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HMGB1, neuronal excitability and epilepsy

HMGB1, neuronal excitability and epilepsy Epilepsy is a common neurological disease caused by synchronous firing of hyperexcitable neurons. Currently, anti- epileptic drugs remain the main choice to control seizure, but 30% of patients are resistant to the drugs, which calls for more research on new promising targets. Neuroinflammation is closely associated with the development of epilepsy. As an important inflammatory factor, high mobility group protein B1 (HMGB1) has shown elevated expression and an increased proportion of translocation from the nucleus to the cytoplasm in patients with epilepsy and in multiple animal models of epilepsy. HMGB1 can act on downstream receptors such as Toll-like receptor 4 and receptor for advanced glycation end products, thereby activating interleukin (IL)-1β and nuclear factor kappa-B (NF-κB), which in turn act with glutamate receptors such as the N-methyl-D-aspartate (NMDA) receptors to aggravate hyperexcitability and epilepsy. The hyperexcitability can in turn stimulate the expression and translocation of HMGB1. Blocking HMGB1 and its downstream signaling pathways may be a direction for antiepileptic drug therapy. Here, we review the changes of HMGB1-related pathway in epileptic brains and its role in the modulation of neuronal excitability and epileptic seizure. Furthermore, we discuss the potentials of HMGB1 as a therapeutic target for epilepsy and provide perspective on future research on the role of HMGB1 signaling in epilepsy. Keywords: HMGB1, Neuronal excitability, Epilepsy Background the central nervous system (CNS) [7, 8]. Seizures can Epilepsy is a common neurological disease that affects also cause inflammatory responses in the CNS, further about 60 million people worldwide, characterized by re- resulting in damage of the CNS, which may be one of current epileptic seizures [1]. Based on the typical con- the pathological bases of refractory epilepsy [9]. Thus, cept that seizures are caused by synchronized firing of neuroinflammation is closely related to the development overexcited neurons, current antiepileptic drugs are used of epilepsy. Understanding the underlying mechanisms to control seizures by blocking the excitatory mecha- of neuroinflammation in epilepsy would shed light on nisms or enhancing the inhibitory mechanisms. How- new targets for the treatment of refractory epilepsy. ever, 30% of patients are still drug-resistant [2]. High mobility group (HMG) protein is a structural Repeated and unpredictable seizures not only affect the protein in the eukaryotic nucleus that modifies, bends patient’s brain function, leading to mental disorders and and alters the structure of DNA [10, 11]. The HMG cognitive impairment, but may also be life-threatening superfamily mainly includes three families: HMGA, [3–6]. Previous studies have found that inflammatory HMGB and HMGN [12]. The HMGB family includes factors can directly or indirectly affect the electrical ac- three proteins HMGB1, HMGB2 and HMGB3 (previ- tivities of neurons, thereby regulating the excitability of ously HMG4 or HMG2B). Previous studies have shown that the pro-inflammatory cytokine HMGB1 is present in two different forms: intracellular HMGB1 which is * Correspondence: chenzhong@zju.edu.cn 1 mainly involved in gene transcription and regulation, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China and extracellular HMGB1 which functions as an inflam- Key Laboratory of Neuropharmacology and Translational Medicine of matory factor and participates in promoting tumor me- Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese tastasis and inflammatory response [13, 14]. HMGB1 Medical University, Hangzhou 310053, China © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Dai et al. Acta Epileptologica (2021) 3:13 Page 2 of 9 can bind to a variety of receptors, such as receptors for in developmental lesions and autoimmune-related advanced glycation end products (RAGE), toll-like re- epilepsy. ceptor 2 (TLR2) and toll-like receptor 4 (TLR4) [15]. Apart from an increased level in the brain, elevated Upon binding to TLR2, TLR4 or RAGE, HMGB1 can serum levels of HMGB1 have also been observed in epi- promote the activation of cytokines, thereby affecting lepsy patients. After the onset of epilepsy, the total the downstream inflammatory factors that play an im- serum concentration of HMGB1 increases significantly portant role in the modulation of neural excitability and and is especially high in patients with drug-resistant epi- promote the development of epilepsy [16]. In this paper, lepsy [21], which may be one of the reasons for their we review changes in HMGB1-related pathways in the susceptibility to recurrent seizures. The study of Kan epileptic brain and their modulatory role in neuronal ex- et al. has also reported an increased serum HMGB1con- citability and seizures, and summarize the potentials of centration in epilepsy patients and its correlation with HMGB1 to serve as a therapeutic target for epilepsy. seizure severity [22], which suggests that the serum levels of HMGB1 may be predictive of seizure severity and drug resistance in epilepsy. HMGB1 in epilepsy patients Furthermore, application of anti-HMGB1 monoclonal Activation of the HMGB1-related pathway is evident in antibody (mAb) onto the cortical slices from FCD pa- surgically resected brain tissues from epilepsy patients tients and temporal lobe epilepsy patients lead to a sig- (Table 1). Zurolo et al. reported, for the first time, the nificant decrease in amplitude and frequency of increased expression of HMGB1 and its downstream re- spontaneous discharges and an increase of action poten- ceptors such as TLR2, TLR4 and RAGE in pathological tial threshold of neuron [18], indicating the anti- brain tissues of patients with focal cortical dysplasia epileptic potential of anti-HMGB1 mAbs. (FCD). They showed that IL-1β induced by HMGB1 nu- clear transfer in glial cells mediated downstream inflam- HMGB1-related pathways in experimental matory signaling pathways [17]. Zhang et al. have also epilepsy models found significantly increased proteins levels of TLR4, HMGB1 and its related signaling pathways are also acti- cytoplasm HMGB1 and inflammation factors such as IL- vated in animal models of epilepsy, as reflected by in- 1β and tumor necrosis factor-α (TNF-α) in pathological creased expression and increased exocytosis of HMGB1 tissues of FCD type II, compared to those in peri-FCD (Table 2). In acute seizure models, HMGB1 upregulation controls, together with an increased translocation of and translocation have been commonly observed. Mar- HMGB1 from nucleus to cytoplasm [18]. Furthermore, oso et al. have found that the activated HMGB1 and its autoimmune epilepsy also involves the HMGB1-related translocation from the nucleus to the cytoplasm are in- immune activation. In patients with suspected auto- creased in mice with kainic acid (KA)-induced acute immune epilepsy, the cerebrospinal fluid (CSF) HMGB1 seizure [25]. Similarly, Shi et al. have found that the is upregulated significantly [19]. In patients with anti- HMGB1-TLR4 signaling pathway is activated in mice NMDAR encephalitis, the level of CSF HMGB1 is ele- after seizure attacks [24, 36]. We have previously found vated, reflecting the underlying neuroinflammatory that in diazepam (DZP)-refractory status epilepticus (SE) process [20]. These results suggest that the HMGB1- mice, the increased HMGB1 can rapidly reduce the on- TLR4 signaling pathway is intrinsically activated in epi- set threshold of acute SE, which is mediated by down- lepsy patients and may contribute to the hypereclampsia stream receptor TLR4 [28]. The translocation of Table 1 HMGB1-related findings in patients with epilepsy Type of epilepsy Main findings References FCD ↑HMGB1 expression; Zurolo et al. [17], 2011 ↑TLR2, TLR4, RAGE and IL-1β FCD type II ↑expression and mRNA levels of cytoplasmic HMGB1, TLR4, IL-1β and TNF-α; Zhang et al. [18], 2018 ↑translocation of HMGB1 from nucleus to cytoplasm Suspected autoimmune epilepsy ↑CSF HMGB1 Han et al. [19], 2020. Anti-NMDAR encephalitis ↑CSF HMGB1 Ai et al. [20], 2018 Drug-resistant epilepsy ↑Total serum concentration of HMGB1 Lauren et al. [21], 2018 Drug-resistant epilepsy ↑Total serum concentration of HMGB1 and TLR4 expression Kan et al. [22], 2019 Drug-resistant epilepsy ↑HMGB1 expression and translocation in patients’ brain slices Zhao et al. [23], 2017 ↑ Increased, FCD Focal cortical dysplasia, HMGB1 High mobility group box protein 1, TLR2 Toll-like receptor 2, TLR4 Toll-like receptor 4, RAGE Receptors for advanced glycation end products, IL-1β Interleukin-1β, TNF-α Tumor necrosis factor-α, CSF Cerebrospinal fluid Dai et al. Acta Epileptologica (2021) 3:13 Page 3 of 9 Table 2 HMGB1-related findings in experimental models of epilepsy Experimental model Animal strains or cell Model phases Main findings References lines CL-stimulated human microglial cell model Human microglial cells After the ↑HMGB1, TLR4, RAGE, NF-κB p65 Shi et al. stimulation with and iNOS levels [24], 2018 CL KA-induced acute and chronic seizures in mice C57BL/6 mice and During acute and ↑HMGB1 and TLR4 levels; Maroso −/− −/− TLR4 C3H/HeJ mice chronic seizures TLR4 C3H/HeJ mice are et al. [25], resistant to KA-induced seizures 2010 Sombati’s cell model and kainic acid-induced epilepsy SD rats After 24 h and 72 ↑HMGB1 expression and Huang model h translocation et al. [26], EAE model 8-to-10-week-old male During seizures ↑HMGB1 expression; Liu et al. SD rats ↑activation of the TLR4/NF-kB [27], 2017 signaling pathway Acute seizure models (maximal electroshock seizure, C57BL/6 mice (wild- During seizures Anti-HMGB1 mAb treated: Zhao et al. pentylenetetrazole-induced and kindling-induced), type mice) and C57BL/ ↓seizure activities (dose- [23], 2017 and chronic epilepsy model (KA-induced) 10ScNJ mice dependently with minimal side −/− (TLR4 mice) effects); ↓HMGB1 translocation; ↓seizure frequency; ↑cognitive function; The anti-seizure effect was absent −/− in TLR4 mice DZP-refractory SE Male wild-type mice During refractory ↑HMGB1 expression and Zhao et al. −/− (C57BL/6 J) and TLR4 SE period translocation; [28], 2020 mice (C57BL/10ScNj) Anti-HMGB1 mAb treated: ↓incidence of SE and the severity of seizure activity (TLR4- dependent pathway); Plasma HMGB1 level is closely correlated with the therapeutic response of anti-HMGB1 mAb Pilocarpine-induced SE Female C57BL/6 N mice During status Anti-HMGB1 mAb treated: Fu et al. epilepticus ↓BBB breakdown; [29], 2017 ↓HMGB1 translocation; ↓MCP-1, CXCL-1, TLR4, and IL-6 in the hippocampus and cerebral cortex ↓apoptotic cells KA-induced SE P21 male Wistar rats During status ↑mRNA expression of IL-1β and Li et al. epilepticus TNF-α; [30], 2013 ↑microglial activation; ↑neuronal damage in the hippocampus Anti-HMGB1 mAb treated: ↓synthesis of cytokines; ↓microglial activation; ↓neuronal losses in the hippocampus KA-induced neuronal death model Male BALB/c mice GL 10 mg/kg, i.p. ↑neuronal death in both CA1 and Luo et al. 30 min before KA CA3 regions of the hippocampus; [31], 2013 administration GL treated: ↓COX-2, iNOS, and TNF-α; ↓gliosis; ↓neuronal death KA-induced seizure model Male BALB/c mice After 3 h, 6 h, 12 ↑HMGB1 expression and Luo et al. h, 4 d and 6 days translocation; [32], 2014 ↑HMGB1 serum concentration; GL treated: ↓HMGB1 expression and translocation; ↓HMGB1 serum concentration Lithium-pilocarpine-induced SE Adult male SD rats During status ↑HMGB1 expression and Li et al. epilepticus translocation; [33], 2019 Dai et al. Acta Epileptologica (2021) 3:13 Page 4 of 9 Table 2 HMGB1-related findings in experimental models of epilepsy (Continued) Experimental model Animal strains or cell Model phases Main findings References lines ↑HMGB1 serum concentration; ↑neuronal damage; ↑BBB disruption; GL treated: ↓HMGB1 expression and translocation; ↓HMGB1 serum concentration; ↓neuronal damage; ↓BBB disruption KA-induced recurrent seizures model P10 neonatal SD rats At early (14 PND) Celecoxib-treated: Morales- and late (30 PND) ↑time latency of seizures; Sosa et al. time points ↓HMGB1 and TLR4 transcripts; [34], 2018 ↓COX-2 protein expression Pilocarpine-induced SE SD rats After 24 h BoxA-treated: Yu et al. ↓IL-1β, IL-6 and TNF-α but not [35], 2019 HMGB1; ↓BBB permeability; ↓hippocampal neuronal apoptosis; ↓hippocampal microglial activation; ↓TLR4, TLR2 ↑ Increased, ↓ Decreased, CL Coriaria lactone, KA Kainic acid, DZP Diazepam, SE Status epilepticus, HMGB1 High mobility group box protein 1, mAb Monoclonal antibody, TLR4 Toll-like receptor 4, RAGE Receptors for advanced glycation end products, NF-κB Nuclear factor kappa-B, MCP-1 Monocyte chemotactic protein 1, CXCL-1 CXC chemokine ligands 1, iNOS Inducible nitric-oxide synthase, IL-6 Interleukin-6, COX-2 Cyclooxygenase-2, TNF-α Tumor necrosis factor-α, GL Glycyrrhizin, BBB Blood-brain-barrier, PND Postnatal days, SD Sprague-Dawley, EAE experimental autoimmune encephalitis HMGB1 from the nucleus to the cytoplasm in astrocytes seizure models (maximal electroshock seizures, and neurons is upregulated at the injury site in acute pentylenetetrazol-induced and kindling-induced sei- injury-induced epilepsy model [37]. zures) and chronic epilepsy models (KA-induced seizure) The upregulation and translocation of HMGB1 have [23]. The anti-seizure effect of anti-HMGB1 mAb is me- −/− also been observed in chronic epilepsy models. In the diated by downstream TLR4, as TLR4 mice are resist- above-mentioned study by Maroso et al., the same acti- ant to seizure induction and the anti-seizure effect of −/− vation and translocation of HMGB1 were also observed anti-HMGB1 mAb is also vanished in TLR4 mice. in KA-induced chronic epilepsy mouse model. Huang Similar anti-seizure effect of anti-HMGB1 mAb has also et al. have also found upregulation of the expression and been found in coriaria lactone-induced epilepsy model the translocation of HMGB1 in Sombati’s cell model [24], pilocarpine-induced SE in mice [28, 29], and KA- and in KA-induced epilepsy model [26]. In the rat model induced SE in juvenile rats [30]. In DZP-refractory SE, of experimental autoimmune encephalitis, elevated anti-HMGB1 mAb can also reduce the incidence of SE, HMGB1 expression and activation of the TLR4/NF-kB and prolong the DZP treatment time window from 30 signaling pathway also occur in the brain [27]. These re- min to 180 min [39]. These results suggest that anti- sults suggest that during the development of epilepsy, HMGB1 mAb have potential anti-epileptic effects in var- HMGB1 expression and translocation from the nucleus ous epilepsy models. to the cytoplasm are upregulated. Therefore, it is specu- Some other pharmacological agents have also been lated that HMGB1 plays an important role in both acute used to block the HMGB1-related signaling pathways and chronic epileptogenesis [38]. (Table 2). In the acute KA-induced seizure model, gly- In previous studies, HMGB1-related signaling path- cyrrhizin suppression of HMGB1 in the hippocampus ways have been blocked to test the anti-epileptic effects and serum induces attenuation of neuronal cell loss in of HMGB1 in different animal models [39] (Table 2). mouse hippocampus [31, 32]. Li et al. have found similar The most frequently used approach is the use of anti- results in rats after lithium pilocarpine-induced SE [33]. HMGB1 mAbs. We have found that injection of anti- In immature rats with KA-induced chronic epilepsy, cel- HMGB1 mAb into epileptic mice could effectively raise ecoxib could exert neuroprotective effects through the the epileptic seizure threshold, and reduce the duration HMGB1/TLR4 pathway [34]. Administration of nuclear of generalized seizures, as well as the frequency and se- factor kappa-B (NF-κB) inhibitors in rats with SE could verity of epileptic seizures. These inhibitory effects are reduce the mRNA expression of multi-drug resistance observed in a dose-dependent manner in both acute gene-1 and the level of p-gp through blocking the Dai et al. Acta Epileptologica (2021) 3:13 Page 5 of 9 HMGB1/RAGE/NF-κB signaling pathway, thereby redu- receptors, which promotes the excitotoxicity and sei- cing the drug resistance rate of epilepsy [15]. In addition, zures [46, 50, 51]. IL-1β or HMGB1 may lower the seiz- in Sprague-Dawley rats with pilocarpine-induced SE, sig- ure threshold by increasing neuronal sensitivity to nificant down-regulation of IL-1β, IL-6 and TNF-α, but NMDA, allowing more neurons to be recruited into the not of HMGB1, was found after treatment with BoxA NMDA receptor-mediated excitatory loops [52]. (an anti-HMGB1 peptide), and these changes were asso- In addition to the HMGB1-TLR4 signaling pathway, ciated with decreased maintenance of blood-brain bar- Iori et al. have found that HMGB1 activates RAGE, rier (BBB) integrity, reduced hippocampal neuronal which contributes to the hyperexcitability and acute/ apoptosis and reduced hippocampal microglial activation chronic epilepsies, as well as the pro-seizure effects of [35]. All these studies suggest that HMGB1-related path- HMGB1 [50]. However, RAGE appears to have a less way may be a potential target for antiepileptic drug ther- prominent contribution to seizures than TLR4, as a apy. Although previous studies have suggested that greater reduction in KA seizures has been found in −/− blocking HMGB1 signaling has promising anticonvul- TLR4 mice, whereas no delay in seizures found in −/− sant effects, the therapeutic effect remains to be vali- RAGE mice. dated in a more detailed manner, i.e., in different stages of epilepsy, as well as in different etiologies of epilepsy. Hyperexcitability upregulates the HMGB1 signaling On the other hand, studies have revealed that hyperex- HMGB1 relationship with neuronal excitability: citability could upregulate HMGB1 expression and mechanistic insights translocation. For example, activated astrocytes can re- HMGB1 is usually located in the nucleus, and under lease cytokines such as HMGB1 and IL-1β that induce various stressors (for example, cytokines, chemokines, transcriptional and post-transcriptional signaling in as- heat, hypoxia, H O and oncogenes), can transfer to the 2 2 trocytes themselves (autocrine actions) and in nearby cytoplasm, including mitochondria and lysosome. One cells (paracrine actions) [53]. De Simoni et al. have also function of HMGB1 in the cytoplasm is to act as a posi- found that under the hyperexcitability induced by SE in tive regulator of autophagy [40]. HMGB1 can be actively rats, HMGB1-related inflammatory cytokines such as IL- secreted by immune cells or passively released by dead, 1β are upregulated [54], which might then be correlated dying or injured cells. Extracellular HMGB1 has a variety with the upregulation of HMGB1. Hyperexcitability can of activities and participates in multiple processes such also activate microglia, inducing upregulation of inflam- as inflammation, immunity, cell migration, invasion, cell matory mediators such as HMGB1. The excitability- proliferation, cell differentiation, antibacterial defense, induced upregulation of HMGB1 is associated with seiz- and tissue regeneration. However, under pathological ure frequency and duration in patients with drug- conditions such as epilepsy, the expression and trans- resistant epilepsy [55, 56]. In addition, the hyperexcit- location of HMGB1 are significantly increased. ability induced by seizures can upregulate the expression of inflammatory factors including HMGB1 [57]. There- HMGB1 promotes hyperexcitability fore, the upregulation of HMGB1 expression and trans- The mechanisms underlying the role of HMGB1 (usually location is closely associated with hyperexcitability. extracellular HMGB1) in epilepsy have been studied ex- tensively, from perspectives of signaling pathways down- stream of HMGB1 and the upregulation of HMGB1 Sources of HMGB1 signaling induced by hyperexcitability. Harris et al. and Ravizza In addition, some studies have revealed possible cell et al. have found that HMGB1 exerts a pro-epileptic ef- types that contribute to the release of HMGB1. Devinsky fect through the TLR4/NF-κB signaling pathway [41, et al. have found that the HMGB1 pathways mediated by 42]. Iori et al. have further found that blocking the IL-1 the activation of astrocytes and microglia play an im- receptor-1 (IL-1R1)/TLR4 pathway has a therapeutic ef- portant role in the development of epilepsy [53]. fect in models of acquired epilepsy [43]. In addition, HMGB1 is released from necrotic neurons via a NMDA blocking the TLR4 signaling pathway could exert an receptor subunit 2 B-mediated mechanism during trau- anti-epileptic effect [44, 45]. This effect has also been matic brain injury. HMGB1 secretion occurs after severe observed in brain specimens from patients with refrac- injury and tissue hypoperfusion and is associated with tory epilepsy caused by FCD type II [46–48]. Yang fur- post-traumatic coagulation abnormalities, activation of ther found that the HMGB1-TLR4 axis promotes the complement, and severe systemic inflammatory re- development of mesial temporal lobe epilepsy in sponses [58]. Other studies have found that macro- pilocarpine-induced SE model of immature rats and in phages also release HMGB1 [59, 60]. These studies children [49]. In addition, activation of the IL-1R1/TLR4 suggest the presence of various sources of HMGB1: it is 2+ axis in neurons can enhance Ca influx via the NMDA mainly released by neurons, glial cells such as astrocytes Dai et al. Acta Epileptologica (2021) 3:13 Page 6 of 9 and microglia, and other immune cells such as transduction and cell phenotype of vascular endothelial macrophages. cells and pericytes might account for the HMGB1- Furthermore, immune cells such as macrophages and induced BBB damage [66]. monocytes can actively secrete HMGB1 upon stimula- In conclusion, HMGB1 can act on downstream recep- tion by cytokines such as interferon-γ, TNF and IL-1, or tors such as TLR4 and RAGE, activating their down- pathogen-derived molecules such as lipopolysaccharide stream IL-1β and NF-κB, which in turn act with NMDA [59, 61, 62]. Moreover, macrophages release HMGB1 receptors to aggravate hyperexcitability and epilepsy. Hy- upon activation by nucleotide-binding oligomerization perexcitability can also stimulate the expression and domain (NOD) -like receptors-3 (NLRP3) or NLRC4 translocation of HMGB1 mainly in neurons, glial cells (nucleotide-binding oligomerization domains, leucine- and immune cells. These effects may promote each rich repeats and inflammasomes containing caspase re- other in a closed-loop manner. Extracellular HMGB1 cruitment domain-containing-4) [59, 60]. The inflamma- may participate in the destruction of BBB. Blocking somes can mediate the release of cytoplasmic HMGB1 extracellular HMGB1 and its downstream signaling in activated immune cells. Further studies have shown pathways, or inhibiting the hyperexcitability of glial cells that hyperexcitability could lead to the activation of the may be a potential therapeutic target for antiepileptic Janus kinase/signal transducer and activator of tran-ions drug development. (JAK/STAT1) pathway, which induces HMGB1 trans- location from the nucleus to the cytoplasm and conse- Outlook quently cytoplasmic HMGB1 release [63]. Frank et al. Traditional epilepsy treatment strategies primarily target further found that the redox state is a key molecular fea- ion channels to reduce the excitability of neurons, ture of HMGB1, as the reduced form of HMGB1 is thereby inhibiting the generation and development of chemotactic, whereas the disulfide form of HMGB1 (ds- epilepsy. However, long-term use of these drugs may HMGB1) is pro-inflammatory. The NLRP3 inflamma- affect the normal physiological functions of patients some may play a role in the priming effects of ds- [69]. As an important inflammatory factor, HMGB1 bind HMGB1 [64]. These results indicate that the upregula- to downstream receptors, such as TLR4 and RAGE, tion of HMGB1 is mainly induced by cytokines, which in turn mediates neuroinflammatory responses pathogen-derived molecules and inflammasomes, and through signaling pathways such as NMDA receptors. In ds-HMGB1 plays an important role in hyperexcitability. this context, neurons can become over-excited and the In particular, some studies have investigated signaling brain network reshaped, lowering the threshold for seiz- pathways associated with extracellular HMGB1. The ure attack. In addition, the expression of HMGB1 and extracellular HMGB1 forms complexes with other in- TLR4 in patient serum correlates with an increased risk flammatory molecules and is endocytosed into the endo- and severity of seizures, and is associated with resistance lysosomal system via RAGE. The internalized HMGB1 to anti-epileptic drugs. There are still many questions causes destabilization of lysosomal membranes and the waiting to be resolved (Fig. 1). leaky lysosomes allow HMGB1 partner molecules to (1) It remains not fully clear concerning the specific enter cytoplasm that promote the transcription or regu- cellular origin of HMGB1 after the onset of epilepsy and lation of inflammatory factors. Blockade of extracellular whether the answer varies across epileptic stages. If the HMGB1 has the unique potential to improve clinical specific cellular origin of HMGB1 in specific epileptic outcomes of various sterile and infectious inflammation. stages can be elucidated, and the role of HMGB1 in sig- This therapeutic potential has already been proved in ex- naling pathways related with different seizures can be perimental sepsis models, in which the extracellular fully revealed with consideration of confounding factors, HMGB1 can successfully target TLR4 and RAGE even at precise treatment may not be far from us. later time points [65]. However, how intracellular (2) Given the strong association between HMGB1 acti- HMGB1 is related to epileptic seizure is still unclear. In vation and seizures, it remains unclear whether the addition, studies have shown that the destruction of BBB serum level of HMGB1 can be harnessed as a biomarker may be an important mediator in the detrimental effect of epilepsy for its severity, prognosis or therapeutic re- of HMGB1 on epileptogenesis. HMGB1 can lead to BBB sponse. In addition, the sensitivity of serum HMGB1 damage in the pilocarpine-induced SE model [29, 33, concentration in predicting seizure severity in different 35], which further leads to aggravation of epilepsy in SE epilepsy types needs to be further investigated. The model [23, 66–68]. Therefore, blocking the expression translocation ratio of HMGB1 may be referred to as a and release of HMGB1 may be a potential therapeutic potential predictor of epilepsy susceptibility. choice for epilepsy treatment. However, it remains elu- (3) The specific involvement of HMGB1 in epilepto- sive how HMGB1 causes BBB damage. It has been pro- genesis is only partially resolved. The key molecules in posed that changes in gene expression, cell signal the HMGB1-related pathway, and at a more macro level, Dai et al. Acta Epileptologica (2021) 3:13 Page 7 of 9 Fig. 1 Perspectives on the role of HMGB1 in epilepsy. HMGB1 exerts its epilepsy-promoting effects mainly by acting on receptors such as TLR4 and RAGE, activating their downstream IL-1β and NF-κB, which in turn act with glutamate receptors such as NMDA receptors to promote hyperexcitablilty and epilepsy. However, many questions remain to be resolved as listed in the schematic whether HMGB1 upregulation underlies switch-on of oligomerization domain-like receptors-3; NMDA: N-methyl-D-aspartic acid; NOD: Nucleotide binding oligomerization domain; RAGE: Receptors for certain brain circuits or activation of several brain re- advanced glycation end products; SE: Status epilepticus; TLR2: Toll-like gions, are important questions to be addressed. receptor 2; TLR4: Toll-like receptor 4; TNF-α: Tumor necrosis factor-α (4) Previous studies have suggested that anti-HMGB1 Acknowledgments mAb has anticonvulsant effects. The therapeutic effect Not applicable. remains to be validated in a more individualized manner, i.e. at different stages of epilepsy, and for epilepsy of dif- Authors’ contributions ZC conceptualized the review, and revised the manuscript. SJD and YZ ferent etiologies. Clinical trials are also needed to further conducted the systematic search and extracted the eligible studies. SJD confirm the anticonvulsant or antiepileptogenic effect of drafted the study. YW and YZ revised the manuscript. All authors read and HMGB1 inhibition. In addition, whether selective inhib- approved the final manuscript. ition of neuroglia such as astrocytes or microglia to Funding downregulate the HMGB1 level can provide a more tar- This project was supported by grants from the National Natural Science geted anti-seizure effect needs further investigation. Foundation of China (81630098, and 81973298). Availability of data and materials Conclusions Not applicable. In this review, we summarize the changes of HMGB1- related pathway in epileptic brain and their role in the Declarations regulation of neuronal excitability and epileptic seizure. Ethics approval and consent to participate Further, we provide some perspectives for future studies Not applicable. that help reveal the exact roles of the HMGB1 signaling in epilepsy. Notably, a detailed understanding of Consent for publication All authors gave consent to publication of this review. HMGB1 at the microscale and macroscale level is needed. It remains a pivotal task to resolve the previous Competing interests knowledge gap at different levels, from the signaling The authors declare no conflicts of interest. pathway to brain circuits and to epilepsy expression Received: 18 May 2021 Accepted: 16 June 2021 [60]. The use of modern neuroscience tools, including high-resolution recordings and genetically targeted ma- nipulations might help to address those issues. References 1. Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al. Abbreviations ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014; BBB: Blood-brain barrier; CNS: Central nervous system; CSF: Cerebrospinal 55(4):475–82. https://doi.org/10.1111/epi.12550. fluid; ds-HMGB1: Disulfide form HMGB1; DZP: Diazepam; FCD: Focal cortical 2. 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HMGB1, neuronal excitability and epilepsy

Acta Epileptologica , Volume 3 (1) – Jun 30, 2021

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Abstract

Epilepsy is a common neurological disease caused by synchronous firing of hyperexcitable neurons. Currently, anti- epileptic drugs remain the main choice to control seizure, but 30% of patients are resistant to the drugs, which calls for more research on new promising targets. Neuroinflammation is closely associated with the development of epilepsy. As an important inflammatory factor, high mobility group protein B1 (HMGB1) has shown elevated expression and an increased proportion of translocation from the nucleus to the cytoplasm in patients with epilepsy and in multiple animal models of epilepsy. HMGB1 can act on downstream receptors such as Toll-like receptor 4 and receptor for advanced glycation end products, thereby activating interleukin (IL)-1β and nuclear factor kappa-B (NF-κB), which in turn act with glutamate receptors such as the N-methyl-D-aspartate (NMDA) receptors to aggravate hyperexcitability and epilepsy. The hyperexcitability can in turn stimulate the expression and translocation of HMGB1. Blocking HMGB1 and its downstream signaling pathways may be a direction for antiepileptic drug therapy. Here, we review the changes of HMGB1-related pathway in epileptic brains and its role in the modulation of neuronal excitability and epileptic seizure. Furthermore, we discuss the potentials of HMGB1 as a therapeutic target for epilepsy and provide perspective on future research on the role of HMGB1 signaling in epilepsy. Keywords: HMGB1, Neuronal excitability, Epilepsy Background the central nervous system (CNS) [7, 8]. Seizures can Epilepsy is a common neurological disease that affects also cause inflammatory responses in the CNS, further about 60 million people worldwide, characterized by re- resulting in damage of the CNS, which may be one of current epileptic seizures [1]. Based on the typical con- the pathological bases of refractory epilepsy [9]. Thus, cept that seizures are caused by synchronized firing of neuroinflammation is closely related to the development overexcited neurons, current antiepileptic drugs are used of epilepsy. Understanding the underlying mechanisms to control seizures by blocking the excitatory mecha- of neuroinflammation in epilepsy would shed light on nisms or enhancing the inhibitory mechanisms. How- new targets for the treatment of refractory epilepsy. ever, 30% of patients are still drug-resistant [2]. High mobility group (HMG) protein is a structural Repeated and unpredictable seizures not only affect the protein in the eukaryotic nucleus that modifies, bends patient’s brain function, leading to mental disorders and and alters the structure of DNA [10, 11]. The HMG cognitive impairment, but may also be life-threatening superfamily mainly includes three families: HMGA, [3–6]. Previous studies have found that inflammatory HMGB and HMGN [12]. The HMGB family includes factors can directly or indirectly affect the electrical ac- three proteins HMGB1, HMGB2 and HMGB3 (previ- tivities of neurons, thereby regulating the excitability of ously HMG4 or HMG2B). Previous studies have shown that the pro-inflammatory cytokine HMGB1 is present in two different forms: intracellular HMGB1 which is * Correspondence: chenzhong@zju.edu.cn 1 mainly involved in gene transcription and regulation, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China and extracellular HMGB1 which functions as an inflam- Key Laboratory of Neuropharmacology and Translational Medicine of matory factor and participates in promoting tumor me- Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese tastasis and inflammatory response [13, 14]. HMGB1 Medical University, Hangzhou 310053, China © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Dai et al. Acta Epileptologica (2021) 3:13 Page 2 of 9 can bind to a variety of receptors, such as receptors for in developmental lesions and autoimmune-related advanced glycation end products (RAGE), toll-like re- epilepsy. ceptor 2 (TLR2) and toll-like receptor 4 (TLR4) [15]. Apart from an increased level in the brain, elevated Upon binding to TLR2, TLR4 or RAGE, HMGB1 can serum levels of HMGB1 have also been observed in epi- promote the activation of cytokines, thereby affecting lepsy patients. After the onset of epilepsy, the total the downstream inflammatory factors that play an im- serum concentration of HMGB1 increases significantly portant role in the modulation of neural excitability and and is especially high in patients with drug-resistant epi- promote the development of epilepsy [16]. In this paper, lepsy [21], which may be one of the reasons for their we review changes in HMGB1-related pathways in the susceptibility to recurrent seizures. The study of Kan epileptic brain and their modulatory role in neuronal ex- et al. has also reported an increased serum HMGB1con- citability and seizures, and summarize the potentials of centration in epilepsy patients and its correlation with HMGB1 to serve as a therapeutic target for epilepsy. seizure severity [22], which suggests that the serum levels of HMGB1 may be predictive of seizure severity and drug resistance in epilepsy. HMGB1 in epilepsy patients Furthermore, application of anti-HMGB1 monoclonal Activation of the HMGB1-related pathway is evident in antibody (mAb) onto the cortical slices from FCD pa- surgically resected brain tissues from epilepsy patients tients and temporal lobe epilepsy patients lead to a sig- (Table 1). Zurolo et al. reported, for the first time, the nificant decrease in amplitude and frequency of increased expression of HMGB1 and its downstream re- spontaneous discharges and an increase of action poten- ceptors such as TLR2, TLR4 and RAGE in pathological tial threshold of neuron [18], indicating the anti- brain tissues of patients with focal cortical dysplasia epileptic potential of anti-HMGB1 mAbs. (FCD). They showed that IL-1β induced by HMGB1 nu- clear transfer in glial cells mediated downstream inflam- HMGB1-related pathways in experimental matory signaling pathways [17]. Zhang et al. have also epilepsy models found significantly increased proteins levels of TLR4, HMGB1 and its related signaling pathways are also acti- cytoplasm HMGB1 and inflammation factors such as IL- vated in animal models of epilepsy, as reflected by in- 1β and tumor necrosis factor-α (TNF-α) in pathological creased expression and increased exocytosis of HMGB1 tissues of FCD type II, compared to those in peri-FCD (Table 2). In acute seizure models, HMGB1 upregulation controls, together with an increased translocation of and translocation have been commonly observed. Mar- HMGB1 from nucleus to cytoplasm [18]. Furthermore, oso et al. have found that the activated HMGB1 and its autoimmune epilepsy also involves the HMGB1-related translocation from the nucleus to the cytoplasm are in- immune activation. In patients with suspected auto- creased in mice with kainic acid (KA)-induced acute immune epilepsy, the cerebrospinal fluid (CSF) HMGB1 seizure [25]. Similarly, Shi et al. have found that the is upregulated significantly [19]. In patients with anti- HMGB1-TLR4 signaling pathway is activated in mice NMDAR encephalitis, the level of CSF HMGB1 is ele- after seizure attacks [24, 36]. We have previously found vated, reflecting the underlying neuroinflammatory that in diazepam (DZP)-refractory status epilepticus (SE) process [20]. These results suggest that the HMGB1- mice, the increased HMGB1 can rapidly reduce the on- TLR4 signaling pathway is intrinsically activated in epi- set threshold of acute SE, which is mediated by down- lepsy patients and may contribute to the hypereclampsia stream receptor TLR4 [28]. The translocation of Table 1 HMGB1-related findings in patients with epilepsy Type of epilepsy Main findings References FCD ↑HMGB1 expression; Zurolo et al. [17], 2011 ↑TLR2, TLR4, RAGE and IL-1β FCD type II ↑expression and mRNA levels of cytoplasmic HMGB1, TLR4, IL-1β and TNF-α; Zhang et al. [18], 2018 ↑translocation of HMGB1 from nucleus to cytoplasm Suspected autoimmune epilepsy ↑CSF HMGB1 Han et al. [19], 2020. Anti-NMDAR encephalitis ↑CSF HMGB1 Ai et al. [20], 2018 Drug-resistant epilepsy ↑Total serum concentration of HMGB1 Lauren et al. [21], 2018 Drug-resistant epilepsy ↑Total serum concentration of HMGB1 and TLR4 expression Kan et al. [22], 2019 Drug-resistant epilepsy ↑HMGB1 expression and translocation in patients’ brain slices Zhao et al. [23], 2017 ↑ Increased, FCD Focal cortical dysplasia, HMGB1 High mobility group box protein 1, TLR2 Toll-like receptor 2, TLR4 Toll-like receptor 4, RAGE Receptors for advanced glycation end products, IL-1β Interleukin-1β, TNF-α Tumor necrosis factor-α, CSF Cerebrospinal fluid Dai et al. Acta Epileptologica (2021) 3:13 Page 3 of 9 Table 2 HMGB1-related findings in experimental models of epilepsy Experimental model Animal strains or cell Model phases Main findings References lines CL-stimulated human microglial cell model Human microglial cells After the ↑HMGB1, TLR4, RAGE, NF-κB p65 Shi et al. stimulation with and iNOS levels [24], 2018 CL KA-induced acute and chronic seizures in mice C57BL/6 mice and During acute and ↑HMGB1 and TLR4 levels; Maroso −/− −/− TLR4 C3H/HeJ mice chronic seizures TLR4 C3H/HeJ mice are et al. [25], resistant to KA-induced seizures 2010 Sombati’s cell model and kainic acid-induced epilepsy SD rats After 24 h and 72 ↑HMGB1 expression and Huang model h translocation et al. [26], EAE model 8-to-10-week-old male During seizures ↑HMGB1 expression; Liu et al. SD rats ↑activation of the TLR4/NF-kB [27], 2017 signaling pathway Acute seizure models (maximal electroshock seizure, C57BL/6 mice (wild- During seizures Anti-HMGB1 mAb treated: Zhao et al. pentylenetetrazole-induced and kindling-induced), type mice) and C57BL/ ↓seizure activities (dose- [23], 2017 and chronic epilepsy model (KA-induced) 10ScNJ mice dependently with minimal side −/− (TLR4 mice) effects); ↓HMGB1 translocation; ↓seizure frequency; ↑cognitive function; The anti-seizure effect was absent −/− in TLR4 mice DZP-refractory SE Male wild-type mice During refractory ↑HMGB1 expression and Zhao et al. −/− (C57BL/6 J) and TLR4 SE period translocation; [28], 2020 mice (C57BL/10ScNj) Anti-HMGB1 mAb treated: ↓incidence of SE and the severity of seizure activity (TLR4- dependent pathway); Plasma HMGB1 level is closely correlated with the therapeutic response of anti-HMGB1 mAb Pilocarpine-induced SE Female C57BL/6 N mice During status Anti-HMGB1 mAb treated: Fu et al. epilepticus ↓BBB breakdown; [29], 2017 ↓HMGB1 translocation; ↓MCP-1, CXCL-1, TLR4, and IL-6 in the hippocampus and cerebral cortex ↓apoptotic cells KA-induced SE P21 male Wistar rats During status ↑mRNA expression of IL-1β and Li et al. epilepticus TNF-α; [30], 2013 ↑microglial activation; ↑neuronal damage in the hippocampus Anti-HMGB1 mAb treated: ↓synthesis of cytokines; ↓microglial activation; ↓neuronal losses in the hippocampus KA-induced neuronal death model Male BALB/c mice GL 10 mg/kg, i.p. ↑neuronal death in both CA1 and Luo et al. 30 min before KA CA3 regions of the hippocampus; [31], 2013 administration GL treated: ↓COX-2, iNOS, and TNF-α; ↓gliosis; ↓neuronal death KA-induced seizure model Male BALB/c mice After 3 h, 6 h, 12 ↑HMGB1 expression and Luo et al. h, 4 d and 6 days translocation; [32], 2014 ↑HMGB1 serum concentration; GL treated: ↓HMGB1 expression and translocation; ↓HMGB1 serum concentration Lithium-pilocarpine-induced SE Adult male SD rats During status ↑HMGB1 expression and Li et al. epilepticus translocation; [33], 2019 Dai et al. Acta Epileptologica (2021) 3:13 Page 4 of 9 Table 2 HMGB1-related findings in experimental models of epilepsy (Continued) Experimental model Animal strains or cell Model phases Main findings References lines ↑HMGB1 serum concentration; ↑neuronal damage; ↑BBB disruption; GL treated: ↓HMGB1 expression and translocation; ↓HMGB1 serum concentration; ↓neuronal damage; ↓BBB disruption KA-induced recurrent seizures model P10 neonatal SD rats At early (14 PND) Celecoxib-treated: Morales- and late (30 PND) ↑time latency of seizures; Sosa et al. time points ↓HMGB1 and TLR4 transcripts; [34], 2018 ↓COX-2 protein expression Pilocarpine-induced SE SD rats After 24 h BoxA-treated: Yu et al. ↓IL-1β, IL-6 and TNF-α but not [35], 2019 HMGB1; ↓BBB permeability; ↓hippocampal neuronal apoptosis; ↓hippocampal microglial activation; ↓TLR4, TLR2 ↑ Increased, ↓ Decreased, CL Coriaria lactone, KA Kainic acid, DZP Diazepam, SE Status epilepticus, HMGB1 High mobility group box protein 1, mAb Monoclonal antibody, TLR4 Toll-like receptor 4, RAGE Receptors for advanced glycation end products, NF-κB Nuclear factor kappa-B, MCP-1 Monocyte chemotactic protein 1, CXCL-1 CXC chemokine ligands 1, iNOS Inducible nitric-oxide synthase, IL-6 Interleukin-6, COX-2 Cyclooxygenase-2, TNF-α Tumor necrosis factor-α, GL Glycyrrhizin, BBB Blood-brain-barrier, PND Postnatal days, SD Sprague-Dawley, EAE experimental autoimmune encephalitis HMGB1 from the nucleus to the cytoplasm in astrocytes seizure models (maximal electroshock seizures, and neurons is upregulated at the injury site in acute pentylenetetrazol-induced and kindling-induced sei- injury-induced epilepsy model [37]. zures) and chronic epilepsy models (KA-induced seizure) The upregulation and translocation of HMGB1 have [23]. The anti-seizure effect of anti-HMGB1 mAb is me- −/− also been observed in chronic epilepsy models. In the diated by downstream TLR4, as TLR4 mice are resist- above-mentioned study by Maroso et al., the same acti- ant to seizure induction and the anti-seizure effect of −/− vation and translocation of HMGB1 were also observed anti-HMGB1 mAb is also vanished in TLR4 mice. in KA-induced chronic epilepsy mouse model. Huang Similar anti-seizure effect of anti-HMGB1 mAb has also et al. have also found upregulation of the expression and been found in coriaria lactone-induced epilepsy model the translocation of HMGB1 in Sombati’s cell model [24], pilocarpine-induced SE in mice [28, 29], and KA- and in KA-induced epilepsy model [26]. In the rat model induced SE in juvenile rats [30]. In DZP-refractory SE, of experimental autoimmune encephalitis, elevated anti-HMGB1 mAb can also reduce the incidence of SE, HMGB1 expression and activation of the TLR4/NF-kB and prolong the DZP treatment time window from 30 signaling pathway also occur in the brain [27]. These re- min to 180 min [39]. These results suggest that anti- sults suggest that during the development of epilepsy, HMGB1 mAb have potential anti-epileptic effects in var- HMGB1 expression and translocation from the nucleus ous epilepsy models. to the cytoplasm are upregulated. Therefore, it is specu- Some other pharmacological agents have also been lated that HMGB1 plays an important role in both acute used to block the HMGB1-related signaling pathways and chronic epileptogenesis [38]. (Table 2). In the acute KA-induced seizure model, gly- In previous studies, HMGB1-related signaling path- cyrrhizin suppression of HMGB1 in the hippocampus ways have been blocked to test the anti-epileptic effects and serum induces attenuation of neuronal cell loss in of HMGB1 in different animal models [39] (Table 2). mouse hippocampus [31, 32]. Li et al. have found similar The most frequently used approach is the use of anti- results in rats after lithium pilocarpine-induced SE [33]. HMGB1 mAbs. We have found that injection of anti- In immature rats with KA-induced chronic epilepsy, cel- HMGB1 mAb into epileptic mice could effectively raise ecoxib could exert neuroprotective effects through the the epileptic seizure threshold, and reduce the duration HMGB1/TLR4 pathway [34]. Administration of nuclear of generalized seizures, as well as the frequency and se- factor kappa-B (NF-κB) inhibitors in rats with SE could verity of epileptic seizures. These inhibitory effects are reduce the mRNA expression of multi-drug resistance observed in a dose-dependent manner in both acute gene-1 and the level of p-gp through blocking the Dai et al. Acta Epileptologica (2021) 3:13 Page 5 of 9 HMGB1/RAGE/NF-κB signaling pathway, thereby redu- receptors, which promotes the excitotoxicity and sei- cing the drug resistance rate of epilepsy [15]. In addition, zures [46, 50, 51]. IL-1β or HMGB1 may lower the seiz- in Sprague-Dawley rats with pilocarpine-induced SE, sig- ure threshold by increasing neuronal sensitivity to nificant down-regulation of IL-1β, IL-6 and TNF-α, but NMDA, allowing more neurons to be recruited into the not of HMGB1, was found after treatment with BoxA NMDA receptor-mediated excitatory loops [52]. (an anti-HMGB1 peptide), and these changes were asso- In addition to the HMGB1-TLR4 signaling pathway, ciated with decreased maintenance of blood-brain bar- Iori et al. have found that HMGB1 activates RAGE, rier (BBB) integrity, reduced hippocampal neuronal which contributes to the hyperexcitability and acute/ apoptosis and reduced hippocampal microglial activation chronic epilepsies, as well as the pro-seizure effects of [35]. All these studies suggest that HMGB1-related path- HMGB1 [50]. However, RAGE appears to have a less way may be a potential target for antiepileptic drug ther- prominent contribution to seizures than TLR4, as a apy. Although previous studies have suggested that greater reduction in KA seizures has been found in −/− blocking HMGB1 signaling has promising anticonvul- TLR4 mice, whereas no delay in seizures found in −/− sant effects, the therapeutic effect remains to be vali- RAGE mice. dated in a more detailed manner, i.e., in different stages of epilepsy, as well as in different etiologies of epilepsy. Hyperexcitability upregulates the HMGB1 signaling On the other hand, studies have revealed that hyperex- HMGB1 relationship with neuronal excitability: citability could upregulate HMGB1 expression and mechanistic insights translocation. For example, activated astrocytes can re- HMGB1 is usually located in the nucleus, and under lease cytokines such as HMGB1 and IL-1β that induce various stressors (for example, cytokines, chemokines, transcriptional and post-transcriptional signaling in as- heat, hypoxia, H O and oncogenes), can transfer to the 2 2 trocytes themselves (autocrine actions) and in nearby cytoplasm, including mitochondria and lysosome. One cells (paracrine actions) [53]. De Simoni et al. have also function of HMGB1 in the cytoplasm is to act as a posi- found that under the hyperexcitability induced by SE in tive regulator of autophagy [40]. HMGB1 can be actively rats, HMGB1-related inflammatory cytokines such as IL- secreted by immune cells or passively released by dead, 1β are upregulated [54], which might then be correlated dying or injured cells. Extracellular HMGB1 has a variety with the upregulation of HMGB1. Hyperexcitability can of activities and participates in multiple processes such also activate microglia, inducing upregulation of inflam- as inflammation, immunity, cell migration, invasion, cell matory mediators such as HMGB1. The excitability- proliferation, cell differentiation, antibacterial defense, induced upregulation of HMGB1 is associated with seiz- and tissue regeneration. However, under pathological ure frequency and duration in patients with drug- conditions such as epilepsy, the expression and trans- resistant epilepsy [55, 56]. In addition, the hyperexcit- location of HMGB1 are significantly increased. ability induced by seizures can upregulate the expression of inflammatory factors including HMGB1 [57]. There- HMGB1 promotes hyperexcitability fore, the upregulation of HMGB1 expression and trans- The mechanisms underlying the role of HMGB1 (usually location is closely associated with hyperexcitability. extracellular HMGB1) in epilepsy have been studied ex- tensively, from perspectives of signaling pathways down- stream of HMGB1 and the upregulation of HMGB1 Sources of HMGB1 signaling induced by hyperexcitability. Harris et al. and Ravizza In addition, some studies have revealed possible cell et al. have found that HMGB1 exerts a pro-epileptic ef- types that contribute to the release of HMGB1. Devinsky fect through the TLR4/NF-κB signaling pathway [41, et al. have found that the HMGB1 pathways mediated by 42]. Iori et al. have further found that blocking the IL-1 the activation of astrocytes and microglia play an im- receptor-1 (IL-1R1)/TLR4 pathway has a therapeutic ef- portant role in the development of epilepsy [53]. fect in models of acquired epilepsy [43]. In addition, HMGB1 is released from necrotic neurons via a NMDA blocking the TLR4 signaling pathway could exert an receptor subunit 2 B-mediated mechanism during trau- anti-epileptic effect [44, 45]. This effect has also been matic brain injury. HMGB1 secretion occurs after severe observed in brain specimens from patients with refrac- injury and tissue hypoperfusion and is associated with tory epilepsy caused by FCD type II [46–48]. Yang fur- post-traumatic coagulation abnormalities, activation of ther found that the HMGB1-TLR4 axis promotes the complement, and severe systemic inflammatory re- development of mesial temporal lobe epilepsy in sponses [58]. Other studies have found that macro- pilocarpine-induced SE model of immature rats and in phages also release HMGB1 [59, 60]. These studies children [49]. In addition, activation of the IL-1R1/TLR4 suggest the presence of various sources of HMGB1: it is 2+ axis in neurons can enhance Ca influx via the NMDA mainly released by neurons, glial cells such as astrocytes Dai et al. Acta Epileptologica (2021) 3:13 Page 6 of 9 and microglia, and other immune cells such as transduction and cell phenotype of vascular endothelial macrophages. cells and pericytes might account for the HMGB1- Furthermore, immune cells such as macrophages and induced BBB damage [66]. monocytes can actively secrete HMGB1 upon stimula- In conclusion, HMGB1 can act on downstream recep- tion by cytokines such as interferon-γ, TNF and IL-1, or tors such as TLR4 and RAGE, activating their down- pathogen-derived molecules such as lipopolysaccharide stream IL-1β and NF-κB, which in turn act with NMDA [59, 61, 62]. Moreover, macrophages release HMGB1 receptors to aggravate hyperexcitability and epilepsy. Hy- upon activation by nucleotide-binding oligomerization perexcitability can also stimulate the expression and domain (NOD) -like receptors-3 (NLRP3) or NLRC4 translocation of HMGB1 mainly in neurons, glial cells (nucleotide-binding oligomerization domains, leucine- and immune cells. These effects may promote each rich repeats and inflammasomes containing caspase re- other in a closed-loop manner. Extracellular HMGB1 cruitment domain-containing-4) [59, 60]. The inflamma- may participate in the destruction of BBB. Blocking somes can mediate the release of cytoplasmic HMGB1 extracellular HMGB1 and its downstream signaling in activated immune cells. Further studies have shown pathways, or inhibiting the hyperexcitability of glial cells that hyperexcitability could lead to the activation of the may be a potential therapeutic target for antiepileptic Janus kinase/signal transducer and activator of tran-ions drug development. (JAK/STAT1) pathway, which induces HMGB1 trans- location from the nucleus to the cytoplasm and conse- Outlook quently cytoplasmic HMGB1 release [63]. Frank et al. Traditional epilepsy treatment strategies primarily target further found that the redox state is a key molecular fea- ion channels to reduce the excitability of neurons, ture of HMGB1, as the reduced form of HMGB1 is thereby inhibiting the generation and development of chemotactic, whereas the disulfide form of HMGB1 (ds- epilepsy. However, long-term use of these drugs may HMGB1) is pro-inflammatory. The NLRP3 inflamma- affect the normal physiological functions of patients some may play a role in the priming effects of ds- [69]. As an important inflammatory factor, HMGB1 bind HMGB1 [64]. These results indicate that the upregula- to downstream receptors, such as TLR4 and RAGE, tion of HMGB1 is mainly induced by cytokines, which in turn mediates neuroinflammatory responses pathogen-derived molecules and inflammasomes, and through signaling pathways such as NMDA receptors. In ds-HMGB1 plays an important role in hyperexcitability. this context, neurons can become over-excited and the In particular, some studies have investigated signaling brain network reshaped, lowering the threshold for seiz- pathways associated with extracellular HMGB1. The ure attack. In addition, the expression of HMGB1 and extracellular HMGB1 forms complexes with other in- TLR4 in patient serum correlates with an increased risk flammatory molecules and is endocytosed into the endo- and severity of seizures, and is associated with resistance lysosomal system via RAGE. The internalized HMGB1 to anti-epileptic drugs. There are still many questions causes destabilization of lysosomal membranes and the waiting to be resolved (Fig. 1). leaky lysosomes allow HMGB1 partner molecules to (1) It remains not fully clear concerning the specific enter cytoplasm that promote the transcription or regu- cellular origin of HMGB1 after the onset of epilepsy and lation of inflammatory factors. Blockade of extracellular whether the answer varies across epileptic stages. If the HMGB1 has the unique potential to improve clinical specific cellular origin of HMGB1 in specific epileptic outcomes of various sterile and infectious inflammation. stages can be elucidated, and the role of HMGB1 in sig- This therapeutic potential has already been proved in ex- naling pathways related with different seizures can be perimental sepsis models, in which the extracellular fully revealed with consideration of confounding factors, HMGB1 can successfully target TLR4 and RAGE even at precise treatment may not be far from us. later time points [65]. However, how intracellular (2) Given the strong association between HMGB1 acti- HMGB1 is related to epileptic seizure is still unclear. In vation and seizures, it remains unclear whether the addition, studies have shown that the destruction of BBB serum level of HMGB1 can be harnessed as a biomarker may be an important mediator in the detrimental effect of epilepsy for its severity, prognosis or therapeutic re- of HMGB1 on epileptogenesis. HMGB1 can lead to BBB sponse. In addition, the sensitivity of serum HMGB1 damage in the pilocarpine-induced SE model [29, 33, concentration in predicting seizure severity in different 35], which further leads to aggravation of epilepsy in SE epilepsy types needs to be further investigated. The model [23, 66–68]. Therefore, blocking the expression translocation ratio of HMGB1 may be referred to as a and release of HMGB1 may be a potential therapeutic potential predictor of epilepsy susceptibility. choice for epilepsy treatment. However, it remains elu- (3) The specific involvement of HMGB1 in epilepto- sive how HMGB1 causes BBB damage. It has been pro- genesis is only partially resolved. The key molecules in posed that changes in gene expression, cell signal the HMGB1-related pathway, and at a more macro level, Dai et al. Acta Epileptologica (2021) 3:13 Page 7 of 9 Fig. 1 Perspectives on the role of HMGB1 in epilepsy. HMGB1 exerts its epilepsy-promoting effects mainly by acting on receptors such as TLR4 and RAGE, activating their downstream IL-1β and NF-κB, which in turn act with glutamate receptors such as NMDA receptors to promote hyperexcitablilty and epilepsy. However, many questions remain to be resolved as listed in the schematic whether HMGB1 upregulation underlies switch-on of oligomerization domain-like receptors-3; NMDA: N-methyl-D-aspartic acid; NOD: Nucleotide binding oligomerization domain; RAGE: Receptors for certain brain circuits or activation of several brain re- advanced glycation end products; SE: Status epilepticus; TLR2: Toll-like gions, are important questions to be addressed. receptor 2; TLR4: Toll-like receptor 4; TNF-α: Tumor necrosis factor-α (4) Previous studies have suggested that anti-HMGB1 Acknowledgments mAb has anticonvulsant effects. The therapeutic effect Not applicable. remains to be validated in a more individualized manner, i.e. at different stages of epilepsy, and for epilepsy of dif- Authors’ contributions ZC conceptualized the review, and revised the manuscript. SJD and YZ ferent etiologies. Clinical trials are also needed to further conducted the systematic search and extracted the eligible studies. SJD confirm the anticonvulsant or antiepileptogenic effect of drafted the study. YW and YZ revised the manuscript. All authors read and HMGB1 inhibition. In addition, whether selective inhib- approved the final manuscript. ition of neuroglia such as astrocytes or microglia to Funding downregulate the HMGB1 level can provide a more tar- This project was supported by grants from the National Natural Science geted anti-seizure effect needs further investigation. Foundation of China (81630098, and 81973298). Availability of data and materials Conclusions Not applicable. In this review, we summarize the changes of HMGB1- related pathway in epileptic brain and their role in the Declarations regulation of neuronal excitability and epileptic seizure. Ethics approval and consent to participate Further, we provide some perspectives for future studies Not applicable. that help reveal the exact roles of the HMGB1 signaling in epilepsy. Notably, a detailed understanding of Consent for publication All authors gave consent to publication of this review. HMGB1 at the microscale and macroscale level is needed. It remains a pivotal task to resolve the previous Competing interests knowledge gap at different levels, from the signaling The authors declare no conflicts of interest. pathway to brain circuits and to epilepsy expression Received: 18 May 2021 Accepted: 16 June 2021 [60]. The use of modern neuroscience tools, including high-resolution recordings and genetically targeted ma- nipulations might help to address those issues. References 1. Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al. Abbreviations ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014; BBB: Blood-brain barrier; CNS: Central nervous system; CSF: Cerebrospinal 55(4):475–82. https://doi.org/10.1111/epi.12550. fluid; ds-HMGB1: Disulfide form HMGB1; DZP: Diazepam; FCD: Focal cortical 2. 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Journal

Acta EpileptologicaSpringer Journals

Published: Jun 30, 2021

Keywords: HMGB1; Neuronal excitability; Epilepsy

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