Blood–brain barrier transport and neuroprotective potential of blackberry-digested polyphenols: an in vitro study

  • Inês Figueira
  • Lucélia Tavares
  • Carolina Jardim
  • Inês Costa
  • Ana P. Terrasso
  • Andreia F. Almeida
  • Coen Govers
  • Jurriaan J. Mes
  • Rui Gardner
  • Jörg D. Becker
  • Gordon J. McDougall
  • Derek Stewart
  • Augusto Filipe
  • Kwang S. Kim
  • Dora Brites
  • Catarina Brito
  • M. Alexandra Brito
  • Cláudia N. Santos
Original Contribution



Epidemiological and intervention studies have attempted to link the health effects of a diet rich in fruits and vegetables with the consumption of polyphenols and their impact in neurodegenerative diseases. Studies have shown that polyphenols can cross the intestinal barrier and reach concentrations in the bloodstream able to exert effects in vivo. However, the effective uptake of polyphenols into the brain is still regarded with some reservations. Here we describe a combination of approaches to examine the putative transport of blackberry-digested polyphenols (BDP) across the blood–brain barrier (BBB) and ultimate evaluation of their neuroprotective effects.


BDP was obtained by in vitro digestion of blackberry extract and BDP major aglycones (hBDP) were obtained by enzymatic hydrolysis. Chemical characterization and BBB transport of extracts were evaluated by LC–MSn. BBB transport and cytoprotection of both extracts was assessed in HBMEC monolayers. Neuroprotective potential of BDP was assessed in NT2-derived 3D co-cultures of neurons and astrocytes and in primary mouse cerebellar granule cells. BDP-modulated genes were evaluated by microarray analysis.


Components from BDP and hBDP were shown to be transported across the BBB. Physiologically relevant concentrations of both extracts were cytoprotective at endothelial level and BDP was neuroprotective in primary neurons and in an advanced 3D cell model. The major canonical pathways involved in the neuroprotective effect of BDP were unveiled, including mTOR signaling and the unfolded protein response pathway. Genes such as ASNS and ATF5 emerged as novel BDP-modulated targets.


BBB transport of BDP and hBDP components reinforces the health benefits of a diet rich in polyphenols in neurodegenerative disorders. Our results suggest some novel pathways and genes that may be involved in the neuroprotective mechanism of the BDP polyphenol components.


Blackberry In vitro digestion Neuronal cells Brain endothelial cells Microarrays 



iNOVA4Health Research Unit (LISBOA-01-0145-FEDER-007344), which is cofunded by Fundação para a Ciência e Tecnologia / Ministério da Ciência e do Ensino Superior, through national funds, and by FEDER under the PT2020 Partnership Agreement, is acknowledged. Authors would like to acknowledge to COST FA1005–INFOGEST and to FCT for financial support of CNS (IF/01097/2013), IF (SFRH/BD/86584/2012), APT (PD/BD/52473/2014), and DB and MAB (Strategic Project to iMed.ULisboa, UID/DTP/04138/2013). CNS and DS acknowledge funding via BacHBerry (Project No. FP7-613793; and DS and GMcD acknowledge funding from the Scottish Government Rural and Environmental Sciences and Analytical Services (RESAS) Department. Funding from Tecnimede - Sociedade Técnico Medicinal S.A. (Abrunheira, Sintra, Portugal), the European Regional Development Fund (FEDER) and the System of Incentives for the Research and Technological Development (QREN) of the Portuguese Government is also acknowledged. Extensive revising of the English written work by GMcD is also acknowledged.

Compliance with ethical standards

Conflict of interest

AF is employee of Tecnimede-Sociedade Técnico Medicinal, S.A. The other authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Supplementary material

394_2017_1576_MOESM1_ESM.tif (333 kb)
Supplementary Fig. 1 Representative picture of the isolation of SK-N-MC cells that presented cellular membrane integrity (PI negative) and high mitochondrial transmembrane potential (DiOC6(3) positive) using FACSAria High Speed Cell Sorter. SSC-A – side scatter, FSC-A – forward scatter. Top panels: control cells; Bottom panels: cells incubated with BDP (TIF 332 KB)
394_2017_1576_MOESM2_ESM.docx (14 kb)
Supplementary material 2 (DOCX 13 KB)


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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Inês Figueira
    • 1
    • 2
  • Lucélia Tavares
    • 1
    • 2
  • Carolina Jardim
    • 1
    • 2
  • Inês Costa
    • 1
    • 2
  • Ana P. Terrasso
    • 1
    • 2
  • Andreia F. Almeida
    • 1
    • 2
  • Coen Govers
    • 3
  • Jurriaan J. Mes
    • 3
  • Rui Gardner
    • 4
  • Jörg D. Becker
    • 4
  • Gordon J. McDougall
    • 5
  • Derek Stewart
    • 5
    • 6
    • 7
  • Augusto Filipe
    • 8
  • Kwang S. Kim
    • 9
  • Dora Brites
    • 10
    • 11
  • Catarina Brito
    • 1
    • 2
  • M. Alexandra Brito
    • 10
    • 11
  • Cláudia N. Santos
    • 1
    • 2
  1. 1.Instituto de Tecnologia Quı́mica e Biológica-António XavierUniversidade Nova de LisboaOeirasPortugal
  2. 2. iBET, Instituto de Biologia Experimental e TecnológicaOeirasPortugal
  3. 3.Wageningen Food & Biobased ResearchWageningen University and ResearchWageningenThe Netherlands
  4. 4.Instituto Gulbenkian de CiênciaOeirasPortugal
  5. 5.The James Hutton InstituteDundeeUK
  6. 6.School of Engineering and Physical SciencesHeriot Watt UniversityEdinburghUK
  7. 7.NIBIO, Norwegian Institute of Bioeconomy ResearchÅsNorway
  8. 8.Medical DepartmentGrupo TecnimedeSintraPortugal
  9. 9.Division of Infectious DiseasesJohns Hopkins University School of MedicineBaltimoreUSA
  10. 10.Research Institute for Medicines (iMed.ULisboa), Faculty of PharmacyUniversidade de LisboaLisbonPortugal
  11. 11.Department of Biochemistry and Human Biology, Faculty of PharmacyUniversidade de LisboaLisbonPortugal

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