Leaky blood vessels may cause seizures

While most patients with epilepsy respond well to anticonvulsant medications, up to one third of those who have seizures do not (1). This patient group needs alternative strategies for managing seizures. In a recent Nature Communications  study, researchers identified a tight junction protein in the brain vasculature as a potential new drug target that may one day help these patients (2).

The blood-brain barrier dictates what molecules can or cannot enter the brain. While seizures associate with disruption of the blood-brain barrier, before this study, researchers did not know which specific proteins or functions in the blood-brain barrier were responsible.  

The tight junction protein claudin-5 sits between endothelial cells that comprise blood vessels and works as a size-selective molecular gate between the vasculature and the brain (3). Campbell and his team previously studied the claudin-5 protein in the context of neurological disorders such as schizophrenia and traumatic brain injury. For a previous study on the role of the blood-brain barrier in schizophrenia, Campbell and his team generated a claudin-5 knockdown mouse line and documented that in addition to anticipated cognitive decline, the knockdown mice showed evidence of seizure activity (4). “Claudin-5 deficits seem to be a really, really key hallmark of temporal lobe epilepsy and treatment-resistant epilepsy,” said Matthew Campbell, a neuroscientist at Trinity College Dublin.   

To see if this connection extended to humans, Campbell’s team observed 80 patients with treatment-resistant seizures who planned to undergo temporal lobe surgery, a last resort for halting seizures. The team noticed compromised blood-brain barriers in contrast-enhanced MRI images from patients prior to their surgeries. When the team reassessed the patients several months after surgery, their blood brain barrier integrities were restored.

“We suggest that restoration of claudin-5 of the blood-brain barrier actually stops seizure activity. It's throwing the gauntlet down to say that claudin-5 is a therapeutic target for epilepsy treatment,” Campbell said. 

Campbell and his team next plan to develop targeted therapeutic techniques such as gene therapy to improve claudin-5 expression in patients with treatment-resistant seizures. Standard epileptic therapies may fail to permeate the blood-brain barrier for treatment-resistant patients because the barrier is disrupted and upregulating drug efflux transporters and drug-metabolizing enzymes. 

“This is not the first work, but it's joining important studies that show that you can target vasculature in order to repair blood-brain barrier damage, and by that, indirectly maybe prevent epilepsy, reduce the seizure burden, and so on,” said Alon Friedman, a neuroscientist at Dalhousie University who was not affiliated with the study.

A disrupted blood-brain barrier can play a role in many neurological conditions by triggering an inflammatory response and immune cell infiltration. While dysfunctional claudin-5 expression has been linked to many disorders in the brain, its upregulation as a therapeutic target has yet to be studied. 

“Anywhere where there’s neurodegeneration in neural tissue, I think this will have applicability to where you can restore barrier integrity, because let's face it, every neurological condition at some stage will have blood-brain barrier deficiency,” Campbell said. “It just stands to reason as a neuron is dying, a capillary is going to die as well. So, I do think that this will have applicability across a range of neurological disorders.”

References

1. Picot, M.C. et al. The prevalence of epilepsy and pharmacoresistant epilepsy in adults: a population-based study in a Western European country. Epilepsia  49, 1230-1238 (2008).  
2. Greene C., Hanley, N., Reschke, C.R. et al. Microvascular stabilization via blood-brain barrier regulation prevents seizure activity. Nat Commun  13, 2003 (2022).  
3. Greene C., Hanley, N., and Campbell, M. Claudin-5: Gatekeeper of neurological function. Fluids Barriers CNS  16, 3 (2019).
4. Greene C., Kealy, J., Humphries, M.M., et al. Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia. Mol Psychiatry  23, 2156-2166 (2018).