The blood-brain barrier: a focus on neurovascular unit components

Abstract

The blood–brain barrier (BBB) provides an optimum environment for neurons by ensuring the integrity and homeostasis of highly fragile brain cells under physiological conditions, protecting the brain from changes in the blood with both structural (tight junctions) and metabolic (enzymes) barriers, selective transport, and the metabolism and modification of substances in the blood and brain. The endothelial cells of the brain capillaries, located at the interfaces between the blood and the brain, are critical components that limit the permeability of the BBB. These cells have unique morphological, biochemical, and functional characteristics that distinguish them from those found in the peripheral vascular system. In addition to endothelial cells, astrocytic perivascular end-feet, pericytes, neurons, microglia, and smooth muscle cells also play significant roles in maintaining the homeostasis of the brain parenchyma. Thus, the BBB effectively prevents various molecules and therapeutic drugs from entering the brain parenchyma and reaching the target area at sufficiently high concentrations. The passage of a substance through the BBB and its entry into the brain depends on various factors, including the substance’s lipophilicity, diffusion capability, molecular weight, electrical charge, blood concentration, and multiple primary and secondary factors. Drug delivery systems developed in recent years, through techniques and methods aimed at controlled and safe opening or bypassing of the BBB, are believed to provide significant benefits in the lesion area by allowing therapeutic substances to optimally enter the brain from the circulation. This article provides a review of the BBB and its components, highlighting their significance among the brain’s different interfaces. It also discusses approaches for delivering therapeutic substances to the affected area under optimal conditions and concentrations in various brain pathologies.

Keywords

• Astrocytic perivascular end-feet
• blood-brain barrier
• drug delivery
• microglia
• neurovascular unit

References

1. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis. (2010);37(1):13-25. https://doi.org/10.1016/j.nbd.2009.07.030.
2. Saunders NR, Ek CJ, Habgood MD, Dziegielewska KM. Barriers in the brain: a renaissance? Trends Neurosci. (2008);31(6):279-86. https://doi.org/10.1016/j.tins.2008.03.003
3. Stokum JA, Gerzanich V, Simard JM. Molecular pathophysiology of cerebral edema. J Cereb Blood Flow Metab. (2016);36(3):513-38. https://doi.org/10.1177/0271678X15617172
4. Badaut J, Ghersi-Egea JF, Thorne RG, Konsman JP. Blood-brain borders: a proposal to address limitations of historical blood-brain barrier terminology. Fluids Barriers CNS. (2024);21(1):3. https://doi.org/10.1186/s12987-023-00478-5
5. McConnell HL, Mishra A. Cells of the Blood-Brain Barrier: An Overview of the Neurovascular Unit in Health and Disease. Methods Mol Biol. (2022);2492:3-24. https://doi.org/10.1007/978-1-0716-2289-6_1
6. Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci. (2011);12(12):723-38. https://doi.org/10.1038/nrn3114
7. Engelhardt B, Sorokin L. The blood-brain and the blood-cerebrospinal fluid barriers: function and dysfunction. Semin Immunopathol. (2009);31(4):497-511. https://doi.org/10.1007/s00281-009-0177-0
8. Sá-Pereira I, Brites D, Brito MA. Neurovascular unit: a focus on pericytes. Mol Neurobiol. (2012);45(2):327-47. https://doi.org/10.1007/s12035-012-8244-2

9. Srinivasan B, Kolli AR, Esch MB, Abaci HE, Shuler ML, Hickman JJ. TEER measurement techniques for in vitro barrier model systems. J Lab Autom. (2015);20(2):107-26. https://doi.org/10.1177/2211068214561025
10. Hawkins BT, Davis TP. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev. (2005);57(2):173-85. https://doi.org/10.1124/pr.57.2.4
11. Kadry H, Noorani B, Cucullo L. A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS. (2020);17(1):69. https://doi.org/10.1186/s12987-020-00230-3
12. Koziara JM, Lockman PR, Allen DD, Mumper RJ. The blood-brain barrier and brain drug delivery. J Nanosci Nanotechnol. (2006);6(9-10):2712-35. https://doi.org/10.1166/jnn.2006.441
13. Minn A, Ghersi-Egea JF, Perrin R, Leininger B, Siest G. Drug metabolizing enzymes in the brain and cerebral microvessels. Brain Res Brain Res Rev. (1991);16(1):65-82. https://doi.org/10.1016/0165-0173(91)90020-9
14. Cardoso FL, Brites D, Brito MA. Looking at the blood-brain barrier: molecular anatomy and possible investigation approaches. Brain Res Rev. (2010);64(2):328-63. https://doi.org/10.1016/j.brainresrev.2010.05.003
15. Abbott NJ, Friedman A. Overview and introduction: the blood-brain barrier in health and disease. Epilepsia. (2012);53 Suppl 6(0 6):1-6. https://doi.org/10.1111/j.1528-1167.2012.03696.x
16. Carvey PM, Hendey B, Monahan AJ. The blood-brain barrier in neurodegenerative disease: a rhetorical perspective. J Neurochem. (2009);111(2):291-314. https://doi.org/10.1111/j.1471-4159.2009.06319.x
17. Filosa JA, Morrison HW, Iddings JA, Du W, Kim KJ. Beyond neurovascular coupling, role of astrocytes in the regulation of vascular tone. Neuroscience. (2016);323:96-109. https://doi.org/10.1016/j.neuroscience.2015.03.064
18. Cohen-Kashi Malina K, Cooper I, Teichberg VI. Closing the gap between the in-vivo and in-vitro blood-brain barrier tightness. Brain Res. (2009);1284:12-21. https://doi.org/10.1016/j.brainres.2009.05.072
19. Haydon PG, Carmignoto G. Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev. (2006);86(3):1009-31. https://doi.org/10.1152/physrev.00049.2005
20. Salmina AB. Neuron-glia interactions as therapeutic targets in neurodegeneration. J Alzheimers Dis. (2009);16(3):485-502. https://doi.org/10.3233/JAD-2009-0988
21. Koehler RC, Roman RJ, Harder DR. Astrocytes and the regulation of cerebral blood flow. Trends Neurosci. (2009);32(3):160-9. https://doi.org/10.1016/j.tins.2008.11.005
22. Krueger M, Bechmann I. CNS pericytes: concepts, misconceptions, and a way out. Glia. (2010);58(1):1-10. https://doi.org/10.1002/glia.20898
23. Alarcon-Martinez L, Yemisci M, Dalkara T. Pericyte morphology and function. Histol Histopathol. (2021);36(6):633-643. https://doi.org/10.14670/HH-18-314
24. Bonkowski D, Katyshev V, Balabanov RD, Borisov A, Dore-Duffy P. The CNS microvascular pericyte: pericyte-astrocyte crosstalk in the regulation of tissue survival. Fluids Barriers CNS. (2011);8(1):8. https://doi.org/10.1186/2045-8118-8-8
25. Dore-Duffy P, Katychev A, Wang X, Van Buren E. CNS microvascular pericytes exhibit multipotential stem cell activity. J Cereb Blood Flow Metab. (2006);26(5):613-24. https://doi.org/10.1038/sj.jcbfm.9600272
26. Peppiatt CM, Howarth C, Mobbs P, Attwell D. Bidirectional control of CNS capillary diameter by pericytes. Nature. (2006);443(7112):700-4. https://doi.org/10.1038/nature05193
27. Muoio V, Persson PB, Sendeski MM. The neurovascular unit - concept review. Acta Physiol (Oxf). (2014);210(4):790-8. https://doi.org/10.1111/apha.12250
28. Armulik A, Genové G, Mäe M, Nisancioglu MH, Wallgard E, Niaudet C, He L, Norlin J, Lindblom P, Strittmatter K, Johansson BR, Betsholtz C. Pericytes regulate the blood-brain barrier. Nature. (2010);468(7323):557-61. https://doi.org/10.1038/nature09522
29. Bouchard BA, Shatos MA, Tracy PB. Human brain pericytes differentially regulate expression of procoagulant enzyme complexes comprising the extrinsic pathway of blood coagulation. Arterioscler Thromb Vasc Biol. (1997);17(1):1-9. https://doi.org/10.1161/01.atv.17.1.1
30. Kim JA, Tran ND, Li Z, Yang F, Zhou W, Fisher MJ. Brain endothelial hemostasis regulation by pericytes. J Cereb Blood Flow Metab. (2006);26(2):209-17. https://doi.org/10.1038/sj.jcbfm.9600181
31. Kim SU, de Vellis J. Microglia in health and disease. J Neurosci Res. (2005);81(3):302-13. https://doi.org/10.1002/jnr.20562
32. Nayak D, Roth TL, McGavern DB. Microglia development and function. Annu Rev Immunol. (2014);32:367-402. https://doi.org/10.1146/annurev-immunol-032713-120240
33. Colonna M, Butovsky O. Microglia Function in the Central Nervous System During Health and Neurodegeneration. Annu Rev Immunol. (2017);35:441-468. https://doi.org/10.1146/annurev-immunol-051116-052358
34. Rodríguez-Gómez JA, Kavanagh E, Engskog-Vlachos P, Engskog MKR, Herrera AJ, Espinosa-Oliva AM, Joseph B, Hajji N, Venero JL, Burguillos MA. Microglia: Agents of the CNS Pro-Inflammatory Response. Cells. (2020);9(7):1717. https://doi.org/10.3390/cells9071717
35. Ronaldson PT, Davis TP. Regulation of blood-brain barrier integrity by microglia in health and disease: A therapeutic opportunity. J Cereb Blood Flow Metab. (2020);40(1_suppl):S6-S24. https://doi.org/10.1177/0271678X20951995
36. Bernier LP, Bohlen CJ, York EM, Choi HB, Kamyabi A, Dissing-Olesen L, Hefendehl JK, Collins HY, Stevens B, Barres BA, MacVicar BA. Nanoscale Surveillance of the Brain by Microglia via cAMP-Regulated Filopodia. Cell Rep. (2019);27(10):2895-2908.e4. https://doi.org/10.1016/j.celrep.2019.05.010
37. Mosser CA, Baptista S, Arnoux I, Audinat E. Microglia in CNS development: Shaping the brain for the future. Prog Neurobiol. (2017);149-150:1-20. https://doi.org/10.1016/j.pneurobio.2017.01.002
38. Liu LR, Liu JC, Bao JS, Bai QQ, Wang GQ. Interaction of Microglia and Astrocytes in the Neurovascular Unit. Front Immunol. (2020);11:1024. https://doi.org/10.3389/fimmu.2020.01024
39. Kaur IP, Bhandari R, Bhandari S, Kakkar V. Potential of solid lipid nanoparticles in brain targeting. J Control Release. (2008);127(2):97-109. https://doi.org/10.1016/j.jconrel.2007.12.018
40. Witt KA, Gillespie TJ, Huber JD, Egleton RD, Davis TP. Peptide drug modifications to enhance bioavailability and blood-brain barrier permeability. Peptides. (2001);22(12):2329-2343. https://doi:10.1016/s0196-9781(01)00537-x
41. Pardridge WM. Blood-brain barrier delivery. Drug Discov Today. (2007);12(1-2):54-61. https://doi.org/10.1016/j.drudis.2006.10.013
42. Pardridge WM. Molecular Trojan horses for blood-brain barrier drug delivery. Curr Opin Pharmacol. (2006);6(5):494-500. https://doi:10.1016/j.coph.2006.06.001
43. Gosselet F, Loiola RA, Roig A, Rosell A, Culot M. Central nervous system delivery of molecules across the blood-brain barrier. Neurochem Int. (2021);144:104952. https://doi: 10.1016/j.neuint.2020.104952.
44. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. (2001);46(1-3):3-26. https://doi:10.1016/s0169-409x(00)00129-0
45. Roskoski R Jr. Rule of five violations among the FDA-approved small molecule protein kinase inhibitors. Pharmacol Res. (2023);191:106774. https://doi:10.1016/j.phrs.2023.106774
46. Murugesan A, Konda Mani S, Koochakkhani S, et al. Design, synthesis and anticancer evaluation of novel arylhydrazones of active methylene compounds. Int J Biol Macromol. (2024);254(Pt 3):127909. https://doi:10.1016/j.ijbiomac.2023.127909
47. Huwyler J, Wu D, Pardridge WM. Brain drug delivery of small molecules using immunoliposomes. Proc Natl Acad Sci U S A. (1996) Nov 26;93(24):14164-9. https://doi.org/10.1073/pnas.93.24.14164
48. Chen TC, Wang W, Schönthal AH. From the groin to the brain: a transfemoral path to blood-brain barrier opening. Oncotarget. (2023);14:413-416. https://doi.org/10.18632/oncotarget.28414
49. Sánchez-Dengra B, González-Álvarez I, Bermejo M, González-Álvarez M. Access to the CNS: Strategies to overcome the BBB. Int J Pharm. (2023);636:122759. https://doi: 10.1016/j.ijpharm.2023.122759
50. Fong H, Zhou B, Feng H, Luo C, Bai B, Zhang J, Wang Y. Recapitulation of Structure-Function-Regulation of Blood-Brain Barrier under (Patho)Physiological Conditions. Cells. (2024);13(3):260. https://doi.org/10.3390/cells13030260
51. Virtanen PS, Ortiz KJ, Patel A, Blocher WA 3rd, Richardson AM. Blood-Brain Barrier Disruption for the Treatment of Primary Brain Tumors: Advances in the Past Half-Decade. Curr Oncol Rep. (2024);26(3):236-249. https://doi.org/10.1007/s11912-024-01497-7
52. Wang M, Etu J, Joshi S. Enhanced disruption of the blood brain barrier by intracarotid mannitol injection during transient cerebral hypoperfusion in rabbits. J Neurosurg Anesthesiol. (2007);19(4):249-56. https://doi.org/10.1097/ANA.0b013e3181453851
53. Hasegawa Y, Iuchi T, Sakaida T, Yokoi S, Kawasaki K. The influence of carmustine wafer implantation on tumor bed cysts and peritumoral brain edema. J Clin Neurosci. (2016);31:67-71. https://doi.org/10.1016/j.jocn.2015.12.033
54. Liu HL, Hua MY, Chen PY, Chu PC, Pan CH, Yang HW, Huang CY, Wang JJ, Yen TC, Wei KC. Blood-brain barrier disruption with focused ultrasound enhances delivery of chemotherapeutic drugs for glioblastoma treatment. Radiology. (2010);255(2):415-25. https://doi.org/10.1148/radiol.10090699
55. Gernert M, Feja M. Bypassing the Blood-Brain Barrier: Direct Intracranial Drug Delivery in Epilepsies. Pharmaceutics. (2020);12(12):1134. https://doi:10.3390/pharmaceutics12121134
56. Sousa F, Dhaliwal HK, Gattacceca F, Sarmento B, Amiji MM. Enhanced anti-angiogenic effects of bevacizumab in glioblastoma treatment upon intranasal administration in polymeric nanoparticles. J Control Release. (2019);309:37-47. https://doi:10.1016/j.jconrel.2019.07.033
57. Ferreira NN, de Oliveira Junior E, Granja S, Boni FI, Ferreira LMB, Cury BSF, Santos LCR, Reis RM, Lima EM, Baltazar F, Gremião MPD. Nose-to-brain co-delivery of drugs for glioblastoma treatment using nanostructured system. Int J Pharm. (2021);603:120714. https://doi:10.1016/j.ijpharm.2021.120714