A New Perspective on the Modulation of the Blood Brain Barrier: The Role of Nutrition and Environmental Factors

Abstract

The blood-brain barrier (BBB) is a highly selective and dynamic endothelial barrier tightly regulated between the central nervous system (CNS) and the peripheral nervous system, that prevents the passage of toxic compounds and pathogens from passing from the blood to the brain while also ensuring nutrient transmission. It provides brain homeostasis for the healthy fulfilment of synaptic and neuronal functions. The blood-brain barrier performs its functions through elements of the neurovascular unit such as tight junctions, astrocytes, and pericytes. Nutrition, neuronal activity, and environmental factors such as aging, air pollution, exposure to heavy metals, smoking, alcohol, stress play a role in blood-brain barrier modulation. Neuroinflammation is a coordinated response to brain damage. In response to altered brain homeostasis, a number of inflammatory mediators are released that affect blood-brain barrier permeability. Several dietary factors including diet composition, antioxidant components, nutraceuticals, and vitamins influence blood-brain barrier permeability by affecting neuroinflammation. While the diet can be neuroprotective with the beneficial components, it can also cause destructive effects in the CNS by causing neuroinflammation in the blood-brain barrier. The impact of nutrition in the prevention, development, progression and treatment of neurodegenerative diseases is a fascinating new field for researchers. Addressing the effects of foods and dietary habits on blood-brain barrier modulation will provide a new perspective on the disease-diet interaction.

Keywords

• Blood brain barrier
• neurodegenerative diseases
• diet
• environmental factors

Kan Beyin Bariyeri Modülasyonuna Yeni Bir Bakış Açısı: Beslenme ve Çevresel Faktörlerin Etkisi

Abstract

Kan beyin bariyeri (KBB), toksik bileşiklerin ve patojenlerin kandan beyne geçişini engelleyen, besin ögelerinin ise beyne iletilmesini sağlayan merkezi sinir sistemi (MSS) ve periferik sinir sistemi arasında regüle edilen oldukça seçici ve dinamik endotel bir bariyerdir. Kan beyin bariyeri, sinaptik ve nöronal işlevlerin sağlıklı bir biçimde yerine getirilmesi için beyin homeostazını sağlar. Kan beyin bariyeri işlevlerini sıkı bağlantı proteinleri (tight junctions), astrositler, perisitler gibi nörovasküler ünitenin elemanları vasıtasıyla gerçekleştirir. Beslenme, nöronal aktivite ve yaşlanma, hava kirliliği, ağır metallere maruziyet, sigara, alkol, stres, egzersiz gibi çevresel faktörler kan beyin bariyeri modülasyonunda rol oynamaktadır. Nöroinflamasyon, beyinde gerçekleşen hasarı takiben gelişen koordine bir yanıttır. Değişen beyin homeostazına yanıt olarak kan beyin bariyeri geçirgenliğine etki eden bir dizi inflamatuar mediatör salınır. Diyetin bileşimi, antioksidan bileşenler, nutrasötikler, vitaminler gibi çeşitli diyete bağlı faktörler nöroinflamasyona etki ederek kan beyin bariyeri geçirgenliğinde rol oynamaktadır. Diyet içerdiği yararlı bileşenler ile nöroprotektif olabilirken, kan beyin bariyerinde nöroinflamasyona neden olarak MSS’de yıkıcı etkilere de neden olabilir. Beslenmenin nörodejeneratif hastalıkların önlenmesinde, gelişiminde, progresyonunda ve tedavisindeki etkisi araştırmacılar için merak uyandıran yeni bir alandır. Besinlerin ve beslenme alışkanlıklarının kan beyin bariyeri modülasyonuna etkisinin ele alınması hastalık-diyet etkileşimine yeni bir bakış açısı sağlayacaktır.

Keywords

• Kan beyin bariyeri
• nörodejeneratif hastalıklar
• beslenme
• çevresel etmenler
• Blood brain barrier
• neurodegenerative diseases
• diet
• environmental factors

References

1. Sweeney MD, Sagare AP, Zlokovic BV. Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018;14(3):133-150.
2. Fu BM. Transport across the blood-brain barrier. Molecular, cellular, and tissue engineering of the vascular system. Adv Exp Med Biol. 2018:235-259.
3. Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV. Blood-brain barrier: from physiology to disease and back. Physiol Rev. 2019;99(1):21-78.
4. Sahin A, Yoyen-Ermis D, Caban-Toktas S, et al. Evaluation of brain-targeted chitosan nanoparticles through blood–brain barrier cerebral microvessel endothelial cells. J Microencapsul. 2017;34(7):659-666.
5. Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV. Blood-brain barrier: from physiology to disease and back. Physiol Rev. 2019;99(1):21-78.
6. Segarra M, Aburto MR, Acker-Palmer A. Blood-Brain Barrier Dynamics to Maintain Brain Homeostasis. Trends Neurosci. 2021;44(5):393-405.
7. Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV. Blood-brain barrier: from physiology to disease and back. Physiol Rev. 2019; 99(1):21-78.
8. Winger RC, Koblinski JE, Kanda T, Ransohoff RM, Muller WA. Rapid remodeling of tight junctions during paracellular diapedesis in a human model of the blood-brain barrier. J Immun. 2014;193(5):2427-2437.

9. Barichello T, Collodel A, Hasbun R, Morales R. An overview of the blood-brain barrier. In: Barichello T, editor. Blood-brain barrier. New York. 2019. p.1-8.
10. Bell AH, Miller SL, Castillo-Melendez M, Malhotra A. The neurovascular unit: Effects of brain insults during the perinatal period. Front Neurosci. 2020;13:1452.
11. Profaci CP, Munji RN, Pulido RS, Daneman R. The blood–brain barrier in health and disease: Important unanswered questions. J Exp Med. 2020;217(4): 20190062.
12. Sun Q, Xu X, Wang T, et al. Neurovascular units and neural-glia networks in intracerebral hemorrhage: from mechanisms to translation. Transl Stroke Res. 2021;12(3):447-460.
13. Curry FE, Adamson RH. Endothelial glycocalyx: permeability barrier and mechanosensor. Ann Biomed Eng. 2012;40(4):828-839.
14. Wang Y, Fu AKY, Ip NY. Instructive roles of astrocytes in hippocampal synaptic plasticity: neuronal activity-dependent regulatory mechanisms. FEBS J [Preprint]. 2021 [cited 2022 March 20]. Available from: https://pubmed.ncbi.nlm.nih.gov/33864430/
15. Spampinato SF, Bortolotto V, Canonico PL, Sortino MA, Grilli M. Astrocyte-derived paracrine signals: relevance for neurogenic niche regulation and blood–brain barrier Integrity. Front Pharmacol [Preprint] 2019 Nov [cited 2022 Feb 22] ;10:1346. Available at: https://www. frontiersin.org/article/10.3389/fphar.2019.01346.
16. Erdő F, Denes L, Lange E de. Age-associated physiological and pathological changes at the blood-brain barrier: a review. J Cereb Blood Flow Metab. 2017;37(1):4-24.
17. Thurgur H, Pinteaux E. Microglia in the neurovascular unit: blood-brain barrier-microglia interactions after central nervous system disorders. Neurosci. 2019;405:55-67.
18. Galea I, Perry VH. The blood-brain interface: a culture change. Brain Behav Immun. 2018;68:11-16.
19. Varatharaj A, Galea I. The blood-brain barrier in systemic inflammation. Brain Behav Immun. 2017;60:1-12.
20. Hladky SB, Barrand MA. Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence. Fluids Barriers CNS. 2014;11(1):26.
21. Ransohoff RM, Kivisäkk P, Kidd G. Three or more routes for leukocyte migration into the central nervous system. Nat Rev Immunol. 2003;3(7):569-581.
22. Galea I. The blood–brain barrier in systemic infection and inflammation. Cell Mol Immunol. 2021;18(11):2489-2501.
23. Young TL, Zychowski KE, Denson JL, Campen MJ. Blood-brain barrier at the interface of air pollution-associated neurotoxicity and neuroinflammation. Adv Neurotoxicol. 2019;3:295-337.
24. Segarra M, Aburto MR, Acker-Palmer A. Blood–brain barrier dynamics to maintain brain homeostasis. Trends Neurosci. 2021;44(5):393-405.
25. DiSabato DJ, Quan N, Godbout JP. Neuroinflammation: the devil is in the details. J Neurochem. 2016;139:136-153.
26. Małkiewicz MA, Szarmach A, Sabisz A, Cubała WJ, Szurowska E, Winklewski PJ. Blood-brain barrier permeability and physical exercise. J Neuroinflammation. 2019;16(1):1-16.
27. Young TL, Zychowski KE, Denson JL, Campen MJ. Blood-brain barrier at the interface of air pollution-associated neurotoxicity and neuroinflammation. In: Aschner M, Costa LG, editors. Advances in neurotoxicology: role of inflammation in environmental neurotoxicity. United States; 2019. p. 295-337.
28. Spezzano P. Mapping the susceptibility of UNESCO World Cultural Heritage sites in Europe to ambient (outdoor) air pollution. Sci Total Environ. 2021;754:142345.
29. Noorimotlagh Z, Azizi M, Pan H-F, Mami S, Mirzaee SA. Association between air pollution and Multiple Sclerosis: a systematic review. Environ Res. 2021;196:110386.
30. Lochhead JJ, McCaffrey G, Quigley CE, et al. Oxidative stress increases blood–brain barrier permeability and induces alterations in occludin during hypoxia–reoxygenation. J Cereb Blood Flow Metab. 2010;30(9):1625-1636.
31. Thiankhaw K, Chattipakorn N, Chattipakorn SC. PM2.5 exposure in association with AD-related neuropathology and cognitive outcomes. Environ Pollut. 2022;292:118320.
32. Hameed S, Zhao J, Zare RN. Ambient PM particles reach mouse brain, generate ultrastructural hallmarks of neuroinflammation, and stimulate amyloid deposition, tangles, and plaque formation. Talanta. 2020;2:100013.
33. Weichenthal S, Olaniyan T, Christidis T, et al. Within-city spatial variations in ambient ultrafine particle concentrations and incident brain tumors in adults. Epidemiology. 2020;31(2):177-183.
34. Kreyling WG. Discovery of unique and ENM- specific pathophysiologic pathways: Comparison of the translocation of inhaled iridium nanoparticles from nasal epithelium versus alveolar epithelium towards the brain of rats. Toxicol Appl Pharmacol. 2016;299:41-46.
35. Heusinkveld HJ, Wahle T, Campbell A, et al. Neurodegenerative and neurological disorders by small inhaled particles. Neurotoxicol. 2016;56:94-106.
36. Bjork JM, Gilman JM. The effects of acute alcohol administration on the human brain: insights from neuroimaging. Neuropharmacology. 2014;84:101-110.
37. Carrino D, Branca JJV, Becatti M, et al. Alcohol-induced blood-brain barrier impairment: an in vitro study. J Environ Res Public Health. 2021;18(5).
38. Austin V, Crack PJ, Bozinovski S, Miller AA, Vlahos R. COPD and stroke: are systemic inflammation and oxidative stress the missing links? Clin Sci. 2016;130(13):1039-1050.
39. Sajja RK, Rahman S, Cucullo L. Drugs of abuse and blood-brain barrier endothelial dysfunction: A focus on the role of oxidative stress. J Cereb Blood Flow Metab. 2016;36(3):539-554.
40. Kousik SM, Napier TC, Carvey PM. The effects of psychostimulant drugs on blood brain barrier function and neuroinflammation. Front Pharmacol. 2012;3:121.
41. Sajja RK, Rahman S, Cucullo L. Drugs of abuse and blood-brain barrier endothelial dysfunction: A focus on the role of oxidative stress. J Cereb Blood Flow Metab. 2016;36(3):539-554.
42. Esposito P, Gheorghe D, Kandere K, et al. Acute stress increases permeability of the blood–brain-barrier through activation of brain mast cells. Brain Res. 2001;888(1):117-127.
43. Lee S, Kang B-M, Kim JH, et al. Real-time in vivo two-photon imaging study reveals decreased cerebro-vascular volume and increased blood-brain barrier permeability in chronically stressed mice. Sci Rep. 2018;8(1):1-14.
44. Menard C, Pfau ML, Hodes GE, et al. Social stress induces neurovascular pathology promoting depression. Nat Neurosci. 2017;20(12):1752-1760.
45. Keep RF, Jones HC, Drewes LR. Progress in brain barriers and brain fluid research in 2017. Fluids Barriers CNS. 2018;15(1):6.
46. Welcome MO, Mastorakis NE. Stress-induced blood brain barrier disruption: molecular mechanisms and signaling pathways. Pharmacol Res. 2020;157:104769.
47. Agnihotri SK, Kesari KK. Mechanistic effect of heavy metals in neurological disorder and brain cancer. In: Kumar Kesari K, editor. Networking of mutagens in environmental toxicology. United States; 2019. p. 25-47.
48. Spencer PS, Lein PJ. Neurotoxicity. In: Wexler P, editor. Encyclopedia of Toxicology. Oxford; 2014. p. 489-500.
49. Jaishankar M, Tseten T, Anbalagan N, Mathew BB, Beeregowda KN. Toxicity, mechanism and health effects of some heavy metals. Interdiscip Toxicol. 2014;7(2):60-72.
50. Kumar A, Singh N, Pandey R, Gupta VK, Sharma B. Biochemical and molecular targets of heavy metals and their actions. In: Rai M, Ingle AP, Medici SM, editors. Biomedical applications of metals. United States; 2018. p. 297-319.
51. Bernard A, Ku JM, Vlahos R, Miller AA. Cigarette smoke extract exacerbates hyperpermeability of cerebral endothelial cells after oxygen glucose deprivation and reoxygenation. Sci Rep. 2019;9(1):1-10.
52. Zheng W, Aschner M, Ghersi-Egea J-F. Brain barrier systems: a new frontier in metal neurotoxicological research. Toxicol Appl Pharmacol. 2003;192(1):1-11.
53. Wang B, Du Y. Cadmium and its neurotoxic effects. Oxid Med Cell Longev. 2013;2013:898034.
54. Moneim AEA. Mercury-induced neurotoxicity and neuroprotective effects of berberine. Neural Regen Res. 2015;10(6):881-882.
55. Yin Z, Jiang H, Syversen T, Rocha JBT, Farina M, Aschner M. The methylmercury‐l‐cysteine conjugate is a substrate for the L‐type large neutral amino acid transporter. J Neurochem. 2008;107(4):1083-1090.
56. Zimmermann LT, Santos DB, Naime AA, et al. Comparative study on methyl-and ethylmercury-induced toxicity in C6 glioma cells and the potential role of LAT-1 in mediating mercurial-thiol complexes uptake. Neurotoxicol. 2013;38:1-8.
57. Müller SM, Ebert F, Raber G, et al. Effects of arsenolipids on in vitro blood-brain barrier model. Arch Toxicol. 2018;92(2):823-832.
58. Müller SM, Ebert F, Raber G, et al. Effects of arsenolipids on in vitro blood-brain barrier model. Arch Toxicol. 2018;92(2):823-832.
59. Singh AP, Goel RK, Kaur T. Mechanisms pertaining to arsenic toxicity. Toxicol Int. 2011;18(2):87.
60. Miller F, Afonso PV, Gessain A, Ceccaldi PE. Blood-brain barrier and retroviral infections. Virulence. 2012;3(2):222-229.
61. Strazza M, Pirrone V, Wigdahl B, Nonnemacher MR. Breaking down the barrier: the effects of HIV-1 on the blood–brain barrier. Brain Res. 2011;1399:96-115.
62. Verma S, Lo Y, Chapagain M, et al. West Nile virus infection modulates human brain microvascular endothelial cells tight junction proteins and cell adhesion molecules: transmigration across the in vitro blood-brain barrier. Virology. 2009;385(2):425-433.
63. Chiu C-F, Chu L-W, Liao I-C, et al. The mechanism of the Zika virus crossing the placental barrier and the blood-brain barrier. Front Microbiol. 2020;11:214.
64. Leda AR, Bertrand L, Andras IE, El-Hage N, Nair M, Toborek M. Selective disruption of the blood-brain barrier by Zika virus. Front Microbiol. 2019;10:2158.
65. Paniz-Mondolfi A, Bryce C, Grimes Z, et al. Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). J Med Virol. 2020;92(7):699-702.
66. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the `Cytokine Storm' in COVID-19. J Infect. 2020;80(6):607-613.
67. Afonso PV, Ozden S, Cumont M-C, et al. Alteration of blood– brain barrier integrity by retroviral infection. PLoS Pathog. 2008;4(11):e1000205.
68. Kim J, Chuang HC, Wolf NK, Nicolai CJ, Raulet DH, Saijo K, Bilder D. Tumor-induced disruption of the blood-brain barrier promotes host death. Dev Cell. 2021; 56 (19), 2712–2721.
69. Starr JM, Wardlaw J, Ferguson K, MacLullich A, Deary IJ, Marshall I. Increased blood–brain barrier permeability in type II diabetes demonstrated by gadolinium magnetic resonance imaging. J Neurol Neurosurg Psychiatry. 2003;74(1):70-76.
70. Xu Z, Zeng W, Sun J, et al. The quantification of blood-brain barrier disruption using dynamic contrast-enhanced magnetic resonance imaging in aging rhesus monkeys with spontaneous type 2 diabetes mellitus. Neuroimage. 2017;158:480-487.
71. Li W, Maloney RE, Aw TY. High glucose, glucose fluctuation and carbonyl stress enhance brain microvascular endothelial barrier dysfunction: implications for diabetic cerebral microvasculature. Redox Biol. 2015;5:80-90.
72. Li W, Maloney RE, Circu ML, Alexander JS, Aw TY. Acute carbonyl stress induces occludin glycation and brain microvascular endothelial barrier dysfunction: role for glutathione-dependent metabolism of methylglyoxal. Free Radic Biol Med. 2013;54:51-61.
73. Setiadi A, Korim WS, Elsaafien K, Yao ST. The role of the blood–brain barrier in hypertension. Experiment Physiol. 2018;103(3):337-342.
74. Biancardi VC, Son SJ, Ahmadi S, Filosa JA, Stern JE. Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood–brain barrier. Hypertension. 2014;63(3):572-579.
75. Mohammadi MT, Dehghani GA. Acute hypertension induces brain injury and blood–brain barrier disruption through reduction of claudins mRNA expression in rat. Pathol Res Pract. 2014;210(12):985-990.
76. Farrall AJ, Wardlaw JM. Blood-brain barrier: ageing and microvascular disease-systematic review and meta-analysis. Neurobiol Aging. 2009;30(3):337-352.
77. Montagne A, Nation DA, Sagare AP, Barisano G, Sweeney MD, Chakhoyan A, Zlokovic BV. APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline. Nature. 2020; 581(7806):71- 76.
78. Banks WA, Reed MJ, Logsdon AF, Rhea EM, Erickson MA. Healthy aging and the blood–brain barrier. Nat Aging. 2021;1(3):243-254.
79. Nation DA, Sweeney MD, Montagne A, et al. Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med. 2019;25(2):270-276.
80. Butterfield DA. The 2013 SFRBM discovery award: selected discoveries from the butterfield laboratory of oxidative stress and its sequela in brain in cognitive disorders exemplified by Alzheimer disease and chemotherapy induced cognitive impairment. Free Rad Biol Med. 2014;74:157-174.
81. Welcome MO. Gut microbiota disorder, gut epithelial and blood–brain barrier dysfunctions in etiopathogenesis of dementia: molecular mechanisms and signaling pathways. Neuromolecular Med. 2019;21(3):205-226.
82. Braniste V, Al-Asmakh M, Kowal C, et al. The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med. 2014;6(263):158-263.
83. Hoyles L, Pontifex MG, Rodriguez-Ramiro I, et al. Regulation of blood-brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine N-oxide. Microbiome. 2021;9(1):235.
84. Devi A, Narayanan R. A review on neuronutrition. Asian J Dairy Food Res. 2019;38(2):128-133.
85. Verrotti A, D'Egidio C, Agostinelli S, Gobbi G. Glut1 deficiency: when to suspect and how to diagnose? Eur J Paediatr Neurol. 2012;16(1):3-9.
86. Spector R, Robert Snodgrass S, Johanson CE. A balanced view of the cerebrospinal fluid composition and functions: focus on adult humans. Experiment Neurol. 2015;273:57-68.
87. Fatyga P, Pac A, Fedyk-Łukasik M, Grodzicki T, Skalska A. The relationship between malnutrition risk and inflammatory biomarkers in outpatient geriatric population. Eur Geriatr Med. 2020;11(3):383-391.
88. Ellulu MS, Patimah I, Khaza’ai H, Rahmat A, Abed Y. Obesity and inflammation: the linking mechanism and the complications. AMS. 2017;13(4):851.
89. Griffiths H, Irundika D, Lip G, Spickett C, Polidori C. Oxidised LDL lipids, statins and a blood-brain barrier. Free Rad. Biol Med. 2014;75(1):6-15.
90. Smith SE, Figley SA, Schreyer DJ, Paterson PG. Protein-energy malnutrition developing after global brain ischemia induces an atypical acute-phase response and hinders expression of GAP-43. PloS One. 2014;9(9):107570.
91. Aquino CC de, Leitão RA, Oliveira Alves LA, et al. Effect of hypoproteic and high-fat diets on hippocampal blood-brain barrier permeability and oxidative stress. Front Nutr. 2019;5:131.
92. Nerurkar PV, Johns LM, Buesa LM, et al. Momordica charantia (bitter melon) attenuates high-fat diet-associated oxidative stress and neuroinflammation. J Neuroinflammation. 2011;8(1):1-19.
93. Chang H-C, Tai Y-T, Cherng Y-G, et al. Resveratrol attenuates high-fat diet-induced disruption of the blood–brain barrier and protects brain neurons from apoptotic insults. J Agric Food Chem. 2014;62(15):3466-3475.
94. Kanoski SE, Zhang Y, Zheng W, Davidson TL. The effects of a high-energy diet on hippocampal function and blood-brain barrier integrity in the rat. J Alzheimer's Dis. 2010;21(1):207-219.
95. Snelson M, Mamo JCL, Lam V, Giles C, Takechi R. Differential effects of high-protein diets derived from soy and casein on blood–brain barrier integrity in wild-type mice. Frontiers Nutr. 2017;4:35.
96. Rijnsburger M, Unmehopa UA, Eggels L, Serlie MJ, La Fleur SE. One-week exposure to a free-choice high-fat high-sugar diet does not disrupt blood–brain barrier permeability in fed or overnight fasted rats. Nutr Neurosci. 2019;22(8):541-550.
97. de Aquino CC, Leitão RA, Oliveira Alves LA, Coelho-Santos V, Guerrant RL, Ribeiro CF, Malva JO, Silva AP, Oriá RB. Effect of hypoproteic and high-fat diets on hippocampal blood-brain barrier permeability and oxidative Stress. Front Nutr. 2019;5,131.
98. Banjara M, Janigro D. Effects of the ketogenic diet on the blood-brain barrier. In: Susan AM, editor. Ketogenic diet and metabolic therapies: expanded roles in health and disease. Oxford; 2016. p. 289-304.
99. Ma D, Wang AC, Parikh I, et al. Ketogenic diet enhances neurovascular function with altered gut microbiome in young healthy mice. Sci Rep. 2018;8(1):1-10.
100. Leino RL, Gerhart DZ, Duelli R, Enerson BE, Drewes LR. Diet-induced ketosis increases monocarboxylate transporter (MCT1) levels in rat brain. Neurochem Int. 2001;38(6):519-527.
101. Versele R, Corsi M, Fuso A, et al. Ketone bodies promote amyloid-β1-40 clearance in a human in vitro blood-brain barrier model. Int J Mol Sci. 2020;21(3):934.
102. Paoli A, Mancin L, Bianco A, Thomas E, Mota JF, Piccini F. Ketogenic diet and microbiota: friends or enemies? Genes. 2019;10(7): 534.
103. Terry C. Insights from nature: A review of natural compounds that target protein misfolding in vivo. Curr Res Biotechnol. 2020;2:131-144.
104. Youdim KA, McDonald J, Kalt W, Joseph JA. Potential role of dietary flavonoids in reducing microvascular endothelium vulnerability to oxidative and inflammatory insults. J Nutr Biochem. 2002;13(5):282-288.
105. Youdim KA, Shukitt-Hale B, Joseph JA. Flavonoids and the brain: interactions at the blood–brain barrier and their physiological effects on the central nervous system. Free Rad Biol Med. 2004;37(11):1683-1693.
106. Suganuma M, Okabe S, Oniyama M, Tada Y, Ito H, Fujiki H. Wide distribution of [3H](-)-epigallocatechin gallate, a cancer preventive tea polyphenol, in mouse tissue. Carcinogenesis. 1998;19(10):1771-1776.
107. Tsai T, Chen Y. Determination of unbound hesperetin in rat blood and brain by microdialysis coupled to microbore liquid chromatography. J Food Drug Anal. 2000;8(4):331-336.
108. Peng HW, Cheng FC, Huang YT, Chen CF, Tsai TH. Determination of naringenin and its glucuronide conjugate in rat plasma and brain tissue by high-performance liquid chromatography. J Chromatogr B: Biomed Appl. 1998;714(2):369-374.
109. Youdim KA, Dobbie MS, Kuhnle G, Proteggente AR, Abbott NJ, Rice‐ Evans C. Interaction between flavonoids and the blood–brain barrier: in vitro studies. J Neurochem. 2003;85(1):180-192.
110. Tang XC, De Sarno P, Sugaya K, Giacobini E. Effect of huperzine A, a new cholinesterase inhibitor, on the central cholinergic system of the rat. J Neurosci Res 1989;24:276–85.
111. Packer L, Tritschler HJ, Wessel K. Neuroprotection by the metabolic antioxidant α-lipoic acid. Free Radic Biol Med 1997;22:359–78.
112. Lorenz P, Roychowdhury S, Engelmann M, Wolf G, Horn TFW. Oxyresveratrol and resveratrol are potent antioxidants and free radical scavengers: effect on nitrosative and oxidative stress derived from microglial cells. Nitric Oxide 2003;9:64–76.
113. Mecocci P, Polidori MC. Antioxidant clinical trials in mild cognitive impairment and Alzheimer’s disease. Biochim Biophys Acta Mol Basis Dis 2012;1822:631–8.
114. Pervin M, Unno K, Nakagawa A, Takahashi Y, Iguchi K, Yamamoto H, et al. Blood brain barrier permeability of (-)-epigallocatechin gallate, its proliferation-enhancing activity of human neuroblastoma SH-SY5Y cells, and its preventive effect on age-related cognitive dysfunction in mice. Biochem Biophys Rep. 2017; 5;9:180-186.
115. Li Y, Zhou S, Li J, Sun Y, Hasimu H, Liu R, et al. Quercetin protects human brain microvascular endothelial cells from fibrillar beta-amyloid1-40-induced toxicity. Acta Pharm Sin B 2015;5:47–54.
116. Huang J, Agus DB, Winfree CJ, Kiss S, Mack WJ, McTaggart RA, et al. Dehydroascorbic acid, a bloodbrain barrier transportable form of vitamin C, mediates potent cerebroprotection in experimental stroke. Proc Natl Acad Sci U S A 2001;98:11720–4.
117. Yeh CT, Yen GC. Effects of phenolic acids on human phenolsulfotransferases in relation to their antioxidant activity. J Agric Food Chem 2003;51:1474–9.
118. Galaris D, Evangelou A. The role of oxidative stress in mechanisms of metal-induced carcinogenesis. Crit Rev Oncol Hematol 2002;42:93–103.
119. Pinto M, Benfeito S, Fernandes C, Borges F. Antioxidant therapy, oxidative stress, and blood-brain barrier: the road of dietary antioxidants. In: Oxidative stress and dietary antioxidants in neurological diseases. Basel, Switzerland: Academic Press; 2020. 125-141 p
120. Shimazu R, Anada M, Miyaguchi A, Nomi Y, Matsumoto H. Evaluation of blood–brain barrier permeability of polyphenols, anthocyanins, and their metabolites. J Agric Food Chem. 2021;69(39):11676-11686.