Novel Therapeutic Strategies to Resolve Neurovascular Inflammation and Repair Blood-Brain Barrier Dysfunction in Epilepsy

Blood-brain barrier dysfunction is recognized as both a cause and consequence of seizures in epilepsy. Two key
characteristics of barrier dysfunction in epilepsy include 1) neurovascular inflammation and 2) barrier leakage,
both of which have been linked to seizures. In spite of increasing evidence supporting that glutamate causes
blood-brain barrier dysfunction, knowledge of the associated underlying mechanisms remain to be fully defined.
Moreover, therapeutic options for restoring barrier function are currently not available. Thus, there is an unmet
critical need to determine how glutamate promotes blood-brain barrier inflammation and leakage and to develop
targeted strategies to restore barrier function. The consequence of this unmet need is that development of novel
treatments to improve seizure control in epilepsy will likely remain a clinical challenge. The long-term goal of the
investigator is to contribute toward the development of mechanism-based strategies to repair blood-brain barrier
dysfunction in brain diseases. The overall objective in this application is to establish the efficacy of a mechanism-
based intervention to treat blood-brain barrier dysfunction in epilepsy, thereby vertically extending what has been
learned under current funding. Based on preliminary data the central hypothesis of this project is that glutamate
signaling mediates blood-brain barrier dysfunction and that therapeutic intervention targeting this mechanism
will resolve seizure-induced neurovascular inflammation, repair barrier leakage, and reduce seizure burden. The
rationale for the proposed research is that its successful completion will provide a robust framework for the
continued development and clinical translation of a novel evidence-based therapeutic intervention to help treat
seizures in patients with epilepsy. The hypothesis will be tested by pursuing three specific aims: 1) Identify
signaling steps responsible for seizure-induced inflammation of the blood-brain barrier. 2) Determine the
mechanism responsible for capillary leakage at the human blood-brain barrier, and 3) Develop a therapeutic
intervention to reduce seizure burden in a chronic epilepsy model. Under Aim 1, signaling steps that lead to
seizure-mediated neuroinflammation will be determined in capillaries isolated from knockout mouse models and
verified in vivo. Under Aim 2, key signaling steps that trigger barrier leakage will be determined in human brain
capillaries from seizure-free control individuals and from patients with epilepsy. Under Aim 3, an intervention
therapy designed to repair barrier dysfunction will be developed and the therapeutic benefit of this strategy on
reducing seizure burden will be evaluated in a rat chronic epilepsy model. The proposed research is innovative,
because it represents a substantive departure from the status quo by shifting the focus to molecular targets at
the blood-brain barrier to resolve neurovascular inflammation, restore barrier function, and improve epilepsy
symptoms. The proposed research is significant because it holds the promise of a novel therapeutic approach
to repair barrier dysfunction that has translational potential for clinical use to advance treatment of patients with
epilepsy and other seizure disorders with underlying barrier dysfunction.

Grant Number: 5R01NS079507-11
NIH Institute/Center: NIH
Principal Investigator: Bjoern Bauer