Endocannabinoid Signaling as a Therapeutic Target for Blood-Brain Barrier Repair and Seizure Management in Epilepsy
Abstract number :
1.054
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2025
Submission ID :
795
Source :
www.aesnet.org
Presentation date :
12/6/2025 12:00:00 AM
Published date :
Authors :
Manekya Sumithrarachchi, MS – University of Kentucky
Rebecca Smith, PhD – University of Kentucky
Bryan Maloney, MS – University of Kentucky
Jasmine Perdeh, PharmD – University of Kentucky
Makenna Pelfrey, BS – University of Kentucky
Sukriti Kapoor, - – University of Kentucky
Jackson Truesdell, - – University of Kentucky
Fisher Quigley, - – University of Kentucky
Matthew Sepulveda, BS – University of Kentucky
Elizabeth Clark, BS – University of Kentucky
Anika Hartz, PhD – University of Kentucky
Presenting Author: Bjoern Bauer, PhD – University of Kentucky
Rationale: Blood-brain barrier dysfunction is both a cause and consequence of seizures in patients with epilepsy, yet therapeutic options to repair barrier dysfunction do not exist. We have discovered that glutamate activates endocannabinoid signaling, which drives neurovascular inflammation and barrier leakage. Other data support that an inflamed and leaky barrier contributes to seizure generation through a pernicious feedback loop in which seizures trigger inflammation and barrier leakage, further increasing seizure burden. We recently found that cannabidiol (CDB), a non-addictive compound of Cannabis sativa L., blocks endocannabinoid signaling and mitigates seizure-induced barrier dysfunction. CBD is also known to reduce seizures in animals and patients. Together, these findings suggest that CBD has the potential to block the signaling that drives barrier dysfunction and seizure progression. Our goal is to gain mechanistic insights into endocannabinoid signaling underlying barrier dysfunction in epilepsy and to develop a CBD-based intervention to repair barrier dysfunction with translational potential.
Methods: We used a unique ex vivo/in vivo approach consisting of isolated brain capillaries from acute seizure and chronic epilepsy models to study underlying mechanisms and evaluate our intervention strategy. By integrating neuroimaging techniques (MRI, MP imaging, confocal microscopy), piezo/video/ECoG data, and quantitative bioanalysis with AI-driven data analysis, we gained in-depth insights into the mechanism underlying barrier dysfunction.
Results: Our key findings are: 1) Blocking mGluR1 and CB1R prevents glutamate-mediated capillary leakage. 2) Glutamate triggers release of the endocannabinoid 2-AG from the brain capillary endothelium. 3) CBD and the CBD derivatives CBDa, CBDV, and 7-Hydroxy-CBD attenuate glutamate-induced capillary leakage. 4) CBD reduces inflammation, repairs barrier leakage, and lowers seizure burden in chronic epileptic rats.
Conclusions: Endocannabinoid signaling is critical in promoting barrier dysfunction in epilepsy. Our data indicate that CBD treatment repairs barrier dysfunction and reduces seizures. Our findings form the basis for a disease-modifying intervention to repair barrier dysfunction and reduce seizure burden in patients with epilepsy.
Funding: Research supported by NIH R01NS079507, NIH R21 NS131903, and the University of Kentucky College of Pharmacy Team Science Project Award (all to BB).
Basic Mechanisms