Permeability Studies on In Vitro Blood–Brain Barrier Models: Physiology, Pathology, and Pharmacology

Abstract

(1) The specifically regulated restrictive permeability barrier to cells and molecules is the most important feature of the blood-brain barrier (BBB). The aim of this review was to summarize permeability data obtained on in vitro BBB models by measurement of transendothelial electrical resistance and by calculation of permeability coefficients for paracellular or transendothelial tracers. (2) Results from primary cultures of cerebral microvascular endothelial cells or immortalized cell lines from bovine, human, porcine, and rodent origin are presented. Effects of coculture with astroglia, neurons, mesenchymal cells, blood cells, and conditioned media, as well as physiological influence of serum components, hormones, growth factors, lipids, and lipoproteins on the barrier function are discussed. (3) BBB permeability results gained on in vitro models of pathological conditions including hypoxia and reoxygenation, neurodegenerative diseases, or bacterial and viral infections have been reviewed. Effects of cytokines, vasoactive mediators, and other pathogenic factors on barrier integrity are also detailed. (4) Pharmacological treatments modulating intracellular cyclic nucleotide or calcium levels, and activity of protein kinases, protein tyrosine phosphatases, phospholipases, cyclooxygenases, or lipoxygenases able to change BBB integrity are outlined. Barrier regulation by drugs involved in the metabolism of nitric oxide and reactive oxygen species, as well as influence of miscellaneous treatments are also listed and evaluated. (5) Though recent advances resulted in development of improved in vitro BBB model systems to investigate disease modeling, drug screening, and testing vectors targeting the brain, there is a need for checking validity of permeability models and cautious interpretation of data.

Uptake and Transport of Superparamagnetic Iron Oxide Nanoparticles through Human Brain Capillary Endothelial Cells

“…28−30 TEER depends on how tightly BCECs are interconnected via tight junctions, and a low TEER could theoretically indicate that there are open areas between BCECs. 28 An immunostaining was performed on the BCECs to visualize the state of the tight junctions. BCECs stained positive for the tight junction protein ZO-1, showing the presence of tight junctions between the cells (Figure 1), but some inconsistencies were observed in terms of less prominent ZO-1 immunoreactivity.…”

Retinoic acid and hydrocortisone strengthen the barrier function of human RPMI 2650 cells, a model for nasal epithelial permeability

“…Several studies have shown that the levels of cAMP are inversely related to the rate of cell division, with high levels present in non-dividing cells (Otten et al 1972;Bombik and Burger 1973). In brain endothelial cells cAMP is a strong inducer of barrier functions (Deli et al 2005). However, in contrast to our previous findings on brain endothelial cells and to the effects of retinoic acid and hydrocortisone on RPMI 2650 cells no increase of cell index was seen in nasal epithelial cells treated with 250 lM cAMP either in the presence or absence of serum (Fig.…”

“…Retinoic acid, a metabolite of vitamin A, hydrocortisone, a glucocorticoid hormone and cyclic adenosine monophosphate (cAMP), a second messenger, which influence barrier formation and function of epithelial and endothelial cell layers were selected for the study (Yoon et al 2000;Deli et al 2005).…”

Synthesis and Antiprotozoal Activity of N-Alkoxy Analogues of the Trypanocidal Lead Compound 4,4′-Bis(imidazolinylamino)diphenylamine with Improved Human Blood−Brain Barrier Permeability

“…Note that LY is widely used and accepted as a marker of tight junction integrity. 40 If LY permeability was affected by the presence of the compound, the concentration of the compound was decreased until a non-affecting dose was reached.…”