Blood-brain barrier dysfunction is both a cause and consequence of seizures in patients with epilepsy, yet ther-
apeutic options to repair barrier dysfunction do not exist. Key characteristics of barrier dysfunction in epilepsy
are neurovascular inflammation and barrier leakage, both result from seizure-mediated release of glutamate.
Data support that an inflamed and leaky, and thus, dysfunctional barrier contributes to seizure genesis through
a pernicious feedback loop that promotes epilepsy progression. However, current therapeutic options to treat
epilepsy are largely neuron-centric and do not address barrier dysfunction. In addition, existing antiseizure drugs
(ASDs) do not reliably control all seizures, leaving patients with difficult-to-treat epilepsies prone to uncontrolled
seizures. We recently discovered that Cannabidiol (CBD) mitigates barrier dysfunction in epilepsy. We also found
that CBD blocks glutamate-mediated barrier leakage in isolated capillaries and repairs seizure-induced barrier
dysfunction in vivo. These findings suggest that CBD has the potential to block the feedback signaling that drives
barrier dysfunction and seizure progression in epilepsy. However, data that support the use of CBD to repair
barrier dysfunction in epilepsy are not available. This knowledge gap represents a critical unmet need that pre-
vents us from achieving therapeutic advances for patients with epilepsy. The overall objective in this application
is to define the mechanistic link between cannabinoid signaling and barrier dysfunction to explain observed CBD
effects and to evaluate CBD as therapeutic agent to repair barrier dysfunction in epilepsy. Based on preliminary
data the central hypothesis of this project is that CBD repairs barrier dysfunction thereby lowering seizure burden
in epilepsy. The rationale for the proposed research is that its successful completion will provide mechanistic
and preclinical data supporting future research for the clinical translation of CBD to treat patients with epilepsy.
The hypothesis will be tested by pursuing two specific aims: 1) Describe cannabinoid signaling in glutamate-
mediated barrier dysfunction and 2) Evaluate CBD for its potential to repair barrier dysfunction in epilepsy. Under
Aim 1, we will describe key mechanistic steps between cannabinoid signaling and glutamate-mediated barrier
dysfunction by using brain capillaries isolated from knockout mouse models. We will verify these signaling steps
in isolated human brain capillaries. Under Aim 2, we will evaluate the therapeutic benefit of CBD on seizure-
mediated neurovascular inflammation, barrier leakage, and seizure burden in chronic epileptic rats. The pro-
posed research is innovative, because it focuses on a thus far unaddressed topic: cannabinoid signaling at the
blood-brain barrier and CBD as therapeutic agent to repair barrier dysfunction and reduce seizures in epilepsy.
The proposed research is significant because it holds the promise of a novel therapeutic approach to repair
barrier dysfunction that has translational potential to advance treatment of patients with epilepsy and other sei-
zure disorders with underlying barrier dysfunction.
