Molecular Heterogeneity of the Brain Endothelium

Abstract

The blood–brain barrier (BBB) is part of a neurovascular structure located in the brain’s micro vessels, that is essential to maintain brain homeostasis, but prevents the brain uptake of most drugs. Because of its importance in neuro-pharmacotherapy, the BBB has been the subject of extensive research since its discovery over 100 years ago. Major advances in understanding the structure and function of the barrier have been made. Drugs are re-designed to cross the BBB. However, despite these efforts, overcoming the BBB efficiently to treat brain diseases safely remains challenging. The majority of BBB research studies focus on the BBB as a homogenous structure throughout the different brain regions. However, this simplification may lead to an inadequate understanding of the BBB function with significant therapeutic consequences. From this perspective, we analyzed the gene and protein expression profiles of the BBB in the micro vessels from the brains of mice that were isolated from two different brain regions, namely the cortex and the hippocampus. The expression profile of the inter-endothelial junctional protein (claudin-5), three ABC transporters (P-glycoprotein, Bcrp and Mrp-1), and three BBB receptors (lrp-1, TRF and GLUT-1) were analyzed. Our gene and protein analysis showed that the brain endothelium in the hippocampus exhibits different expression profiles compared to the brain cortex. Specifically, brain endothelial cells (BECs) of the hippocampus express higher gene levels of abcb1, abcg2, lrp1, and slc2a1 compared to the BECs of the cortex regions with a trend of increase for claudin-5, while BECs of the cortex express higher gene levels of abcc1 and trf compared to the hippocampus. At the protein levels, the P-gp expression was found to be significantly higher in the hippocampus compared to the cortex, while TRF was found to be up-regulated in the cortex. These data suggest that the structure and function of the BBB are not homogeneous, and imply that drugs are not delivered similarly among the different brain regions. Appreciation of the BBB heterogeneity by future research programs is thus critical for efficient drug delivery and the treatment of brain diseases.

Heterogeneous brain distribution of bumetanide following systemic administration in rats

“…shown by the latter studies, inhibiting efflux transporters by probenecid markedly increases bumetanide brain levels. Transporters involved in the uptake and efflux of drugs at the BBB are not homogeneously expressed at the BBB of different brain regions (Alnaqbi et al, 2023;Villabona-Rueda et al, 2019;Zhao & Pollack, 2009), which thus likely add to the heterogeneous brain distribution of bumetanide following systemic administration in rats observed here.…”

“…The regional differences in bumetanide brain levels reported here are likely related to the regional heterogeneity of the BBB (Löscher & Friedman, 2020;Villabona-Rueda et al, 2019;Wilhelm et al, 2016), regional differences in drug transporters (Alnaqbi et al, 2023;Villabona-Rueda et al, 2019;Zhao & Pollack, 2009), and regional differences in capillary density and perfusion rate (Beck & Krieglstein, 1987;Horton et al, 1980;Zhao & Pollack, 2009). Zhao and Pollack (2009) reported that the regional perfusion flow rate varies 7.5-fold, and capillary density (based on vascular volume) varies 3.7-fold, across 13 brain regions (olfactory bulb, striatum, hippocampus, frontal cortex, parietal cortex, occipital cortex, superior and inferior colliculi, hypothalamus, thalamus, midbrain, pons, medulla, and cerebellum) examined in the mouse.…”

Exploration of the Noncoding Genome for Human-Specific Therapeutic Targets—Recent Insights at Molecular and Cellular Level

“…These will need to have wellestablished molecular and cellular mechanisms of action, including carrier ligand-cell surface receptor [184][185][186][187][188][189]281] interactions, as well as clearly characterized in vivo behavior [191][192][193]. The latter encompasses possible crossing of the blood-brain barrier via transcytosis [282][283][284][285][286], as well as local drug delivery through stereotactic approaches. Furthermore, non-invasive monitoring of therapeutic drug function in patients is highly desirable.…”

“…Anatomical barriers against nanoparticle or vector-based therapeutics: One study [291] reported that a particular serotype, AAV9, is capable to cross the blood-brain barrier (BBB) [286,297], raising the possibility of intravascular administration as a non-invasive delivery route to achieve widespread CNS gene expression (Figure 7). Crossing of the bloodbrain barrier appears to occur via transcytosis [282][283][284][285]. Notably, this same AAV serotype is also capable to enter the myocardium across the tight cardiovascular endothelium (impermeable for other AAV serotypes) and has previously been successfully employed for cardiac gene transfer [258,293] and the first demonstration of cardiac RNA interference (RNAi) therapy [93].…”