HMGB1 Is a Therapeutic Target and Biomarker in Diazepam-Refractory Status Epilepticus with Wide Time Window

Zhao, Junli; Zheng, Yang; Liu, Keyue; Chen, Junzi; Lai, Nanxi; Fan, Fudong; Shi, Jiaying; Xu, Cenglin; Wang, Shuang; Nishibori, Masahiro; Wang, Yi; Chen, Zhong

doi:10.1007/s13311-019-00815-3

Cited by 38 publications

(30 citation statements)

References 60 publications

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“…Pre-treatment with mAb 2.5 and mAb 5 decreases the GABA level when compared to the second hit PTZ group. This might be due to the fact that DZP being positive allosteric modulator of the GABA A receptors, HMGB1 decrease the effectiveness of GABA-mediated inhibitory functions ( Zhao et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Anti-High Mobility Group Box-1 Monoclonal Antibody Attenuates Seizure-Induced Cognitive Decline by Suppressing Neuroinflammation in an Adult Zebrafish Model

2021

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Epilepsy is a chronic brain disease afflicting around 70 million global population and is characterized by persisting predisposition to generate epileptic seizures. The precise understanding of the etiopathology of seizure generation is still elusive, however, brain inflammation is considered as a major contributor to epileptogenesis. HMGB1 protein being an initiator and crucial contributor of inflammation is known to contribute significantly to seizure generation via activating its principal receptors namely RAGE and TLR4 reflecting a potential therapeutic target. Herein, we evaluated an anti-seizure and memory ameliorating potential of an anti-HMGB1 monoclonal antibody (mAb) (1, 2.5 and 5 mg/kg, I.P.) in a second hit Pentylenetetrazol (PTZ) (80 mg/kg, I.P.) induced seizure model earlier stimulated with Pilocarpine (400 mg/kg, I.P.) in adult zebrafish. Pre-treatment with anti-HMGB1 mAb dose-dependently lowered the second hit PTZ-induced seizure but does not alter the disease progression. Moreover, anti-HMGB1 mAb also attenuated the second hit Pentylenetetrazol induced memory impairment in adult zebrafish as evidenced by an increased inflection ration at 3 and 24 h trail in T-maze test. Besides, decreased level of GABA and an upregulated Glutamate level was observed in the second hit PTZ induced group, which was modulated by pre-treatment with anti-HMGB1 mAb. Inflammatory responses occurred during the progression of seizures as evidenced by upregulated mRNA expression of HMGB1, TLR4, NF-κB, and TNF-α, in a second hit PTZ group, which was in-turn downregulated upon pre-treatment with anti-HMGB1 mAb reflecting its anti-inflammatory potential. Anti-HMGB1 mAb modulates second hit PTZ induced changes in mRNA expression of CREB-1 and NPY. Our findings indicates anti-HMGB1 mAb attenuates second hit PTZ-induced seizures, ameliorates related memory impairment, and downregulates the seizure induced upregulation of inflammatory markers to possibly protect the zebrafish from the incidence of further seizures through via modulation of neuroinflammatory pathway.

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Section: Discussionmentioning

confidence: 99%

Anti-High Mobility Group Box-1 Monoclonal Antibody Attenuates Seizure-Induced Cognitive Decline by Suppressing Neuroinflammation in an Adult Zebrafish Model

2021

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“…Taking these results together, we speculate that the HMGB1 released from different sources in response to epileptogenic stimuli may mediate the specific processes leading to status epilepticus, with increased neuronal excitability, including glutamate release, upregulation of IL-1b, TNF-a, TLR-4, and disruption of the BBB [ 21 , 25 , 111 , 112 ]. Moreover, Zhao et al [ 113 ] demonstrated that neutralization of HMGB1 with mAb inhibited a diazepam-resistant status epilepticus model, and this inhibition was mediated by a TLR-4-dependent pathway. Most of the antiepileptics currently available are activators or inhibitors of ion channels in the plasma membrane.…”

Section: Epilepsy and Bbb Disruptionmentioning

confidence: 99%

High Mobility Group Box-1 and Blood–Brain Barrier Disruption

Nishibori

Wang

Ousaka

et al. 2020

Cells

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Increasing evidence suggests that inflammatory responses are involved in the progression of brain injuries induced by a diverse range of insults, including ischemia, hemorrhage, trauma, epilepsy, and degenerative diseases. During the processes of inflammation, disruption of the blood–brain barrier (BBB) may play a critical role in the enhancement of inflammatory responses and may initiate brain damage because the BBB constitutes an interface between the brain parenchyma and the bloodstream containing blood cells and plasma. The BBB has a distinct structure compared with those in peripheral tissues: it is composed of vascular endothelial cells with tight junctions, numerous pericytes surrounding endothelial cells, astrocytic endfeet, and a basement membrane structure. Under physiological conditions, the BBB should function as an important element in the neurovascular unit (NVU). High mobility group box-1 (HMGB1), a nonhistone nuclear protein, is ubiquitously expressed in almost all kinds of cells. HMGB1 plays important roles in the maintenance of chromatin structure, the regulation of transcription activity, and DNA repair in nuclei. On the other hand, HMGB1 is considered to be a representative damage-associated molecular pattern (DAMP) because it is translocated and released extracellularly from different types of brain cells, including neurons and glia, contributing to the pathophysiology of many diseases in the central nervous system (CNS). The regulation of HMGB1 release or the neutralization of extracellular HMGB1 produces beneficial effects on brain injuries induced by ischemia, hemorrhage, trauma, epilepsy, and Alzheimer’s amyloidpathy in animal models and is associated with improvement of the neurological symptoms. In the present review, we focus on the dynamics of HMGB1 translocation in different disease conditions in the CNS and discuss the functional roles of extracellular HMGB1 in BBB disruption and brain inflammation. There might be common as well as distinct inflammatory processes for each CNS disease. This review will provide novel insights toward an improved understanding of a common pathophysiological process of CNS diseases, namely, BBB disruption mediated by HMGB1. It is proposed that HMGB1 might be an excellent target for the treatment of CNS diseases with BBB disruption.

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“…), mice were mounted in a stereotaxic apparatus (512600, Stoelting, United States). Electrodes were implanted into the right hippocampus (AP: −2.9 mm, L: −3.0 mm, V: −3.0 mm) ( Zhao et al, 2020 ). The electrodes were made of twisted stainless steel Teflon-coated wires (diameter 0.2 mm, A.M. Systems, United States) insulated except at the tip (0.5 mm); the tip separation was about 0.5 mm.…”

Section: Methodsmentioning

confidence: 99%

Anti-Epileptic Effect of Crocin on Experimental Temporal Lobe Epilepsy in Mice

et al. 2022

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Temporal lobe epilepsy (TLE) is a common kind of refractory epilepsy. More than 30% TLE patients were multi-drug resistant. Some patients may even develop into status epilepticus (SE) because of failing to control seizures. Thus, one of the avid goals for anti-epileptic drug development is to discover novel potential compounds to treat TLE or even SE. Crocin, an effective component of Crocus sativus L., has been applied in several epileptogenic models to test its anti-epileptic effect. However, it is still controversial and its effect on TLE remains unclear. Therefore, we investigated the effects of crocin on epileptogenesis, generalized seizures (GS) in hippocampal rapid electrical kindling model as well as SE and spotaneous recurrent seizure (SRS) in pilocarpine-induced TLE model in ICR mice in this study. The results showed that seizure stages and cumulative afterdischarge duration were significantly depressed by crocin (20 and 50 mg/kg) during hippocampal rapid kindling acquisition. And crocin (100 mg/kg) significantly reduced the incidence of GS and average seizure stages in fully kindled animals. In pilocarpine-induced TLE model, the latency of SE was significantly prolonged and the mortality of SE was significantly decreased by crocin (100 mg/kg), which can also significantly suppress the number of SRS. The underlying mechanism of crocin may be involved in the protection of neurons, the decrease of tumor necrosis factor-α in the hippocampus and the increase of brain derived neurotrophic factor in the cortex. In conclusion, crocin may be a potential and promising anti-epileptic compound for treatment of TLE.

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HMGB1 Is a Therapeutic Target and Biomarker in Diazepam-Refractory Status Epilepticus with Wide Time Window

Cited by 38 publications

References 60 publications

Anti-High Mobility Group Box-1 Monoclonal Antibody Attenuates Seizure-Induced Cognitive Decline by Suppressing Neuroinflammation in an Adult Zebrafish Model

Anti-High Mobility Group Box-1 Monoclonal Antibody Attenuates Seizure-Induced Cognitive Decline by Suppressing Neuroinflammation in an Adult Zebrafish Model

High Mobility Group Box-1 and Blood–Brain Barrier Disruption

Anti-Epileptic Effect of Crocin on Experimental Temporal Lobe Epilepsy in Mice

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