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 4

Early prediction of epilepsy development by monitoring blood HMGB1 level in lithium+pilocarpine SE rats.

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Early prediction of epilepsy development by monitoring blood HMGB1 level...
(A) Longitudinal analysis of total HMGB1 and acetylated, reduced, and disulfide isoform levels in blood at representative time points of disease development (see key in A). Blood was drawn at 23 days (epileptogenic phase prodromal to epilepsy onset), 73 days (encompassing the time of disease onset in 70% of rats), and 7.5 months (chronic epilepsy). Data represent mean ± SEM; n = 7 sham; n = 5 epileptic (Epi); n = 5 nonepileptic (Nonepi) rats. Dot plots are shown in Supplemental Figure 10. **P < 0.01 (refers to both isoforms in each bar); P < 0.05, acetylated HMGB1 in epileptic versus sham, Kruskal-Wallis test. Total HMGB1, acetylated and disulfide isoform levels in the chronic phase (Epi) are significantly different versus corresponding levels in prodromal phase (P < 0.01, repeated measures 1-way ANOVA). (B) Representative immunohistochemical pictures of CA1 stratum radiatum depicting HMGB1 staining in control (sham, n = 7) and in SE rats with (Epi, n = 5 out of 12) or without (Nonepi, n = 5) spontaneous seizures. Rats are the same as reported in A. Brains were harvested 7.5 months after SE. Arrows, nuclear staining of HMGB1 in sham and nonepileptic rats; arrowheads, cytoplasmic HMGB1 staining in glia in epileptic rats. Scale bar: 15 μm.