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Table 2 HMGB1-related findings in experimental models of epilepsy

From: HMGB1, neuronal excitability and epilepsy

Experimental model Animal strains or cell lines Model phases Main findings References
CL-stimulated human microglial cell model Human microglial cells After the stimulation with CL ↑HMGB1, TLR4, RAGE, NF-κB p65 and iNOS levels Shi et al. [24], 2018
KA-induced acute and chronic seizures in mice C57BL/6 mice and TLR4−/− C3H/HeJ mice During acute and chronic seizures ↑HMGB1 and TLR4 levels;
TLR4−/− C3H/HeJ mice are resistant to KA-induced seizures
Maroso et al. [25], 2010
Sombati’s cell model and kainic acid-induced epilepsy model SD rats After 24 h and 72 h ↑HMGB1 expression and translocation Huang et al. [26], 2015
EAE model 8-to-10-week-old male SD rats During seizures ↑HMGB1 expression;
↑activation of the TLR4/NF-kB signaling pathway
Liu et al. [27], 2017
Acute seizure models (maximal electroshock seizure, pentylenetetrazole-induced and kindling-induced), and chronic epilepsy model (KA-induced) C57BL/6 mice (wild-type mice) and C57BL/10ScNJ mice
(TLR4−/− mice)
During seizures Anti-HMGB1 mAb treated:
↓seizure activities (dose-dependently with minimal side effects);
↓HMGB1 translocation;
↓seizure frequency;
↑cognitive function;
The anti-seizure effect was absent in TLR4−/− mice
Zhao et al. [23], 2017
DZP-refractory SE Male wild-type mice (C57BL/6 J) and TLR4−/− mice (C57BL/10ScNj) During refractory SE period ↑HMGB1 expression and translocation;
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
Zhao et al. [28], 2020
Pilocarpine-induced SE Female C57BL/6 N mice During status epilepticus Anti-HMGB1 mAb treated:
↓BBB breakdown;
↓HMGB1 translocation;
↓MCP-1, CXCL-1, TLR4, and IL-6 in the hippocampus and cerebral cortex
↓apoptotic cells
Fu et al. [29], 2017
KA-induced SE P21 male Wistar rats During status epilepticus ↑mRNA expression of IL-1β and TNF-α;
↑microglial activation;
↑neuronal damage in the hippocampus
Anti-HMGB1 mAb treated:
↓synthesis of cytokines;
↓microglial activation;
↓neuronal losses in the hippocampus
Li et al. [30], 2013
KA-induced neuronal death model Male BALB/c mice GL 10 mg/kg, i.p. 30 min before KA administration ↑neuronal death in both CA1 and CA3 regions of the hippocampus;
GL treated:
↓COX-2, iNOS, and TNF-α;
↓neuronal death
Luo et al. [31], 2013
KA-induced seizure model Male BALB/c mice After 3 h, 6 h, 12 h, 4 d and 6 days ↑HMGB1 expression and translocation;
↑HMGB1 serum concentration;
GL treated:
↓HMGB1 expression and translocation;
↓HMGB1 serum concentration
Luo et al. [32], 2014
Lithium-pilocarpine-induced SE Adult male SD rats During status epilepticus ↑HMGB1 expression and translocation;
↑HMGB1 serum concentration;
↑neuronal damage;
↑BBB disruption;
GL treated:
↓HMGB1 expression and translocation;
↓HMGB1 serum concentration;
↓neuronal damage;
↓BBB disruption
Li et al. [33], 2019
KA-induced recurrent seizures model P10 neonatal SD rats At early (14 PND) and late (30 PND) time points Celecoxib-treated:
↑time latency of seizures;
↓HMGB1 and TLR4 transcripts;
↓COX-2 protein expression
Morales-Sosa et al. [34], 2018
Pilocarpine-induced SE SD rats After 24 h BoxA-treated:
↓IL-1β, IL-6 and TNF-α but not HMGB1;
↓BBB permeability;
↓hippocampal neuronal apoptosis;
↓hippocampal microglial activation;
Yu et al. [35], 2019
  1. ↑ 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