Mechanism and Therapeutic Potential of CBD to Repair Blood-Brain Barrier Dysfunction in Epilepsy

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. Despite increasing evidence supporting that glutamate causes blood-brain barrier dysfunction, knowledge of the underlying mechanisms and strategies to repair seizure-induced barrier dysfunction are lacking. In addition, existing antiseizure drugs (ASDs) do not reli- ably control all seizures, leaving patients with difficult-to-treat epilepsies prone to uncontrolled seizures. We re- cently discovered that Cannabidiol (CBD) mitigates barrier dysfunction in epilepsy. We also found that CBD blocks glutamate-mediated barrier leakage in isolated capillaries and reduces seizure-induced barrier dysfunc- tion 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 prevents 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.