Abstract
Our understanding of the etiological mechanisms leading up to epilepsy has undergone radical changes over time due to more insights into the complexity of the disease. The traditional hypothesis emphasized network hyperexcitability and an imbalance of inhibition and excitation, eventually leading to seizures. In this context, the contribution of the vascular system, and particularly the interactions between blood vessels and neuronal tissue, came into focus only recently. Thus, one highly exciting causative or contributing factor of epileptogenesis is the disruption of the blood-brain barrier (BBB) in the context of not only posttraumatic epilepsy, but also other etiologies. This hypothesis is now recognized as a synergistic mechanism that can give rise to epilepsy, and BBB repair for restoration of cerebrovascular integrity is considered a therapeutic alternative. Endothelial cells lining the inner surface of blood vessels are an integral component of the BBB system. Sealed by tight junctions, they are crucial in maintaining homeostatic activities of the brain, as well as acting as an interface in the neurovascular unit. Additional potential vascular mechanisms such as inflammation, altered neurovascular coupling, or changes in blood flow that can modulate neuronal circuit activity have been implicated in epilepsy. Our own work has shown how intrinsic defects within endothelial cells from the earliest developmental time points, which preclude neuronal changes, can lead to vascular abnormalities and autonomously support the development of hyperexcitability and epileptiform activity. In this article, we review the importance of vascular integrity and signaling for network excitability and epilepsy by highlighting complementary basic and clinical research studies and by outlining possible novel therapeutic strategies.
Highlights
Epileptogenesis is the process of developing epilepsy, that is, a chronic neurological disorder characterized by seizures
Many seminal reviews have addressed the role of blood-brain barrier (BBB) dysfunction in the etiology of epilepsy, and the current review focuses on some of the studies in the last two decades and how information gained from these studies can be applied for novel therapeutic interventions
One of the many proposed mechanisms by which BBB damage can lead to epileptogenesis is via a systemic intravascular inflammation (Vezzani and Friedman, 2011; Kim et al, 2017). In light of these findings, one can assume that BBB disruption is the pivotal event, which subsequently can lead to secondary events, such as altered neurovascular coupling (NVC), changes in the morphology of neurovascular network, and altered cerebral blood flow to different brain areas and systemic vascular inflammation (Figure 1)
Summary
Epileptogenesis is the process of developing epilepsy, that is, a chronic neurological disorder characterized by seizures. Just as neuronal networks show plasticity in response to changing electrical activity, vascular endothelial cells show remarkable plasticity in response to changing tissue oxygenation level or blood flow.
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