Matrix Metalloproteinase-Mediated Blood-Brain Barrier Dysfunction in Epilepsy
Open accessAbstract
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 A 2 . 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. SIGNIFICANCE STATEMENT The mechanism leading to seizure-mediated blood-brain barrier dysfunction in epilepsy is poorly understood. In the present study, we focused on defining this mechanism in the brain capillary endothelium. We demonstrate that seizures trigger a pathway that involves glutamate signaling through cytosolic phospholipase A 2 , which increases MMP levels and decreases tight junction protein expression levels, resulting in barrier leakage. These findings may provide potential therapeutic avenues within the blood-brain barrier to limit barrier dysfunction in epilepsy and decrease seizure burden.
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PNNs and CSPGs protect neurons from oxidative stress and glutamate excitotoxicity, and combined actions of glioma-released proteases and Glu might explain the selective vulnerability of PV neurons over principal neurons in the PTC.
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Self-citation
- Authors
- Rempe, R. G., Hartz, A. M. S., Soldner, E. L. B., Sokola, B. S., Alluri, S. R., Abner, E. L., Kryscio, R. J., Pekcec, A., Schlichtiger, J., & Bauer, B.
- Affiliations
- University of Minnesota, Duluth (US)
- University of Kentucky (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2018-04-09
- Volume
- 38
- Issue
- 18
- Pages
- 4301-4315
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC5932641
- OpenAlex
- W2797549990
- Cited by
- 162
- References
- 71
- Citations by year
- 2026: 12 · 2025: 19 · 2024: 23 · 2023: 24 · 2022: 31 · 2021: 16 · 2020: 20 · 2019: 11 · 2018: 5
- FWCI
- 5.83
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UKnowledge (University of Kentucky) (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- National Institute on Aging (P30AG028383)
- National Institute of Neurological Disorders and Stroke (R01NS079507)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- blood-brain barrier dysfunction, epilepsy, MMP-2, MMP-9, glutamate signaling, status epilepticus, tight junction proteins, cytosolic phospholipase A2
- MeSH terms
- Animals, Blood-Brain Barrier, Capillaries, Epilepsy, Female, Male, Seizures, Status Epilepticus, Rats, Sprague-Dawley, Rats, Wistar, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Matrix Metalloproteinases, Mice, Rats, Tight Junction Proteins
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