HMGB1 mediates microglia activation via the TLR4/NF-κB pathway in coriaria lactone induced epilepsy

Abstract

Epilepsy is a chronic and recurrent disease of the central nervous system, with a complex pathology. Recent studies have demonstrated that the activation of glial cells serve an important role in the development of epilepsy. The objective of the present study was to investigate the role of high-mobility group box-1 (HMGB1) in mediating the activation of glial cells through the toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB signaling pathway in seizure, and the underlying mechanism. The brain tissue of post-surgery patients with intractable epilepsy after resection and the normal control brain tissue of patients with craniocerebral trauma induced intracranial hypertension were collected. The expression level and distribution pattern of HMGB1, OX42 and NF-κB p65 were detected by immunohistochemistry. HMGB1, TLR4, receptor for advanced glycation end products (RAGE), NF-κB p65 and inducible nitric oxide synthase (iNOS) expression levels were detected by western blotting, and serum cytokine levels of interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β and IL-10 in patients with epilepsy and craniocerebral trauma were detected by ELISA. And cell model of epilepsy was established by coriaria lactone (CL)-stimulated HM cell, and the same factors were measured. The potential toxic effect of HMGB1 on HM cells was evaluated by MTT and 5-ethynyl-2-deoxyuridine assays. The results demonstrated that compared with the control group, levels of HMGB1, TLR4, RAGE, NF-κB p65 and iNOS in the brain of the epilepsy group were significantly increased, and increased cytokine levels of IL-1, IL-6, TNF-α, TGF-β and IL-10 in patients with epilepsy were also observed. At the same time, the above results were also observed in HM cells stimulated with CL. Overexpression of HMGB1 enhanced the results, while HMGB1 small interfering RNA blocked the function of CL. There was no significant toxic effect of HMGB1 on HM cells. In conclusion, overexpression of HMGB1 potentially promoted epileptogenesis. CL-induced activation of glial cells may act via up-regulation of HMGB1 and TLR4/RAGE receptors, and the downstream transcription factor NF-κB.

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

“…HMGB1 contributes in epileptogenesis mainly through microglial activation, by the TLR4‐NF‐κB signaling axis activation (Shi et al . ). In a Picrotoxin/low Mg 2+ entorhinal cortex (EC) slice model, IL‐1β and HMGB1 favor ictal‐like discharge production whereas in focal seizure model or 4‐aminopyridine (4‐AP) model it lowered ictal‐like discharge threshold.…”

“…Immunohistochemical staining suggested the nuclear to cytoplasmic translocation of HMGB1 in neurons and glial cells and reported its release into the extracellular space. HMGB1 contributes in epileptogenesis mainly through microglial activation, by the TLR4-NF-jB signaling axis activation (Shi et al 2018). In a Picrotoxin/low Mg 2+ entorhinal cortex (EC) slice model, IL-1b and HMGB1 favor ictal-like discharge production whereas in focal seizure model or 4-aminopyridine (4-AP) model it lowered ictal-like discharge threshold.…”

Autoimmune seizures and epilepsy

“…IL-1β, HMGB1, and the corresponding receptors IL-1R1 and TLR4 have downstream effects that converge with the TNF pathway at the transcription factor NF-κΒ, which regulates the synthesis of cytokines and modulates the expression of genes involved in cell death and survival, neurogenesis, and synaptic plasticity (86,87). A separate nontranscriptional pathway related to IL-1R1 and TLR activation involves Src and other kinase systems that result in phosphorylation of the NMDAR GluN2B subunit and other receptor-coupled or voltage-dependent ion channels, affecting neuronal excitability (88,89).…”

Progesterone, 5a-dihydropogesterone and allopregnanolone's effects on seizures: A review of animal and clinical studies

“…Both systemic and CNS inflammatory markers are elevated in drug-resistant seizure disorders such as West syndrome (infantile spasms), viral encephalitis-induced epilepsy [68], drug-resistant temporal lobe epilepsy [69], and status epilepticus [70]. These include markers such as IL-1B, IL-6, TNFa [71] and NF-kB [72].…”