THE BLOOD-BRAIN BARRIER AS A PHYSIOLOGICAL AND TOXICOLOGICAL SYSTEM OF BRAIN PROTECTION: STRUCTURAL AND FUNCTIONAL ORGANIZATION, TRANSPORT MECHANISMS, AND THE SIGNIFICANCE OF DYSFUNCTION IN CENTRAL NERVOUS SYSTEM DISORDERS
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Abstract
This review systematizes data on the structural and functional organization of the blood-brain barrier, its barrier-related and transport-metabolic mechanisms, universal mechanisms of dysfunction, and the significance of impaired barrier integrity for xenobiotic penetration, the development of neurotoxic effects, and changes in the sensitivity of the central nervous system to chemical and pharmacological exposures.
The methodological basis of the study was an analysis of more than 200 literature sources. The search was performed using a specifically developed set of keywords to ensure maximum relevance of the selected publications. PubMed and Scopus were used as the main information resources, which made it possible to cover publications on the problem under consideration published between 2021 and 2026.
The analysis showed that the structural integrity of the neurovascular unit, the functional state of nutrient transport systems and ABC-dependent efflux, as well as inflammatory and proteolytic damage to intercellular junctions and the basement membrane, are key determinants of blood-brain barrier status, xenobiotic penetration into the brain, the severity of neurotoxic effects, and changes in CNS sensitivity to chemical and pharmacological exposures.
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The authors declare that they have no apparent or potential conflicts of interest related to the publication of this article.
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1. Zhao Y, Gan L, Ren L, Lin Y, Ma C, Lin X. Factors influencing the blood-brain barrier permeability. Brain Res. 2022; 1788: 147937. doi: 10.1016/j.brainres.2022.147937
2. Alahmari A. Blood-Brain Barrier Overview: Structural and Functional Correlation. Neural Plast. 2021; 2021: 6564585. doi: 10.1155/2021/6564585
3. Mirzaahmadi B, Salahpour-Anarjan F, Mousakhani A, Haddadi P, Nezamdoust FV, Rahbarghazi R, Karimipour M. Brain neurovascular unit in response to intra- and extra-central nervous system cancers: implications, mechanisms, and challenges. Cancer Cell Int. 2025; 26(1): 40. doi: 10.1186/s12935-025-04134-w
4. Dithmer S, Blasig IE, Fraser PA, Qin Z, Haseloff RF. The Basic Requirement of Tight Junction Proteins in Blood-Brain Barrier Function and Their Role in Pathologies. Int J Mol Sci. 2024; 25(11): 5601. doi: 10.3390/ijms25115601
5. Rust R, Yin H, Achón Buil B, Sagare AP, Kisler K. The blood-brain barrier: a help and a hindrance. Brain. 2025; 148(7): 2262-2282. doi: 10.1093/brain/awaf068
6. Liu G, Wang Q, Tian L, Wang M, Duo D, Duan Y, et al. Blood-Brain Barrier Permeability is Affected by Changes in Tight Junction Protein Expression at High-Altitude Hypoxic Conditions-this may have Implications for Brain Drug Transport. AAPS J. 2024; 26(5): 90. doi: 10.1208/s12248-024-00957-z
7. Naser AN, Lu Q, Chen YH. Trans-Compartmental Regulation of Tight Junction Barrier Function. Tissue Barriers. 2023; 11(4): 2133880. doi: 10.1080/21688370.2022.2133880
8. Yan R, Li Y, Müller J, Zhang Y, Singer S, Xia L, et al. Mechanism of substrate transport and inhibition of the human LAT1-4F2hc amino acid transporter. Cell Discov. 2021; 7(1): 16. doi: 10.1038/s41421-021-00247-4
9. Winter J, Kunze R, Veit N, Kuerpig S, Meisenheimer M, Kraus D, et al. Targeting of Glucose Transport and the NAD Pathway in Neuroendocrine Tumor (NET) Cells Reveals New Treatment Options. Cancers (Basel). 2023; 15(5): 1415. doi: 10.3390/cancers15051415
10. Bay C, Bajraktari-Sylejmani G, Haefeli WE, Burhenne J, Weiss J, Sauter M. Functional Characterization of the Solute Carrier LAT-1 (SLC7A5/SLC2A3) in Human Brain Capillary Endothelial Cells with Rapid UPLC-MS/MS Quantification of Intracellular Isotopically Labelled L-Leucine. Int J Mol Sci. 2022; 23(7): 3637. doi: 10.3390/ijms23073637
11. Luo Y, Gao J, Jiang X, Zhu L, Zhou QT, Murray M, et al. Molecular Insights to the Structure-Interaction Relationships of Human Proton-Coupled Oligopeptide Transporters (PepTs). Pharmaceutics. 2023; 15(10): 2517. doi: 10.3390/pharmaceutics15102517
12. Ogata S, Ito S, Masuda T, Ohtsuki S. Diurnal Changes in Protein Expression at the Blood-Brain Barrier in Mice. Biol Pharm Bull. 2022; 45(6): 751-756. doi: 10.1248/bpb.b22-00016
13. Salminen A. Activation of aryl hydrocarbon receptor (AhR) in Alzheimer's disease: role of tryptophan metabolites generated by gut host-microbiota. J Mol Med (Berl). 2023; 101(3): 201-222. doi: 10.1007/s00109-023-02289-5
14. Yassin LK, Nakhal MM, Alderei A, Almehairbi A, Mydeen AB, Akour A, Hamad MIK. Exploring the microbiota-gut-brain axis: impact on brain structure and function. Front Neuroanat. 2025; 19: 1504065. doi: 10.3389/fnana.2025.1504065
15. Huang X, Hussain B, Chang J. Peripheral inflammation and blood-brain barrier disruption: effects and mechanisms. CNS Neurosci Ther. 2021; 27(1): 36-47. doi: 10.1111/cns.13569
16. Li X, Chen G. CNS-peripheral immune interactions in hemorrhagic stroke. J Cereb Blood Flow Metab. 2023; 43(2): 185-197. doi: 10.1177/0271678X221145089
17. Sugiyama S, Sasaki T, Tanaka H, Yan H, Ikegami T, Kanki H, et al. The tight junction protein occludin modulates blood-brain barrier integrity and neurological function after ischemic stroke in mice. Sci Rep. 2023; 13(1): 2892. doi: 10.1038/s41598-023-29894-1
18. Vigh JP, Kincses A, Ozgür B, Walter FR, Santa-Maria AR, Valkai S, et al. Transendothelial Electrical Resistance Measurement across the Blood-Brain Barrier: A Critical Review of Methods. Micromachines (Basel). 2021; 12(6): 685. doi: 10.3390/mi12060685
19. Choi ES, Shusta EV. Strategies to identify, engineer, and validate antibodies targeting blood-brain barrier receptor-mediated transcytosis systems for CNS drug delivery. Expert Opin Drug Deliv. 2023; 20(12): 1789-1800. doi: 10.1080/17425247.2023.2286371
20. Lawrence JH, Patel A, King MW, Nadarajah CJ, Daneman R, Musiek ES. Microglia drive diurnal variation in susceptibility to inflammatory blood-brain barrier breakdown. JCI Insight. 2024; 9(21): e180081. doi: 10.1172/jci.insight.180081
21. Dingledine R, Varvel NH, Ravizza T, Vezzani A. Neuroinflammation in Epilepsy: Cellular and Molecular Mechanisms. In: Noebels JL, Avoli M, Rogawski MA, Vezzani A, Delgado-Escueta AV, editors. Jasper's Basic Mechanisms of the Epilepsies. 5th ed. New York: Oxford University Press; 2024.
22. Kalra S, Malik R, Singh G, Bhatia S, Al-Harrasi A, Mohan S, et al. Pathogenesis and management of traumatic brain injury (TBI): role of neuroinflammation and anti-inflammatory drugs. Inflammopharmacology. 2022; 30(4): 1153-1166. doi: 10.1007/s10787-022-01017-8
23. Cullis PR, Felgner PL. The 60-year evolution of lipid nanoparticles for nucleic acid delivery. Nat Rev Drug Discov. 2024; 23(9): 709-722. doi: 10.1038/s41573-024-00977-6
24. Li C, Sun T, Jiang C. Recent advances in nanomedicines for the treatment of ischemic stroke. Acta Pharm Sin B. 2021; 11(7): 1767-1788. doi: 10.1016/j.apsb.2020.11.019
25. Grabska-Kobyłecka I, Szpakowski P, Król A, Książek-Winiarek D, Kobyłecki A, Głąbiński A, Nowak D. Polyphenols and Their Impact on the Prevention of Neurodegenerative Diseases and Development. Nutrients. 2023; 15(15): 3454. doi: 10.3390/nu15153454
26. Miyata S. Glial functions in the blood-brain communication at the circumventricular organs. Front Neurosci. 2022; 16: 991779. doi: 10.3389/fnins.2022.991779
27. Matthews J, Herat L, Schlaich MP, Matthews V. The Impact of SGLT2 Inhibitors in the Heart and Kidneys Regardless of Diabetes Status. Int J Mol Sci. 2023; 24(18): 14243. doi: 10.3390/ijms241814243
28. Quintrell E, Russell DJ, Rahmannia S, Wyrwoll CS, Larcombe A, Kelty E. The Safety of Alcohol Pharmacotherapies in Pregnancy: A Scoping Review of Human and Animal Research. CNS Drugs. 2025; 39(1): 23-37. doi: 10.1007/s40263-024-01126-8
29. Hong D, Iakoucheva LM. Therapeutic strategies for autism: targeting three levels of the central dogma of molecular biology. Transl Psychiatry. 2023; 13(1): 58. doi: 10.1038/s41398-023-02356-y
30. Mohd Nurazzi N, Asyraf MRM, Khalina A, Abdullah N, Sabaruddin FA, Kamarudin SH, et al. Fabrication, Functionalization, and Application of Carbon Nanotube-Reinforced Polymer Composite: An Overview. Polymers (Basel). 2021; 13(7): 1047. doi: 10.3390/polym13071047
31. Xia W, Liu Y, Lu J, Cheung HH, Meng Q, Huang B. RNA methylation in neurodevelopment and related diseases. Acta Biochim Biophys Sin (Shanghai). 2024; 56(12): 1723-1732. doi: 10.3724/abbs.2024159
32. Ding Y, Zhong Y, Baldeshwiler A, Abner EL, Bauer B, Hartz AMS. Protecting P-glycoprotein at the blood-brain barrier from degradation in an Alzheimer's disease mouse model. Fluids Barriers CNS. 2021; 18(1): 10. doi: 10.1186/s12987-021-00245-4
33. Alkhalifa AE, Al-Ghraiybah NF, Odum J, Shunnarah JG, Austin N, Kaddoumi A. Blood-Brain Barrier Breakdown in Alzheimer's Disease: Mechanisms and Targeted Strategies. Int J Mol Sci. 2023; 24(22): 16288. doi: 10.3390/ijms242216288
34. Czornyj L, Auzmendi J, Lazarowski A. Transporter hypothesis in pharmacoresistant epilepsies. Is it at the central or peripheral level? Epilepsia Open. 2022; 7 Suppl 1(Suppl 1): S34-S46. doi: 10.1002/epi4.12537
35. Latif S, Kang YS. Blood-Brain Barrier Solute Carrier Transporters and Motor Neuron Disease. Pharmaceutics. 2022; 14(10): 2167. doi: 10.3390/pharmaceutics14102167
36. Nau R, Seele J, Eiffert H. New Antibiotics for the Treatment of Nosocomial Central Nervous System Infections. Antibiotics (Basel). 2024; 13(1): 58. doi: 10.3390/antibiotics13010058
37. Perucca E, White HS, Bialer M. New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development. CNS Drugs. 2023; 37(9): 781-795. doi: 10.1007/s40263-023-01025-4
38. Wierzbiński P, Hubska J, Henzler M, Kucharski B, Bieś R, Krzystanek M. Depressive and Other Adverse CNS Effects of Fluoroquinolones. Pharmaceuticals (Basel). 2023; 16(8): 1105. doi: 10.3390/ph16081105
39. Li C, Zhou P, Liu Y, Zhang L. Treatment of Ventriculitis and Meningitis After Neurosurgery Caused by Carbapenem-Resistant Enterobacteriaceae (CRE): A Challenging Topic. Infect Drug Resist. 2023; 16: 3807-3818. doi: 10.2147/IDR.S416948
40. León-Arcia K, Andrade-Guerrero J, Martínez-Orozco H, Villegas-Rojas MM, Pérez-Segura I, Ramírez IL, et al. First unified time-course of Alzheimer's-like pathology in the intracerebroventricular streptozotocin-rat model: A systematic review. Ageing Res Rev. 2026; 113: 102918. doi: 10.1016/j.arr.2025.102918
41. Schreiner TG, Romanescu C, Popescu BO. The Blood-Brain Barrier-A Key Player in Multiple Sclerosis Disease Mechanisms. Biomolecules. 2022; 12(4): 538. doi: 10.3390/biom12040538
42. Arsiwala TA, Sprowls SA, Blethen KE, Adkins CE, Saralkar PA, Fladeland RA, et al. Ultrasound-mediated disruption of the blood tumor barrier for improved therapeutic delivery. Neoplasia. 2021; 23(7): 676-691. doi: 10.1016/j.neo.2021.04.005
43. Chaves JCS, Dando SJ, White AR, Oikari LE. Blood-brain barrier transporters: An overview of function, dysfunction in Alzheimer's disease and strategies for treatment. Biochim Biophys Acta Mol Basis Dis. 2024; 1870(2): 166967. doi: 10.1016/j.bbadis.2023.166967
44. Schindler KA, Torices S, Schurhoff N, Gallo DI, Toborek M. The intersection of circadian rhythms and the blood-brain barrier with drug efficacy and delivery in neurological disorders. Adv Drug Deliv Rev. 2025; 224: 115645. doi: 10.1016/j.addr.2025.115645
45. Gasca-Salas C, Fernández-Rodríguez B, Pineda-Pardo JA, Rodríguez-Rojas R, Obeso I, Hernández-Fernández F, et al. Blood-brain barrier opening with focused ultrasound in Parkinson's disease dementia. Nat Commun. 2021; 12(1): 779. doi: 10.1038/s41467-021-21022-9
46. Ni G, Hu Z, Wang Z, Zhang M, Liu X, Yang G, et al. Cysteine Donor-Based Brain-Targeting Prodrug: Opportunities and Challenges. Oxid Med Cell Longev. 2022; 2022: 4834117. doi: 10.1155/2022/4834117
47. Song YH, De R, Lee KT. Emerging strategies to fabricate polymeric nanocarriers for enhanced drug delivery across blood-brain barrier: An overview. Adv Colloid Interface Sci. 2023; 320: 103008. doi: 10.1016/j.cis.2023.103008