Structural, Molecular, and Functional Alterations of the Blood-Brain Barrier during Epileptogenesis and Epilepsy: A Cause, Consequence, or Both?

Abstract

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. The endothelial cells lining the brain microvessels are under the inductive influence of neighboring cell types, including astrocytes and pericytes. In addition to the anatomical characteristics of the BBB, various specific transport systems, enzymes and receptors regulate molecular and cellular traffic across the BBB. While the intact BBB prevents many macromolecules and immune cells from entering the brain, following epileptogenic brain insults the BBB changes its properties. Among BBB alterations, albumin extravasation and diapedesis of leucocytes from blood into brain parenchyma occur, inducing or contributing to epileptogenesis. Furthermore, seizures themselves may modulate BBB functions, permitting albumin extravasation, leading to activation of astrocytes and the innate immune system, and eventually modifications of neuronal networks. BBB alterations following seizures are not necessarily associated with enhanced drug penetration into the brain. Increased expression of multidrug efflux transporters such as P-glycoprotein likely act as a ‘second line defense’ mechanism to protect the brain from toxins. A better understanding of the complex alterations in BBB structure and function following seizures and in epilepsy may lead to novel therapeutic interventions allowing the prevention and treatment of epilepsy as well as other detrimental neuro-psychiatric sequelae of brain injury.

Structure, Function, and Regulation of the Blood-Brain Barrier Tight Junction in Central Nervous System Disorders

“…A number of BBB impairments have been shown in epilepsy, which exhibits abnormal brain activity leading to seizures (Loscher and Friedman, 2020). IgG extravasation and loss of ZO-1 immunostaining have been observed postmortem in both human brain tissue derived from patients with a positive diagnosis of temporal lobe epilepsy and a rat model of limbic epilepsy.…”

Novel Intrinsic Mechanisms of Active Drug Extrusion at the Blood-Brain Barrier: Potential Targets for Enhancing Drug Delivery to the Brain?

“…In addition to inducing Pgp expression in endothelial cells of the BBB, glutamate and transforming growth factor beta (TGF-β) are involved in BBB disruption, which is a hallmark of most types of epilepsy, leading to the extravasation of albumin and subsequent functional brain alterations [ 2 ]. A combination of losartan (an angiotensin II type 1 receptor antagonist that blocks brain TGF-β signaling) and clinically available NMDA receptor antagonists such as memantine may be advantageous in preventing BBB disruption in a wide variety of brain diseases, including epilepsy, stroke, Alzheimer’s disease, and traumatic brain injury [ 48 ].…”

“…The blood-brain barrier (BBB) provides a natural defense against toxic or infective agents circulating in the blood but also restricts the brain penetration of most drugs, thus forming a bottleneck in drug development for brain diseases [ 1 , 2 ]. Tight junctions between brain capillary endothelial cells (BCECs) significantly reduce the permeation of small hydrophilic solutes through the intercellular cleft (paracellular pathway), thus forming a “physical barrier” [ 3 ].…”

“…In theory, this problem may be easily resolved by the coadministration of Pgp inhibitors. Indeed, several Pgp inhibitors or modulators have been investigated in clinical trials in patients with brain cancer or pharmacoresistant epilepsy, with limited success [ 2 , 6 , 8 ]. Several alternative strategies are actively being pursued, such as the modification of existing drugs, the development of new drugs, or the combination of novel drug delivery agents to evade Pgp-dependent efflux [ 9 , 10 ].…”

“…For any of these strategies, it is important to understand the transport mechanisms and regulation of ABC transporters such as Pgp at the BBB. Furthermore, the brain disease itself may alter the expression and functionality of efflux transporters at the BBB, as shown for certain types of difficult-to-treat epilepsy [ 2 ], which needs to be dealt with when developing new therapies.…”