Matrix metalloproteinase-mediated blood-brain barrier dysfunction in epilepsy

Ralf G. Rempe, Anika M.S. Hartz, Emma L.B. Soldner, Brent S. Sokola, Satya R. Alluri, Erin L. Abner, Richard J. Kryscio, Anton Pekcec, Juli Schlichtiger, Björn Bauer

Research output: Contribution to journalArticlepeer-review

109 Scopus citations

Abstract

The blood-brain barrier is dysfunctional in epilepsy, thereby contributing to seizure genesis and resistance to antiseizure drugs. Previously, several groups reported that seizures increase brain glutamate levels, which leads to barrier dysfunction. One critical component of barrier dysfunction is brain capillary leakage. Based on our preliminary data, we hypothesized that glutamate released during seizures mediates an increase in matrix-metalloproteinase (MMP) expression and activity levels, thereby contributing to barrier leakage. To test this hypothesis, we exposed isolated brain capillaries from male Sprague Dawley rats to glutamate ex vivo and used an in vivo/ex vivo approach of isolated brain capillaries from female Wistar rats that experienced status epilepticus as an acute seizure model. We found that exposing isolated rat brain capillaries to glutamate increased MMP-2 and MMP-9 protein and activity levels, and decreased tight junction protein levels, which resulted in barrier leakage. We confirmed these findings in vivo in rats after status epilepticus and in brain capillaries from male mice lacking cytosolic phospholipase A2. Together, our data support the hypothesis that glutamate released during seizures signals an increase in MMP-2 and MMP-9 protein expression and activity levels, resulting in blood-brain barrier leakage.

Original languageEnglish
Pages (from-to)4301-4315
Number of pages15
JournalJournal of Neuroscience
Volume38
Issue number18
DOIs
StatePublished - May 2 2018

Bibliographical note

Publisher Copyright:
© 2018 the authors.

Keywords

  • Barrier dysfunction
  • Barrier leakage
  • Blood-Brain barrier
  • MMP
  • cPLA

ASJC Scopus subject areas

  • General Neuroscience

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