Walker, L. E. et al. (2017) Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy. Journal of Clinical Investigation, 127(6), pp. 2118-2132. (doi: 10.1172/JCI92001) (PMID:28504645) (PMCID:PMC5451237)
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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.
| Item Type: | Articles |
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| Additional Information: | Funding was received from the Medical Research Council (G1000417 to LEW), the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n°602102 (EPITARGET), and Citizens United for Research in Epilepsy (CURE) (to AV). There is a retraction associated with this article at http://eprints.gla.ac.uk/184606/. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Sills, Dr Graeme |
| Authors: | Walker, L. E., Frigerio, F., Ravizza, T., Ricci, E., Tse, K., Jenkins, R. E., Sills, G. J., Jorgensen, A., Porcu, L., Thippeswamy, T., Alapirtti, T., Peltola, J., Brodie, M. J., Park, B. K., Marson, A. G., Antoine, D. J., Vezzani, A., and Pirmohamed, M. |
| College/School: | College of Medical Veterinary and Life Sciences |
| Journal Name: | Journal of Clinical Investigation |
| Publisher: | American Society for Clinical Investigation |
| ISSN: | 0021-9738 |
| ISSN (Online): | 1558-8238 |
| Published Online: | 15 May 2017 |
| Copyright Holders: | Copyright © 2017 The Authors |
| First Published: | First published in Journal of Clinical Investigation 127(6):2118-2132 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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