Molecular Heterogeneity of the Brain Endothelium

Nada Alnaqbi; Mohammad G Mohammad; Rifat Hamoudi; Aloïse Mabondzo; Rania Harati

doi:10.3390/cimb45040227

Molecular Heterogeneity of the Brain Endothelium

Curr Issues Mol Biol. 2023 Apr 16;45(4):3462-3478. doi: 10.3390/cimb45040227.

Authors

Nada Alnaqbi^{1

2}, Mohammad G Mohammad^{2

3}, Rifat Hamoudi^{4

5}, Aloïse Mabondzo⁶, Rania Harati^{1

2}

Affiliations

¹ Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates.
² Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates.
³ Department of Medical Laboratories, College of Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates.
⁴ Clinical Sciences Department, College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates.
⁵ Division of Surgery and Interventional Science, University College London, London W1W 7EJ, UK.
⁶ Department of Medicines and Healthcare Technologies, Paris-Saclay University, The French Alternative Energies and Atomic Energy Commission, 91191 Gif-sur-Yvette, France.

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.

Keywords: GLUT-1; P-gp; Trf; bcrp; blood—brain barrier; brain endothelium; claudin-5; cortex; efflux transporters; hippocampus; intercellular junctions; lrp-1; mrp-1.

Abstract

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