Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy

Walker, Lauren; Frigerio, Federica; Ricci, Emanuele; Tse, Karen; Jenkins, Rosalind E.; Sills, Graeme J.; Jorgensen, Andrea; Porcu, Luca; Thippeswamy, Thimmasettappa; Alapirtti, Tiina; Peltola, Jukka; Brodie, Martin J.; Park, Brian Kevin; Marson, Anthony G; Antoine, Daniel J.; Vezzani, Annamaria; Pirmohamed, Munir

doi:10.1172/jci129285

Cited by 37 publications

(72 citation statements)

References 39 publications

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“…This phenomenon is consistent with active release of HMGB1 from activated glial cells [93]. Blood HMGB1 is likely to originate mainly from the brain, since brain changes preceded, and are mirrored by, corresponding blood modifications [93]. In parallel clinical studies, we found that patients with drug-resistant epilepsy have significantly higher blood levels of total HMGB1 than healthy controls and patients with well-controlled epilepsy Fig.…”

Section: Soluble Molecules Reflecting Astrocyte Activationsupporting

confidence: 83%

“…[39] ◂ development, both acetylated and disulfide isoforms progressively increased and accounted for the majority of total HMGB1 blood levels. This phenomenon is consistent with active release of HMGB1 from activated glial cells [93]. Blood HMGB1 is likely to originate mainly from the brain, since brain changes preceded, and are mirrored by, corresponding blood modifications [93].…”

Section: Soluble Molecules Reflecting Astrocyte Activationsupporting

confidence: 71%

“…We have measured total HMGB1, and its acetylated, reduced and disulfide isoforms before epilepsy onset and during disease development in an animal model of acquired epilepsy, correlating brain changes to those in blood [93]. In adult rats exposed to electrical SE, non-acetylated and reduced HMGB1 isoforms increase in blood within hours consistent with passive release of HMGB1 from injured cells.…”

Section: Soluble Molecules Reflecting Astrocyte Activationmentioning

confidence: 99%

“…Another potential candidate molecule is High Mobility Group Box 1 (HMGB1), a chromatin-bound protein which is released by activated astrocytes during epileptogenesis [91][92][93]. HMGB1 exists in several isoforms, and each isoform has distinct pathophysiological functions.…”

Section: Soluble Molecules Reflecting Astrocyte Activationmentioning

confidence: 99%

“…A decay in the rate of learning and accelerated forgetting are common cognitive deficits of animals developing epilepsy [41] and human temporal lobe epilepsy [62], and in animal models these neurobehavioral features anticipate the onset of spontaneous seizures [41]. Animal studies suggest that cognitive deficits and increased excitability resulting in seizures may be reflected by an increased activation of sub-populations of GFAPpositive astrocytes which express S100β (see text for details) [93]. Moreover, a pilot study in patients with newly-diagnosed epilepsy showed an early increase of the pathological disulfide HMGB1 isoform in blood that persists only in patients with seizure relapse under AEDs treatment [93].…”

Section: Soluble Molecules Reflecting Astrocyte Activationmentioning

confidence: 99%

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Biomarkers of Epileptogenesis: The Focus on Glia and Cognitive Dysfunctions

2017

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The need to find measures that reliably predict the onset of epilepsy after injurious events or how the patient will respond to anti-seizure drugs led to intensive pre-clinical and clinical research to discover non-invasive biomarkers that could increase the sensitivity of existing clinical indicators. The use of experimental models of epileptogenesis and of drug-resistance is instrumental to select the most promising approaches to explore such biomarkers in the pre-clinical setting for further clinical validation. The approaches most frequently used to find clinically useful biomarkers of epileptogenesis include molecular brain imaging, EEG signal analysis and the measure of soluble molecules in biofluids which may reflect brain intrinsic events involved in epilepsy development. Among those, we focused our attention on proton magnetic resonance imaging (H-MRS)-based analysis of astrocytic activation, and related blood biomarkers, since this cell population appears to be pivotally involved in various epileptogenesis processes triggered by differing insults. Moreover, we also investigated behavioral biomarkers by focusing on cognitive dysfunctions since this deficit represents a typical co-morbidity in epilepsy which may manifest even before the onset of spontaneous seizures. In this review article, we will report our recently published evidence supporting the utility of measuring astrocyte activation, the soluble molecules they release, and the associated cognitive deficits during epileptogenesis for early stratification of animals developing epilepsy. We will discuss the potential clinical translation of our findings for enriching the patient population in preventive clinical trials designed to study anti-epileptogenic treatments.

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Section: Soluble Molecules Reflecting Astrocyte Activationsupporting

confidence: 83%

Section: Soluble Molecules Reflecting Astrocyte Activationsupporting

confidence: 71%

Section: Soluble Molecules Reflecting Astrocyte Activationmentioning

confidence: 99%

Section: Soluble Molecules Reflecting Astrocyte Activationmentioning

confidence: 99%

Section: Soluble Molecules Reflecting Astrocyte Activationmentioning

confidence: 99%

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Biomarkers of Epileptogenesis: The Focus on Glia and Cognitive Dysfunctions

2017

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Pharmacological targeting of brain inflammation in epilepsy: Therapeutic perspectives from experimental and clinical studies

Ravizza

Vezzani

2018

Epilepsia Open

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SummaryIncreasing evidence supports a pathogenic role of unabated neuroinflammation in various central nervous system (CNS) diseases, including epilepsy. Neuroinflammation is not a bystander phenomenon of the diseased brain tissue, but it may contribute to neuronal hyperexcitability underlying seizure generation, cell loss, and neurologic comorbidities. Several molecules, which constitute the inflammatory milieu in the epileptogenic area, activate signaling pathways in neurons and glia resulting in pathologic modifications of cell function, which ultimately lead to alterations in synaptic transmission and plasticity. Herein we report the up‐to‐date experimental and clinical evidence that supports the neuromodulatory role of inflammatory mediators, their related signaling pathways, and involvement in epilepsy. We discuss how these mechanisms can be harnessed to discover and validate targets for novel therapeutics, which may prevent or control pharmacoresistant epilepsies.

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A companion to the preclinical common data elements for pharmacologic studies in animal models of seizures and epilepsy. A Report of the TASK3 Pharmacology Working Group of the ILAE/AES Joint Translational Task Force

et al. 2018

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SummaryPreclinical pharmacology studies in animal models of seizures and epilepsy have provided a platform to identify more than 20 antiseizure drugs in recent decades. To minimize variability in lab‐to‐lab studies and to harmonize approaches to data collection and reporting methodology in pharmacologic evaluations of the next generation of therapies, we present common data elements (CDEs), case report forms (CRFs), and this companion manuscript to help with the implementation of methods for studies in established preclinical seizure and epilepsy models in adult rodents. The development of and advocacy for CDEs in preclinical research has been encouraged previously by both clinical and preclinical groups. It is anticipated that adoption and implementation of these CDEs in preclinical studies may help standardize approaches to minimize variability and increase the reproducibility of preclinical studies. Moreover, they may provide a methodologic framework for pharmacology studies in atypical animal models or models in development, which may ultimately promote novel therapy development. In the present document, we refer selectively to animal models that have a long history of preclinical use, and in some cases, are clinically validated.

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Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy

Cited by 37 publications

References 39 publications

Biomarkers of Epileptogenesis: The Focus on Glia and Cognitive Dysfunctions

Biomarkers of Epileptogenesis: The Focus on Glia and Cognitive Dysfunctions

Pharmacological targeting of brain inflammation in epilepsy: Therapeutic perspectives from experimental and clinical studies

A companion to the preclinical common data elements for pharmacologic studies in animal models of seizures and epilepsy. A Report of the TASK3 Pharmacology Working Group of the ILAE/AES Joint Translational Task Force

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