The Blood–Brain Barrier and Epilepsy

Abstract

Summary:During the past several years, there has been increasing interest in the role of the blood-brain barrier (BBB) in epilepsy. Advances in neuroradiology have enhanced our ability to image and study the human cerebrovasculature, and further developments in the research of metabolic deficiencies linked to seizure disorders (e.g., GLUT1 deficiency), neuroinflammation, and multiple drug resistance to antiepileptic drugs (AEDs) have amplified the significance of the BBB's relationship to epilepsy.Prior to 1986, BBB research in epilepsy focused on three main areas: ultrastructural studies, brain glucose availability and transport, and clinical uses of AEDs. However, contrast-based imaging techniques and medical procedures such as BBB disruption provided a framework that demonstrated that the BBB could be reversibly disrupted by pathologic or iatrogenic manipulations, with important implications in terms of CNS drug delivery to "multiple drug resistant" brain. This concept of BBB breakdown for therapeutic purposes has also unveiled a previously unrecognized role for BBB failure as a possible etiologic mechanism in epileptogenesis. Finally, a growing body of evidence has shown that inflammatory mechanisms may participate in the pathological changes observed in epileptic brain, with increasing awareness that blood-borne cells or signals may participate in epileptogenesis by virtue of a leaky BBB. In this article we will review the relationships between BBB function and epilepsy. In particular, we will illustrate consensus and divergence between clinical reality and animal studies. Key Words: Antiepileptic drugs-Membrane transport proteins-Monosaccharide transport proteins-Epileptogenesis-Cerebral blood flow.Historically, the convergence between studies of bloodbrain barrier (BBB) and clinical investigation of the epilepsies has been limited to interactions between putative antiepileptic drugs (AED) and the endothelium (for a review of the original BBB studies in epilepsy see (Cornford and Oldendorf, 1986)). These studies were based on the observation that many promising antiepileptic drugs are excluded by the BBB and are thus clinically unusable in spite of significant potency and selectivity, as revealed by in vitro screening or animal models. More recently, it has become apparent that multiple drug resistance is only one of the aspects in BBB research that may impact how we define, prevent and treat seizure disorders. The following paragraphs will summarize recent findings and knowledge within a historical perspective of BBB relevance in the field of epilepsy research (see Fig. 1). Fig. 2 shows the proposed links between BBB and epilepsy. Drug resistance affecting approximately 30%

The Blood-Brain Barrier and Epilepsy

“…However, with increased arterial blood pressure, the BBB becomes permeable to macromolecules under induced epileptiform seizures (Öztas et al, 1991;Sheen et al, 2011). Studies reveal that an acute increase in blood pressure or epileptic activity causes an increase in pinocytosis at the level of the cerebral endothelium Oby and Janigro, 2006). There is also information from earlier experiments indicating that this BBB alteration is reversible and confined to anatomically limited brain areas.…”

“…There have been numerous reports indicating that seizures may produce an increase in cerebral capillary permeability (Ruth et al, 1984;Ilbay et al, 2003;Sheen et al, 2011). On the other hand, epileptogenic process may also be triggered by impaired function of BBB (Oby and Janigro, 2006). Generally, the duration of seizure activity is correlated with reduced BBB functions.…”

“…After injury, local compromise of BBB integrity is common (Abbott et al, 2010;Cacheaux et al 2009;Oby and Janigro, 2006), as revealed by ultrastructural studies of animal and human epileptic tissue in multiple forms of epilepsy. Marchi et al, 2007a;van Vliet et al, 2007), and BBB opening may specifically serve as a trigger event leading to epilepsy.…”

“…However, studies on human epileptic tissue show clear BBB abnormalities, including increased micropinocytosis and fewer mitochondria in ECs, a thickening of the basal membrane, and the presence of abnormal Tjs. Finally, it can be stated that opening of BBB is present before, during or after epileptic seizures, is a hallmark of vascular injury in the brain and there are multiple factors involved in etiology of BBB breakdown in epilepsy (Oby and Janigro., 2006;Stamatovic et al, 2008;Vezzani et al, 2008;).…”

“…There is also information from earlier experiments indicating that this BBB alteration is reversible and confined to anatomically limited brain areas. BBB openings have been mapped for a variety of convulsive agents with different mechanisms of action (i.e., impairment of GABA transmission, increased glutamate neurotransmission, direct excitatory action) (Oby and Janigro, 2006;Vezzani et al, 2008). A direct link between the mechanism of action and the region where BBB breakdown was observed is not obvious.…”