Role of Blood-Brain Barrier Dysfunction in Epileptogenesis

Epileptogenesis is common following brain insults such as trauma, focal ischemia and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown and there is no efficient therapeutic intervention to prevent epilepsy in injured patients. Previous studies demonstrated impaired integrity of the blood-brain barrier (BBB) as an important hallmark in brain injuries. Here we review accumulating clinical and experimental data supporting the role of a primary BBB lesion in seizures and epileptogenesis. Data from animal models of epilepsy indicate a key role for vascular angiogenesis and leak of serum proteins through a dysfunctional BBB in initiating specific signaling cascades within different elements of the neurovascular unit. Transformation of astroglia cell populations, a robust inflammatory response, and angiogenesis are associated with impaired homeostasis of the extracellular milieu, release of cytokines and continuous increase in vessels permeability. Together, these lead to enhanced neuronal excitability, excitatory-inhibitory imbalance and altered synaptic plasticity – all of which may serve as the basis for hyper-synchronicity and epileptic activity within the local network. The primary role of vascular injury and BBB dysfunction in triggering specific pro-epileptogenic signaling pathways highlights new therapeutic targets for the prevention and treatment of epilepsy.