Abstract
The blood-brain barrier (BBB) impedes the influx of intravascular compounds from the blood to the brain. Few blood-borne macromolecules are transferred into the brain because vesicular transcytosis in the endothelial cells is considerably limited and the tight junction is located between the endothelial cells. At the first line of the BBB, the endothelial glycocalyx which is a negatively charged, surface coat of proteoglycans, and adsorbed plasma proteins, contributes to the vasculoprotective effects of the vessels wall and are involved in maintaining vascular permeability. In the endothelial cytoplasm of cerebral capillaries, there is an asymmetrical array of metabolic enzymes such as alkaline phosphatase, acid phosphatase, 5’-nucleotidase, adenosine triphosphatase, and nucleoside diphosphatase and these enzymes contribute to inactivation of substrates. In addition, there are several types of influx or efflux transporters at the BBB, such as P-glycoprotein (P-gp), multidrug resistance associated protein, breast cancer resistance protein, organic anion transporters, organic cation transporters, organic cation transporter novel type transporters, and monocarboxylic acid transporters. P-gp, energy-dependent efflux transporter protein, is instrumental to the barrier function. Several findings recently reported indicate that endothelial P-gp contributes to efflux of undesirable substances such as β-amyloid protein from the brain or periarterial interstitial fluid, while P-gp likely plays a crucial role in the genesis of multiple vascular abnormalities that accompany hypertension. In this review, influx and efflux mechanisms of drugs at the BBB are also reviewed and how medicines pass the BBB to reach the brain parenchyma is discussed.
Highlights
The mammalian brain restricts the entrance of ions and solutes circulating in the bloodstream by the blood-brain barrier (BBB) [13]
The BBB is built up by a monolayer of endothelial cells (ECs) lining the brain capillaries that restricts the movement of small polar molecules and macromolecules between the blood and the brain interstitial fluid with tight junctions between ECs [12,65,88]
The results of several observations indicated a distribution pattern of the enzymatic activity of Na+, K+ATPase, mainly on the abluminal side of the ECs of the rat brain capillary was observed by Firth [28] and by Betz et al [7], while other authors [38,39] did not find a positive reaction for ATPase in the rat brain capillaries after incubation in
Summary
The mammalian brain restricts the entrance of ions and solutes circulating in the bloodstream by the blood-brain barrier (BBB) [13]. The BBB is built up by a monolayer of endothelial cells (ECs) lining the brain capillaries that restricts the movement of small polar molecules and macromolecules between the blood and the brain interstitial fluid with tight junctions between ECs [12,65,88]. Further ultrastructural studies revealed that the continuous endothelium of brain capillaries possesses several unique structural and functional features [11,85,86,89]. Ultrastructural features at the BBB and functional expression of several transporters such as P-gp are discussed. Information on transportation of blood-borne substances from the bloodstream to the brain parenchyma will be useful to understand how medicines are taken into the brain
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