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

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

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)2118-2132
Number of pages15
JournalJournal of Clinical Investigation
Volume127
Issue number6
Early online date15 May 2017
DOIs
Publication statusPublished - 1 Jun 2017

Keywords / Materials (for Non-textual outputs)

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Anti-Inflammatory Agents
  • Anticonvulsants
  • Biomarkers
  • Brain
  • Drug Evaluation, Preclinical
  • Drug Resistance
  • Epilepsy
  • Female
  • HMGB1 Protein
  • Humans
  • Male
  • Middle Aged
  • Protein Isoforms
  • ROC Curve
  • Rats, Sprague-Dawley
  • Young Adult
  • Journal Article

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