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.
|Number of pages||15|
|Journal||Journal of Neuroscience|
|State||Published - May 2 2018|
Bibliographical noteFunding Information:
This work was supported by National Institute of Neurological Disorders and Stroke Grant 1R01NS079507 to B.B. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health. We thank Dr. Joseph V. Bonventre (Brigham and Women’s Hospital, Harvard Medical School) for cPLA2 breeding pairs; Eileen O’Leary for advice on breeding and genotyping; Stephanie Edelmann for technical assistance with breeding and genotyping; and the B.B. and A.M.S.H. laboratories for proofreading the manuscript. The authors declare no competing financial interests.
© 2018 the authors.
- Barrier dysfunction
- Barrier leakage
- Blood-Brain barrier
ASJC Scopus subject areas
- Neuroscience (all)