The blood-brain barrier: Structure, function and therapeutic approaches to cross it

Abstract

The blood-brain barrier (BBB) is constituted by a specialized vascular endothelium that interacts directly with astrocytes, neurons and pericytes. It protects the brain from the molecules of the systemic circulation but it has to be overcome for the proper treatment of brain cancer, psychiatric disorders or neurodegenerative diseases, which are dramatically increasing as the population ages. In the present work we have revised the current knowledge on the cellular structure of the BBB and the different procedures utilized currently and those proposed to cross it. Chemical modifications of the drugs, such as increasing their lipophilicity, turn them more prone to be internalized in the brain. Other mechanisms are the use of molecular tools to bind the drugs such as small immunoglobulins, liposomes or nanoparticles that will act as Trojan Horses favoring the drug delivery in brain. This fusion of the classical pharmacology with nanotechnology has opened a wide field to many different approaches with promising results to hypothesize that BBB will not be a major problem for the new generation of neuroactive drugs. The present review provides an overview of all state-of-the-art of the BBB structure and function, as well as of the classic strategies and these appeared in recent years to deliver drugs into the brain for the treatment of Central Nervous System (CNS) diseases.

Transendothelial glucose transport is not restricted by extracellular hyperglycaemia

“…Type I (GLUT1- 4 and 14) and II (GLUT5, 7, 9 and 11) are largely present on the plasma membrane and typically enable glucose (Type I) or fructose (Type II and GLUT2) flux in/out of the cells. Type III (GLUT 6,8,10, and 12) have an intracellular localization signal but some have also been reported on the plasma membrane [29,30]. GLUTs have various affinities and specificities for different sugars, but glucose transport is most typically associated with Type I GLUT transporters.…”

“…Its many functions include regulating blood flow and maintaining normal vascular tone through production of NO, endothelin-1 and other factors [1][2][3], control of blood clotting and inflammation, and formation of a selective barrier between blood and tissues for distribution and exchange of nutrients, metabolites and gasses [4]. Endothelial cells in different vessels or organs are finely tuned to their specific functions [5][6][7]; for example, the permeability of the endothelial monolayer ranges from tightly controlled in blood brain barrier [8] to leaky in fenestrated endothelium of sinusoidal tissue in liver [9,10]. One of the characteristic features of endothelial cells is their reliance on glycolysis for energy production [11][12][13], with sustained glucose consumption being critical for endothelial cell viability especially during angiogenesis [14,15].…”

Nano based drug delivery

“…On the other hand, dendrimers can be conjugated with a variety of cancer-targeting ligands (biotin, folic acid, amino acids, peptides, aptamers, and monoclonal antibodies) thus they can specifically treat cancer cells by active targeting. Furthermore, dendrimers are suitable as drug delivery systems for gene silencing [155][156][157]. Kesharwani and Iyer discussed some of the literature about dendrimer-mediated drug and gene delivery in their recent study [110].…”

“…For safety purposes, pharmacokinetics, pharmacodynamics, and tissue distribution studies of the nanoparticle and nanoparticle-cargo formulations are highly desirable [152]. Therapies able to cross the blood-brain barrier (BBB) are also needed for brain tumor treatment and/or imaging [153][154][155][156].…”

Minimally Invasive Surgery for Intracerebral Hematoma Evacuation followed by Rosiglitazone Infusion Therapy Increased Perihematomal Occludin, Zonula Occludens-1 Expression and Decreased the Blood Brain Barrier Permeability in Rabbits

“…TJ are elaborate networks of transmembrane and cytosolic proteins that regulate epithelial permeability, localized at the most apical end of the lateral plasma membrane [16,17]. The normal expression of the endothelial TJ associated-proteins are the basis of maintaining BBB structure and functioning [18,19] …”