Epilepsy and Alterations of the Blood-Brain Barrier: Cause or Consequence of Epileptic Seizures or Both?

The blood-brain barrier (BBB) is a dynamic, highly selective barrier primarily formed by endothelial cells connected by tight junctions that separate the circulating blood from the brain extracellular fluid, thereby preserving a narrow and stable homeostatic control of the neuronal environment. The endothelial cells lining the brain microvessels are under the inductive influence of neighboring cell types within the "neurovascular unit" including astrocytes and pericytes. In addition to the morphological characteristics of the BBB, various specific transport systems, enzymes, and receptors regulate the molecular and cellular traffic across the barrier. Furthermore, the intact BBB prevents many macromolecules and immune cells from entering the brain. This changes dramatically following epileptogenic brain insults; such insults, among other BBB alterations, lead to albumin extravasation and diapedesis of leukocytes from blood into brain parenchyma, inducing or contributing to epileptogenesis, which finally leads to development of spontaneous recurrent seizures and epilepsy. Furthermore, seizures themselves may cause BBB disruption with albumin extravasation, which has been shown to be associated with activation of astrocytes, activation of innate immune systems, and modifications of neuronal networks. However, seizure-induced BBB disruption is not necessarily associated with enhanced drug penetration into the brain, because the BBB expression of multidrug efflux transporters such as P-glycoprotein increases, most likely as a "second line defense" mechanism to protect the brain from drug toxicity. Hopefully, a better understanding of the complex BBB alterations in response to seizures and epilepsy can lead to novel therapeutic intervention to prevent epileptogenesis and the development of other detrimental sequelae of brain injury.