Blood-brain barrier leakage in epilepsy suggests a target for treatment

By Wayne Kuznar, for MDLinx
Published May 31, 2018

Key Takeaways

Glutamate released during epileptic seizures increases the expression of matrix metalloproteinases (MMPs), which leads to blood-brain barrier leakage, researchers reported. Barrier leakage was previously found to play a role in epilepsy progression.

“These findings may provide potential therapeutic avenues within the blood-brain barrier to limit barrier dysfunction in epilepsy and decrease seizure burden,” wrote investigators led by Björn Bauer, PhD, associate professor, Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, in the Journal of Neuroscience.

In a study focusing on the mechanism of seizure-induced barrier leakage, Dr. Bauer and colleagues found that exposing isolated rat brain capillaries to glutamate increased MMP-2 and MMP-9 protein and activity levels.

“Based on our data and reports from others, we postulated that seizures cause MMP upregulation at the blood-brain barrier that leads to degradation of tight junctions and results in barrier leakage,” they wrote.

Barrier leakage has been found to be both a consequence and a trigger of seizures, implying that a leaky barrier contributes to seizure genesis through a positive feedback loop. According to the researchers, seizures drive barrier leakage leading to more seizures, thereby promoting epilepsy progression. Therefore, strategies to repair barrier dysfunction “could be valuable add-on treatments to existing pharmacotherapy,” they wrote.

They cautioned that “the mechanism of seizure-induced barrier leakage is not fully understood and strategies to repair a leaky barrier are not available.”

For the study, the researchers isolated brain capillaries from rats induced with status epilepticus, and then analyzed protein expression and functional activity of MMP-2 and MMP-9 at the blood-brain barrier. MMP-2 and MMP-9 protein expression levels were found to be increased in brain capillaries of the rats. The leakage rate constant was 18 times greater from brain capillary lumens of rats with status epilepticus compared with control rats. In serum isolated from the rats with status epilepticus, levels of S100β, a protein marker of barrier leakage, were significantly elevated compared with controls.

In another experiment, when isolated rat brain capillaries were exposed to glutamate, decreased expression levels of tight junction proteins were found. High-dose (100 µM) glutamate increased MMP-2 and MMP-9 protein levels in brain capillaries. Further, when exposed to glutamate, brain capillaries had an increased leakage rate constant compared with untreated control capillaries.

“When we determined MMP activity, we found that exposing brain capillaries to glutamate significantly (P < 0.05) increased total MMP activity levels by 38% compared to control capillaries,” the investigators wrote. They also showed that the glutamate-induced increase in MMP activity could be blocked by an MMP inhibitor.

The investigators determined that seizures triggered a pathway that involves glutamate signaling through cytosolic phospholipase A2 (cPLA2), which increases MMP levels and decreases tight junction protein expression levels, resulting in barrier leakage.

“Our data imply that cPLA2 could be a target to repair barrier dysfunction and improve the treatment of epilepsy and potentially other neurological disorders that are accompanied by blood-brain barrier leakage as well.”

This study was supported by a grant from the National Institute of Neurological Disorders and Stroke.

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