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 1

Brain and blood HMGB1 measurements during epileptogenesis evoked by electrical SE in adult rats.

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Brain and blood HMGB1 measurements during epileptogenesis evoked by elec...
(A) Representative photomicrographs of hippocampi from control rats (sham) or rats at 3 hours, 6 hours, and 4 days after SE (n = 5 each group). Top row shows HMGB1 immunoreactivity in cell nuclei (arrows) or in cytoplasm of glial cells (arrowheads). Immunofluorescence panels show localization of HMGB1 signal (green) in OX-42–positive microglia (red), GFAP-positive astrocytes (red), and EBA-positive endothelial cells (red); colocalization signal is depicted in yellow (merge). White arrows depict cytoplasmic staining. Hoechst-positive nuclei are shown in blue. Rad, stratum radiatum; LMol, stratum lacunosum moleculare. Scale bars: 25 μm (top row); 20 μm (bottom row; immunofluorescence panels). (B) Levels of HMGB1 isoforms in brain tissue (hippocampus) and corresponding blood of rats during epileptogenesis. Data are shown as mean ± SEM (n = 5 each group). Dot plots are shown in Supplemental Figure 4. *P < 0.05; **P < 0.01, Kruskal-Wallis test (referred to both isoforms in each bar). Blood acetylated and disulfide HMGB1 levels at 4 days are significantly different from corresponding 3-hour and 6-hour levels (P < 0.01).