays important roles in the regulation of gene expres-sion and DNA repair,  and contributes to the architec-ture of chromatin DNA [9].  Mice and rats share 100% of the amino-acid sequence for HMGB1,  while rodents and humans have a 99% homology for the protein [10].  HMGB1 has two domains for DNA binding,  known as ????????? ????????? ????????? ???? ???? ??? ???? ??????????????????? ?????????????????????????????????????????http ://escholarship.lib.okayama-u.ac.jp/amo/ReviewThe Role of High Mobility Group Box-1 in EpileptogenesisLi Fu§ and Masahiro Nishibori＊Department of Pharmacology,  Okayama University Graduate School of Medicine,  Dentistry and Pharmaceutical Sciences,   Okayama 700-8558,  JapanHigh mobility group box-1 (HMGB1) is a non-histone,  DNA-binding nuclear protein belonging to the family of damage-associated molecular patterns (DAMPs).  HMGB1 has been reported to play an important role during epileptogenesis although the mechanisms of its actions are still not clear.  Many hypotheses have been suggested especially about the relationship between HMGB1 and inflammation responses and blood-brain barrier disrup-tion during epileptogenesis.  In this review,  we will mainly discuss the role of HMGB1 in epileptogenesis.Key words:  HMGB1,  epileptogenesis,  inflammation,  blood-brain barrierReceived March 22, 2019 ; accepted May 10, 2019.＊Corresponding author. Phone & Fax : +81-86-235-7140E-mail : mbori@md.okayama-u.ac.jp (M. Nishibori)§The winner of the 2017 Incentive Award of the Okayama Medical Associa-tion in Neuroscience.Conflict of Interest Disclosures: No potential conflict of interest relevant to this article was reported.box A and box B,  as well as a C-terminus acidic tail comprised of repeating glutamate and aspartic acid res-idues [11 ,12].  A member of the DAMP family,  HMGB1 is able to influence synaptic function in brain regions such as the hippocampus,  which is itself involved in hyperexcitability and cognitive decline during epilepto-genesis [2].HMGB1 has received increasing attention in regard to its role in epilepsy [13].  Its involvement with epilep-togenesis is hypothesised to pertain to its role in the induction of inflammatory processes in the peripheral environment,  and in the disruption of the blood-brain barrier (BBB) during the initiation and development of epileptic conditions.The Role of HMGB1 in Neuroinflammation  in EpileptogenesisHMGB1 acts as a pathogenic inflammatory response mediator in a range of conditions.  Evidence for its role in many CNS disorders and insults like stroke,  trauma,  epilepsy and even Alzheimer’s Disease has been reported.  HMGB1 also acts as an initiator and amplifier of neuroinflammation in brain injury types that are highly associated with epilepsy and cognitive dysfunc-tion ascribed to neuronal excitation [14-16].  HMGB1 can be passively released by glia and neurons upon inflammasome activation,  and activates the receptor for advanced glycation end products (RAGE) and toll-like receptor (TLR) 4.  Furthermore,  it is released from apoptotic and necrotic cells,  and actively translocated from the nucleus to the cytoplasm during pyroptosis and inflammasome activation.  HMGB1 also contrib-utes to increased inflammatory responses in the periph-eral environment [3 ,13 ,15-23].  Extracellularly-released HMGB1 can be partially oxidized via the formation of a disulfide bond between cysteine 23 (C23) and cysteine 45 (C45).  This disulfide HMGB1 isoform enhances neuronal excitability and proinflammatory activity through the activation of TLR4.  Also,  HMGB1 activity leads to neuronal cell loss,  neuroinflammation,  epi-lepsy and cognitive dysfunction via the activation of its receptors,  RAGE and TLR4 [24].  Moreover,  HMGB1 has been shown to suppress long-term potentiation (LTP) and cause memory deficits in mice in a TLR4- and RAGE-dependent manner.  These effects are associ-ated with increased activation of JNK and NF-κB [25 , 26].  The HMGB1/TLR4 axis is speculated to be a key initiator of neuroinflammatory factors in epilepto-genesis,  and has consequently gained interest in the field.Electrical stimuli or chemiconvulsants,  like kainic acid (KA) or pilocarpine,  are used to induce the acute stages of epilepsy in animal models.  Researchers observed the translocation of HMGB1 in the brain within 1 h of the onset of seizures,  as well as a dramatic increase in plasma concentrations of HMGB1 4 h after seizure induction with pilocarpine [19].  This implies that seizure activity is a trigger for HMGB1 transloca-tion and its subsequent release.  Seizures are also associ-ated with the up-regulation of TLR4 and RAGE expres-sion on neurons and astrocytes [16 , 27 , 28],  as well as with the upregulation of several related inflammatory factors in the hippocampus.  According to these studies,  the neutralisation of HMGB1 might be a novel thera-peutic strategy for epileptogenesis.Previous studies have shown that the neutralisation of HMGB1 with an anti-HMGB1 monoclonal antibody (mAb) can be a potential novel strategy against multiple sclerosis (MS),  possibly due to the resulting inhibition of pro-inflammatory cytokine production in the peripheral environment.  Further,  the mAb therapy reduces CNS pathological injury [29].  Anti-HMGB1 mAb enhances the activity of HMGB1 Box A,  a protein fragment with antagonistic activity against HMGB1 [13 , 15 , 19],  and reduces the frequency and severity of seizure events.  Zhao et al. ’s study [13] report similar findings in that an anti-HMGB1 mAb treatment was sufficient in significantly reducing the number of spon-taneous seizures in developing animals with induced epileptogenesis [13].  Studies concerned with HMGB1 intervention in established CNS animal models propose that the observed neuroprotective effects are due to a reduction in brain and blood HMGB1 levels [20].  The HMGB1 receptors,  TLR4 and RAGE,  play crucial roles in the presence of elevated extracellular HMGB1 levels during epileptogenesis in epileptic models [25].  Evidence therefore indicates that the release of endoge-nous HMGB1 following epileptogenic events is involved in the pathogenesis of seizures,  and likewise contributes to the recurrence of seizures.  HMGB1 neutralisation therapies have been shown to be beneficial,  and confer remarkable neuroprotection in several models of neu-roinflammation,  further supporting the contention for its use as a novel therapy for epileptogenesis.??? ????????? ????????? ????????????? ???? ???? ??The Role of HMGB1 on Blood-brain Barrier (BBB) Disruption in EpileptogenesisRecent studies suggest the involvement of HMGB1 in epileptogenesis,  especially via the disruption of the BBB in contributing to the pathogenesis of epilepsy [19].  HMGB1-related break-down of the BBB is tied to cognitive deficits in aged rats [30].  BBB disruption in the presence of HMGB1 is widely associated with many CNS disorders,  such as brain trauma and epilepsy.  In these CNS disorders,  inflammatory events occur on brain vessels,  leading to serum albumin extravasation,  which marks BBB dysfunction,  thus suggesting the involvement of HMGB1 in the disruption of vascular barriers [31].  In one study,  BBB break-down was observed 4 h after pilocarpine treatment,  while leakage was significantly decreased after HMGB1 neutralisation with intravenous anti-HMGB1 mAbs,  as observed with Evans Blue,  a serum albumin marker [19].  The benefits of anti-HMGB1 mAb have been demonstrated in other animal models of epilepsy as well.Neuroinflammation directly alters BBB permeability via cytokine-mediated activation of metalloproteinases,  or via the disruption of tight junctions [32 , 33].  This suggests the likely benefit of anti-inflammatory treat-ment for epileptogenesis.  In addition,  glial and astro-cyte activation is purported to serve an important role in the development of epilepsy in animal models.  Since HMGB1 might mediate microglial activation via the TLR4/NF-κB signalling pathway [6],  and is also impli-cated in the break-down of the BBB and secreted in the CNS and peripherally,  an anti-inflammatory therapeu-tic strategy might prove to be beneficial in treating epi-leptogenesis.HMGB1: A Biomarker of EpileptogenesisThe translocation and release of HMGB1 occur in different kinds of epilepsy as evidenced in pharmaco-logical studies using animal brains,  as well as in clinical specimens [15].  Abnormal extracellular HMGB1 levels contribute to the pathophysiology of epilepsy-related hyperexcitability,  which might in turn contribute to seizure onset.  Thus,  HMGB1 might play a crucial role in contributing to the onset of epilepsy-related hyperex-citability [16].  HMGB1 expression was significantly elevated in the hippocampus and cortex 24 h after KA-induced status epilepticus,  and increased in plasma 4 h after pilocarpine treatment,  suggesting the poten-tially crucial role of HMGB1 in epilepsy [34].  Anti-HMGB1 mAb is able to reduce the frequency of seizures and to improve cognitive function,  additionally sup-porting evidence for using HMGB1 as a biomarker of epileptogenesis [19].Similarly,  anti-HMGB1 mAb treatment inhibits BBB leakage and HMGB1 translocation in peripheral sites after pilocarpine induction,  suggesting that the inhibi-tion of HMGB1 translocation potentially reduces or affects BBB permeability [19].  The cited studies impli-cate HMGB1 in the generation of seizures,  thus indi-cating a potentially important target in epileptogenesis.  HMGB1 levels in plasma could be a reliable biomarker for epileptogenesis and seizure recurrence,  further implying that treatment using anti-HMGB1 antibodies might be a novel therapeutic strategy for epileptogene-sis.Acknowledgments.　The authors thank Sakura Nakada,  B.Sc.,  for critical reading and language editing of the manuscript.References 1.  Knake S,  Hamer HM and Rosenow F: Status epilepticus: a criti-cal review.  Epilepsy Behav (2009) 15: 10-14. 2.  Ravizza T,  Onat FY,  Brooks-Kayal AR,  Depaulis A,  Galanopoulou AS,  Mazarati A,  Numis AL,  Sankar R and Friedman A: WONOEP appraisal : Biomarkers of epilepsy-associated comorbidities.  Epilepsia (2017) 58: 331-342. 3.  Walker LE,  Frigerio F,  Ravizza T,  Ricci E,  Tse K,  Jenkins RE,  Sills GJ,  Jorgensen A,  Porcu L,  Thippeswamy T,  Alapirtti T,  Peltola J,  Brodie MJ,  Park BK,  Marson AG,  AntoineDJ,  Vezzani A and Pirmohamed M: Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy.  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The Role of High Mobility Group Box-1 in Epileptogenesis

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The Role of High Mobility Group Box-1 in Epileptogenesis

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