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

Abstract

Epilepsy is a serious neurological condition exhibiting complex pathology and deserving of more serious attention. More than 30% of people with epilepsy are not responsive to more than 20 anti‐epileptic drugs currently available, reflecting an unmet clinical need for novel therapeutic strategies. Not much is known about the pathogenesis of epilepsy, but evidence indicates that neuroinflammation might contribute to the onset and progression of epilepsy following acquired brain insults. However, the molecular mechanisms underlying these pathophysiological processes are yet to be fully understood. The emerging research suggests that high‐mobility group box protein 1 (HMGB1), a DNA‐binding protein that is both actively secreted by inflammatory cells and released by necrotic cells, might contribute to the pathogenesis of epilepsy. HMGB1 as an initiator and amplifier of neuroinflammation, and its activation is implicated in the propagation of seizures in animal models. The current review will highlight the potential role of HMGB1 in the pathogenesis of epilepsy, and implications of HMGB1‐targeted therapies against epilepsy. HMGB1 in this context is an emerging concept deserving further exploration. Increased understanding of HMGB1 in seizures and epilepsy will pave the way in designing novel and innovative therapeutic strategies that could modify the disease course or prevent its development.

The potential roles of high mobility group box 1 (HMGB1) in musculoskeletal disease: A systematic review

“…Therefore, one could conclude that HMGB1 might have a protective effect in IVDs, whereas it has a pro‐inflammatory effect in arthritic tissues. Another explanation is that these divergent biological functions may be attributed to differential HMGB1 redox states as a consequence of an extracellular environment 14,93‐97 . However, the HMGB1 redox status remains understudied in human musculoskeletal disease.…”

Microglial polarization in posttraumatic epilepsy: Potential mechanism and treatment opportunity

“…Glycyrrhizin treatment suppressed HMGB1 expression in a weight drop injury model in rats, subsequently inducing M2‐like microglia polarization and improving functional recovery . Accordingly, HMGB1 is also reported to be an important mediator of inflammation in epilepsy models and has potential as a predictive biomarker of epileptic seizures . Rosiglitazone, a potent peroxisome proliferator‐activated receptor γ (PPARγ) agonist with anti‐inflammatory properties, has been reported to induce M2 polarization in a TBI model in mice, attenuating axonal injury and improving neurological function .…”

“…83 Accordingly, HMGB1 is also reported to be an important mediator of inflammation in epilepsy models and has potential as a predictive biomarker of epileptic seizures. 10,84 Rosiglitazone, a potent peroxisome proliferator-activated receptor γ (PPARγ) agonist with anti-inflammatory properties, has been reported to induce M2 polarization in a TBI model in mice, attenuating axonal injury and improving neurological function. 85 However, improved TBI outcomes by rosiglitazone may also involve other biological mechanisms, such as limiting the mitochondrial dysfunction and oxidative damage, as well as suppressing autophagy.…”

“…Such differences in the activation states are mainly characterized to date by the expression of specific immunogenic markers, but are not identified by any distinct morphological traits. M1‐like activated microglia, or more precisely the mediators of M1 signaling, including interleukin (IL)‐1β, tumor necrosis factor α (TNFα), and high‐mobility group box 1 (HMGB1), have been implicated in epileptogenesis . In contrast, M2 inflammation mediators including anti‐inflammatory cytokines act to downregulate the responses of M1‐like microglia, thereby potentially limiting epileptogenesis.…”

“…M1-like activated microglia, or more precisely the mediators of M1 signaling, including interleukin (IL)-1β, tumor necrosis factor α (TNFα), and high-mobility group box 1 (HMGB1), have been implicated in epileptogenesis. 10 In contrast, M2 inflammation mediators including anti-inflammatory cytokines act to downregulate the responses of M1-like microglia, thereby potentially limiting epileptogenesis. In addition, these anti-inflammatory molecules are also directly associated with some of the pathological outcomes thought to be relevant to epileptogenesis, but generally work in opposition to the effects of M1 phenotype activation.…”