Much More than Nutrients: The Protective Effects of Nutraceuticals on the Blood-Brain Barrier in Diseases

Abstract

The dysfunction of the blood-brain barrier (BBB) is well described in several diseases, and is considered a pathological factor in many neurological disorders. This review summarizes the most important groups of natural compounds, including alkaloids, flavonoids, anthocyanidines, carotenoids, lipids, and vitamins that were investigated for their potential protective effects on brain endothelium. The brain penetration of these compounds and their interaction with BBB efflux transporters and solute carriers are discussed. The cerebrovascular endothelium is considered a therapeutic target for natural compounds in diseases. In preclinical studies modeling systemic and central nervous system diseases, nutraceuticals exerted beneficial effects on the BBB. In vivo, they decreased BBB permeability, brain edema, astrocyte swelling, and morphological changes in the vessel structure and basal lamina. At the level of brain endothelial cells, nutraceuticals increased cell survival and decreased apoptosis. From the general endothelial functions, decreased angiogenesis and increased levels of vasodilating agents were demonstrated. From the BBB functions, elevated barrier integrity by tightened intercellular junctions, and increased expression and activity of BBB transporters, such as efflux pumps, solute carriers, and metabolic enzymes, were shown. Nutraceuticals enhanced the antioxidative defense and exerted anti-inflammatory effects at the BBB. The most important signaling changes mediating the increased cell survival and BBB stability were the activation of the WNT, PI3K-AKT, and NRF2 pathways, and inhibition of the MAPK, JNK, ERK, and NF-κB pathways. Nutraceuticals represent a valuable source of new potentially therapeutic molecules to treat brain diseases by protecting the BBB.

Keywords: blood–brain barrier; brain endothelial cell; central nervous system disease; efflux transporter; nutraceutical; plant-derived compound; protection; signal transduction; solute carrier.

Figure 3

The molecular basis of the protective effects of nutraceuticals on cells of the blood–brain barrier. Elements of brain endothelial cell and astrocyte functions that are involved in BBB damage and rescued by nutraceuticals are shown. ABCD3: ATP-binding cassette sub-family D member 3; ALP: alkaline phosphatase; ANG-2: angiopoietin 2; AQP4: aquaporin-4; ATP: adenosine triphosphate; Aβ_1–40: amyloid-β_1–40; BCRP: breast cancer resistance protein; CAT: catalase; CAV-1: caveolin-1; CLDDN-5: claudin-5; COX-2: cyclooxygenase-2; CX43: connexin-43; eNOS: endothelial NOS; ET-1: endothelin 1; GLUT1: glucose transporter 1; GPX: glutathione peroxidase; GSH: glutathione; GSR: glutathione-disulfide reductase; GSTs: glutathione S-transferases; HK1: hexokinase Type I; HO-1: heme oxygenase-1; IL-1β; -6; -8; -18: interleukin-1β; -6; -8; -18; iNOS: inducible nitric oxide synthase; JAM-1; -3: junction associated molecule-1; -3; LRP1; -2: low density lipoprotein receptor-related protein 1; MDA: malondialdehyde; MMP-2; -9: matrix metalloproteinase-2; -9; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B; NO: nitric oxide; NQO1: NAD(P)H quinone oxidoreductase 1 and -2; OCLN: occludin; PDK1; -2: pyruvate dehydrogenase kinase 1; -2; P-gp: P-glycoprotein; PKM2: pyruvate kinase isozyme type 2; ROS: reactive oxygen species; SOD: uperoxide dismutase; TNF-α: tumor necrosis factor-α; TXN1: thioredoxin 1; VCAM-1: vascular cell adhesion molecule-1; VEGF: vascular endothelial growth factor; VEGFR2: vascular endothelial growth factor receptor 2; ZO-1: zonula occludens-1; γGT: gamma-glutamyl transpeptidase; ↑: increase; ↓: decrease. Created in BioRender. Kucsápszky N.; Santa Maria; A. (2025) https://BioRender.com/g20w064 (accessed on 10 February 2025).

Figure 1

The most tested nutraceuticals for protective effects on the blood–brain barrier both in vivo and in vitro. The chemical composition and some of the food sources of the selected 11 compounds are shown. Created in BioRender. Kucsápszky N., Santa Maria, A. (2025) https://BioRender.com/j91e333 (accessed on 10 February 2025).

Figure 2

The structure of the blood–brain barrier in physiological and pathological conditions. The schematic drawing shows the protective effects of nutraceuticals on major components of BBB dysfunction. Created in BioRender. Kucsápszky N., Santa Maria, A. (2025) https://BioRender.com/p74u637 (accessed on 10 February 2025).

Figure 4

Signaling pathways regulated by nutraceuticals in BBB dysfunction. The simplified drawing shows the most important signaling pathways contributing to the protective effects of nutraceuticals on the BBB. The pathways converge on increased brain endothelial cell survival and BBB stability. BAX: BCL-2-like protein 4; BCL2: B-cell lymphoma 2 protein; CK: cytokines; COX-2: cyclooxygenase-2; ERK: extracellular signal-regulated kinases; GSK-3β: Glycogen synthase kinase-3β; JNK: c-Jun N-terminal kinase; MAPK: mitogen-activated protein kinase; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B; NRF2: nuclear factor erythroid 2-related factor 2; PGs: prostaglandins; PI3K: phosphoinositol 3-kinase; TLR4: toll-like receptor 4; VEGF: vascular endothelial growth factor; ↑: increase; ↓: decrease. Created in BioRender. Kucsápszky N., Santa-Maria, AR. (2025) https://BioRender.com/d25n102 (accessed on 10 February 2025).