Stabilizing BBB to prevent seizures

Scientists have announced a significant advance in our understanding of epilepsy, as they have identified a potential method of preventing damaging seizure activity.

Epilepsy is a chronic central nervous system (CNS) disorder affecting approximately 1% of the population and 50 million people worldwide. It is characterised by recurrent, spontaneous seizures caused by disrupted electrical activity in the brain. 

While the brain accounts for just 2% of human body mass, it expends almost 20% of the body’s daily energy production. In order to maintain this high energy demand brain cells are nourished by an intricate network of capillaries that forms the so-called blood-brain barrier (BBB). Such is the extent of these capillaries, we estimate that every brain cell is essentially nourished by its own capillary.

Fundamentally, it is disruption to the integrity of these capillaries and the BBB that the scientists believe is a key driver of seizure activity in humans. Promisingly though, their new research shows that restoring that integrity can prevent seizures.

The researchers report that claudin-5 protein levels are significantly diminished in surgically resected brain tissue from patients with treatment-resistant epilepsy. These patients showed widespread BBB disruption.

The authors show that targeted disruption of claudin-5 in the hippocampus or genetic heterozygosity of claudin-5 in mice exacerbates kainic acid-induced seizures and BBB disruption. Additionally, inducible knockdown of claudin-5 in mice leads to spontaneous recurrent seizures, severe neuroinflammation, and mortality.

RepSox, a regulator of claudin-5 expression, can prevent seizure activity in experimental epilepsy. 

“Our findings suggest that designing medicines aimed at stabilising the integrity of blood vessels in the brain may hold promise in treating patients who are currently non-responsive to anti-seizure medications,” said the senior author.

“This work represents one of the first conclusive studies that pinpoints a key feature of seizures that has to date not been studied in great molecular detail.”

Importantly, the work was translational in nature and included both basic and clinical research arms involving patients diagnosed with epilepsy. Using similar techniques in humans and in pre-clinical models, the scientists were able to show that BBB disruption was a key driver of seizure activity.  

Added to this, they were able to show that restoring BBB integrity could prevent seizures – and it is this finding that holds real potential in moving the discoveries closer to a real and meaningful therapy.