A wind of change characterizes epilepsy research efforts. The traditional approach, based on a neurocentric view of seizure generation, promoted understanding of the neuronal mechanisms of seizures; this resulted in the development of potent anti-epileptic drugs (AEDs). The fact that a significant number of individuals with epilepsy still fail to respond to available AEDs restates the need for an alternative approach. Blood-brain barrier (BBB) dysfunction is an important etiological player in seizure disorders, and combination therapies utilizing an AED in conjunction with a “cerebrovascular” drug could be used to control seizures more effectively than AED therapy alone. The fact that the BBB plays an etiologic role in other neurological diseases will be discussed in the context of a more “holistic” approach to the patient with epilepsy, where comorbidity variables are also encompassed by drug therapy. 1. Introduction The blood-brain barrier (BBB) is a system of capillary endothelial cells that protects the brain from harmful substances present in the blood stream, while supplying the brain with the nutrients required for proper function [1–3]. The capillary endothelium is characterized by the presence of tight junctions, lack of fenestrations, and minimal pinocytotic vesicles. In particular, tight junctions between endothelial cells form a barrier, which selectively excludes most blood-borne substances from entering the brain, protecting it from systemic influences. The BBB is anatomically and functionally associated with brain parenchymal cells. The distance between a BBB capillary and neurons is of few micrometers while the overall surface of exchange between the BBB and the brain parenchyma reaches 20？m2 in the adult human brain [4]. In short, the extent and complexity of the cerebrovascular interface together with the anatomical proximity of BBB vessels and neurons are highly suggestive of an active role in brain disease. In addition to the structural integrity of the BBB, there exists an enzymatic surveillance system that metabolizes drugs and other compounds bypassing the structural barrier. Recently, a strong effect of these enzymes on antiepileptic drugs (AED) metabolism has been shown in human epileptic brain [5]. Failure of the BBB has been traditionally considered the result of brain diseases (e.g., brain tumors, seizures, central nervous system infections, multiple sclerosis). As a result, the potential for a therapeutic approach to restore BBB functions has been overlooked for a more traditional neuronal take of brain pharmacology. The
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