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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-\u03baB pathways. Nutraceuticals represent a valuable source of new potentially therapeutic molecules to treat brain diseases by protecting the BBB.<\/jats:p>","DOI":"10.3390\/nu17050766","type":"journal-article","created":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T09:26:32Z","timestamp":1740129992000},"page":"766","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Much More than Nutrients: The Protective Effects of Nutraceuticals on the Blood\u2013Brain Barrier in Diseases"],"prefix":"10.3390","volume":"17","author":[{"given":"Anna E.","family":"Kocsis","sequence":"first","affiliation":[{"name":"Biological Barriers Research Group, Institute of Biophysics, HUN-REN Biological Research Centre, H-6726 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N\u00f3ra","family":"Kucs\u00e1pszky","sequence":"additional","affiliation":[{"name":"Biological Barriers Research Group, Institute of Biophysics, HUN-REN Biological Research Centre, H-6726 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3505-5477","authenticated-orcid":false,"given":"Ana Raquel","family":"Santa-Maria","sequence":"additional","affiliation":[{"name":"Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0074-3472","authenticated-orcid":false,"given":"Attila","family":"Hunyadi","sequence":"additional","affiliation":[{"name":"Institute of Pharmacognosy, University of Szeged, E\u00f6tv\u00f6s u. 6, H-6720 Szeged, Hungary"},{"name":"Interdisciplinary Centre of Natural Products, University of Szeged, E\u00f6tv\u00f6s u. 6, H-6720 Szeged, Hungary"},{"name":"HUN-REN-SZTE Biologically Active Natural Products Research Group, E\u00f6tv\u00f6s u. 6, H-6720 Szeged, Hungary"},{"name":"Graduate Institute of Natural Products, Kaohsiung Medical University, Shih-Chuan 1st Rd. 100, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6084-6524","authenticated-orcid":false,"given":"M\u00e1ria A.","family":"Deli","sequence":"additional","affiliation":[{"name":"Biological Barriers Research Group, Institute of Biophysics, HUN-REN Biological Research Centre, H-6726 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8145-2823","authenticated-orcid":false,"given":"Fruzsina R.","family":"Walter","sequence":"additional","affiliation":[{"name":"Biological Barriers Research Group, Institute of Biophysics, HUN-REN Biological Research Centre, H-6726 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural products in drug discovery: Advances and opportunities","volume":"20","author":"Atanasov","year":"2021","journal-title":"Nat. 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