Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy
Lauren Elizabeth Walker, … , Annamaria Vezzani, Munir Pirmohamed
Lauren Elizabeth Walker, … , Annamaria Vezzani, Munir Pirmohamed
Published May 15, 2017
Citation Information: J Clin Invest. 2017;127(6):2118-2132. https://doi.org/10.1172/JCI92001.
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Research Article Neuroscience

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

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.

Authors

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

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Figure 2

Blood HMGB1 levels increase before epilepsy onset in electrical SE–exposed rats and predict therapeutic response to antiinflammatory drugs.

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Blood HMGB1 levels increase before epilepsy onset in electrical SE–expos...
Longitudinal analysis of total HMGB1 and levels of acetylated, reduced, and disulfide isoforms in blood plasma at representative time points of disease development in SE-exposed rats receiving treatment (drug) or corresponding vehicle (see key). Treatment included anakinra+BoxA+ifenprodil (SE+drug) (detailed protocol in Methods; Supplemental Figure 5A). Data are shown as mean ± SEM (n = 9 rats each group; dot plots are shown in Supplemental Figure 7). Rats are the same as reported in Figure 3. *P < 0.05; **P < 0.01, 1-way ANOVA (referred to both isoforms in each bar, except for prodromal phase, where P < 0.01 in SE+drug versus SE+vehicle refers only to reduced HMGB1). The acetylated isoform level in the chronic epilepsy phase (SE+vehicle) was significantly different from corresponding levels at disease onset and prodromal phases (P < 0.01, repeated measures 1-way ANOVA). The disulfide isoform (SE+vehicle) level at disease onset and in the chronic epilepsy phase was significantly different from the corresponding level in the prodromal phase (P < 0.05 and P < 0.01, respectively); the disulfide isoform level in the chronic phase was significantly different from the corresponding level at disease onset (P < 0.05, repeated measures 1-way ANOVA).