Potential Therapeutic Targets for Blood-Brain Barrier Dysfunction in Epilepsy Identified in Mouse Study

Potential Therapeutic Targets for Blood-Brain Barrier Dysfunction in Epilepsy Identified in Mouse Study

New insights into what causes small brain vessels to leak and promotes blood-brain barrier dysfunction in people with epilepsy were revealed in a recent mouse study.

Findings were published in the study, “Matrix Metalloproteinase-Mediated Blood-Brain Barrier Dysfunction in Epilepsy,” in the Journal of Neuroscience.

Epilepsy is a complex disorder that does not rely solely on altered brain cell communication, but also on altered immune response, persistent brain inflammation, and a dysfunctional blood-brain barrier — a semipermeable membrane that separates the circulating blood from the brain and the fluid in the central nervous system.

A leaky blood-brain barrier is believed to account for approximately one-third of epilepsy patients who do not respond to treatment.

It is not fully understood what causes the blood-brain barrier to be defective in these patients. However, building evidence has demonstrated that barrier dysfunction is present at the onset of seizures and contributes to epilepsy progression.

As such, finding strategies to prevent or repair barrier dysfunctions may represent a valuable add-on strategy to existing therapies for these patients.

To better understand what factors contribute to brain-blood barrier leakage in epilepsy, University of Kentucky researchers conducted a series of experiments in mice with induced epilepsy.

By looking at the small brain vessels of the mice after a seizure, the researchers found increased levels of two enzymes called MMP-2 and MMP-9. These enzymes are involved in several cellular processes, including blood vessel maintenance, by breaking down structural proteins.

To further evaluate if seizures could compromise blood vessels’ structure, the team used a florescent dye that was injected in brain blood vessels collected from mice that had or had not suffered seizures. Dye leakage rate was 1.8 times higher in the samples from animals that had suffered seizures.

Researchers further discovered that in the presence of glutamate — the primary brain signaling molecule involved in epilepsy — MMP-2 levels increased by 45% and MMP-9 levels by 115%, compared with controls, and were also linked to a two-fold higher leakage rate in brain blood vessels.

Glutamate was found to exert its effects via another enzyme called cytosolic phospholipase A2 (cPLA2). Using a chemical inhibitor to stop cPLA2 activity prevented glutamate-mediated brain blood vessel leakage, suggesting that targeting this specific enzyme could be a potential strategy to prevent brain-blood barrier dysfunction in epilepsy and decrease seizure burden.

“Additional studies are needed to gain more detailed insight into the mechanism responsible for barrier leakage in epilepsy,” the researchers wrote.

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