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

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

doi:10.1172/jci92001

Abstract

Approximately 30% of epilepsy patients do not respond to antiepileptic drugs, representing an unmet medical need. There is evidence that neuroinflammation plays a pathogenic role in drug-resistant epilepsy. The high-mobility group box 1 (HMGB1)/TLR4 axis is a key initiator of neuroinflammation following epileptogenic injuries, and its activation contributes to seizure generation in animal models. However, further work is required to understand the role of HMGB1 and its isoforms in epileptogenesis and drug resistance. Using a combination of animal models and sera from clinically well-characterized patients, we have demonstrated that there are dynamic changes in HMGB1 isoforms in the brain and blood of animals undergoing epileptogenesis. The pathologic disulfide HMGB1 isoform progressively increased in blood before epilepsy onset and prospectively identified animals that developed the disease. Consistent with animal data, we observed early expression of disulfide HMGB1 in patients with newly diagnosed epilepsy, and its persistence was associated with subsequent seizures. In contrast with patients with well-controlled epilepsy, patients with chronic, drug-refractory epilepsy persistently expressed the acetylated, disulfide HMGB1 isoforms. Moreover, treatment of animals with antiinflammatory drugs during epileptogenesis prevented both disease progression and blood increase in HMGB1 isoforms. Our data suggest that HMGB1 isoforms are mechanistic biomarkers for epileptogenesis and drug-resistant epilepsy in humans, necessitating evaluation in larger-scale prospective studies.

Highlights

Epileptogenesis is a dynamic process of molecular, cellular, and functional reorganization following precipitating events that leads to brain pathology capable of generating spontaneous seizures [1]
Our first objective was to establish whether a relationship exists between brain and blood levels of high-mobility group box 1 (HMGB1) during the acute injury and early epileptogenesis following status epilepticus (SE), a brain insult leading to epilepsy in animal models and humans [17, 18]
We investigated whether HMGB1 translocates from the nucleus to the cytoplasm during epileptogenesis (Figure 1A), since this step is required for its cellular release, the consequent biological effects [19], and its potential brain-to-blood transfer

Summary

Introduction

Epileptogenesis is a dynamic process of molecular, cellular, and functional reorganization following precipitating events that leads to brain pathology capable of generating spontaneous seizures [1]. Used antiepileptic drugs (AEDs) merely provide symptomatic control of seizures, and around 30% of patients have epilepsy that is refractory to AEDs [2]. The development of effective therapies to treat or prevent epileptogenesis and drug resistance remains an urgent unmet clinical need. Neuroinflammation in seizure-prone brain regions is a common feature of various forms of drug-resistant, focal-onset symptomatic epilepsies in humans and contributes to mechanisms of seizure generation in animal models [3]. Conflict of interest: The authors have declared that no conflict of interest exists. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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