David Vauzour

Eglantine Balland

Pauline Lafenetre

Frontiers in Neuroscience

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TYPE EditorialPUBLISHED 21 July 2022DOI 10.3389/fnins.2022.947761OPEN ACCESSEDITED AND REVIEWED BYDonato Angelino,University of Teramo, Italy*CORRESPONDENCEEglantine Ballandeglantine.balland@monash.eduSPECIALTY SECTIONThis article was submitted toNeuroenergetics, Nutrition and BrainHealth,a section of the journalFrontiers in NeuroscienceRECEIVED 19 May 2022ACCEPTED 08 July 2022PUBLISHED 21 July 2022CITATIONBalland E, Lafenetre P and Vauzour D(2022) Editorial: Polyphenols’ action onthe brain. Front. Neurosci. 16:947761.doi: 10.3389/fnins.2022.947761COPYRIGHT© 2022 Balland, Lafenetre andVauzour. This is an open-access articledistributed under the terms of theCreative Commons Attribution License(CC BY). The use, distribution orreproduction in other forums ispermitted, provided the originalauthor(s) and the copyright owner(s)are credited and that the originalpublication in this journal is cited, inaccordance with accepted academicpractice. No use, distribution orreproduction is permitted which doesnot comply with these terms.Editorial: Polyphenols’ action onthe brainEglantine Balland1*, Pauline Lafenetre2,3 and David Vauzour41Department of Nutrition, Dietetics and Food, School of Clinical Sciences at Monash Health, Facultyof Medicine, Nursing and Health Sciences, Monash University, Notting Hill, VIC, Australia, 2BordeauxINP, Nutrition and Integrative Neurobiology, UMR1286, Bordeaux, France, 3CNRS, InterdisciplinaryInstitute for Neuroscience, UMR 5297, Bordeaux, France, 4Norwich Medical School, BiomedicalResearch Centre, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich,United KingdomKEYWORDSneuroprotection, nutrition, polyphenol, neurodegenerative disease, blood-brainbarrier, antioxidants, brain healthEditorial on the Research TopicPolyphenols’ Action on the BrainUnlike humans, plants do not possess an immune system to protect them frombiological, physical and chemical threats, hence they had to develop different strategiesto protect themselves from predation and other environmental menaces. (Poly)phenolsare secondary plant metabolites able to fulfill this protective role, so why wouldn’tthey also confer health benefits to humans? Over the last decades, a great body ofscientific evidence has demonstrated the diverse health benefits exerted by these bioactivecompounds on human physiology. (Poly)phenols represent a fantastic preventivetreatment opportunity against many pathologies, including neurodegenerative diseases,as they are already present in many plant-based foods we consume, contributing totheir color, flavor, bitterness, astringency and oxidative stability, and therefore are safeto prescribe. Phenolic acids and flavonoids are the (poly)phenols the most abundantlyfound in plant-based food consumed by humans.Since (poly)phenols are known to cross (Figueira et al., 2017) and possibly modulate(Lee et al., 2020), the blood-brain barrier (BBB) and have been shown to play aprotective role in neurodegenerative diseases such as Parkinson’s and Alzheimer’sdiseases (Ramassamy, 2006), this Research Topic focuses on the health benefits exertedby (poly)phenols specifically on the brain. Studying the molecular mechanisms of actionof (poly)phenols on human physiology represents a challenge for various reasons. First,(poly)phenols can have some profound effects in vitro, when a particular metabolite isapplied at high dose. However, in many cases such high dose isn’t achievable with normalfood consumption and the bioactivity and bioavailability will differ greatly when used invivo. Various metabolites with different potency and actions can be formed accordingto where (which organ or cell type) they are metabolized. Additionally, (poly)phenolscan also be extensively transformed by the gut microbiota and results in numerous novelcompounds harboring a range of different physiological effects. It is therefore importantto take these limitations into account and to use multi-dimensional approaches alongFrontiers inNeuroscience 01 frontiersin.orgBalland et al. 10.3389/fnins.2022.947761with various models (in vitro, animal models, and humanstudies) when investigating the health benefits of (poly)phenols,and in this particular context, be aware of 1/ the possibilityof a specific polyphenol to access the central nervous system(CNS) and 2/ knowing which metabolite(s) derived fromthe polyphenol of interest is/are likely to act on the brainmicroenvironment and target cells.This Research Topic of articles gathers studiesdemonstrating various health benefits exerted by (poly)phenolson the brain. Experimental results obtained from cell lines,rodents, and human studies measure (poly)phenols’ healthbenefits at the molecular level and show how these mechanismsmay translate into behavioral effects.Accuracy and speed of attention analyzes represent agood measurement of some of the function of a healthybrain. In their meta-analysis of the results from 18 of themost recent randomized controlled trials, Hepsomali et al.highlighted the significant positive effect of (poly)phenolconsumption (various compounds and doses) on accuracyand speed of attention, independently of age and gender.Pontifex et al. studied more specifically the effect of citrusfruits-derived (poly)phenols on various homeostatic and physio-pathologic events occurring in/affecting the CNS such asdepression, schizophrenia, stroke, dementia, cellular processescontributing to the maintenance of homeostasis, gut/braincross-talk, antioxidant, and anti-inflammatory activities. Theauthors analyzed and summarized the results from in vitroand pre-clinical studies, using isolated compounds or wholefruit or mixture of compounds in a juice, as well as molecularand behavioral studies performed in rodents with dietarysupplementation or injections of citrus-derived polyphenols todemonstrate that hesperidin, hesperetin, naringenin, naringin,and kaempferol consistently exert beneficial effects on the CNS-dependent parameters studied.Tg4510 is a mutant mouse model of Alzheimer’s diseasewhich spontaneously develops TAU pathology, one of thehallmarks of the neurodegenerative disease in which thehyperphosphorylation of TAU protein leads to its aggregationand propagation, contributing to neuronal dysfunction andultimately neuronal death. The oral administration of relativelyhigh dose of the flavonoid epicatechin for 3 weeks in oldermutant mice was able to prevent the development of TAUpathology in this murine model (Hole et al.). While themolecular mechanisms of this protective effect remain to befurther investigated, it would be interesting to see whetherthis preventive effect translates into better cognitive outcomesas well.Epicatechin has also known beneficial effects on cognitivefunctions and has the potential to prevent neurodegenerativedisorders. Corral-Jara et al. explored a possible molecularmechanism underlying the neuroprotective actions ofthis flavanol, at the level of the vasculature composingthe anatomical and physiological barrier between theblood and the brain. To replicate the physiopathologicalconditions of neurodegenerative diseases, inflammatorystress was mimicked using TNF-a in the culture mediumof brain endothelial cells. After treatment of the cells with5-(4’-Hydroxyphenyl)-γ-valerolactone-3’-sulfate and 5-(4’-Hydroxyphenyl)-γ-valerolactone-3’-O-glucuronide, the twomajor products of gut microbiota catabolism of epicatechin,the authors investigated the multi-omics responses. Study ofgene expression, micro-RNAs, non-coding RNAs and proteinsrevealed that microbiome-derived metabolites of epicatechinmodulate the expression of genes and proteins regulatingcellular processes such as adhesion, cytoskeleton organization,cell permeability and therefore could be involved in themaintenance of BBB integrity. Despite these results needing tobe confirmed in vivo, this study explores the gut/brain axis ina new and original way: the action of metabolites from the gutmicrobiota on BBB function and unravels an unexplored untilrecently an original mechanism by which flavonoids could exerttheir well-known neuroprotective effects.Grewia asiatica, a popular native berry of Pakistanrepresents a very promising plant to treat and/or preventvarious pathologies linked to oxidative stress and inflammation.The authors of the study showed that the berry containsvarious (poly)phenols including phenolic compounds,anthocyanins and flavonoids. Following 28 days of Grewiaasiatica consumption in drinking water, the rats were subjectedto diverse behavioral tests well-recognized to detect, quantifyand analyze depression, anxiety, learning and memory.Interestingly, the rats treated with the highest doses ofGrewia asiatica displayed low anxiety levels, similar todiazepam-treated animals, low depressive behavior similar tofluoxetine-treated animals and better learning and memoryscores, counteracting the deleterious effect of scopolamineadministration. Biochemical analysis of rat brains revealed thatconsumption of Grewia asiatica resulted in higher oxidativestress resistance indicated by elevated levels of superoxidedismutase and glutathione peroxidase and a reduction ofmalondialdehyde production. This effect was further paralleledby a beneficial modulation of the cholinergic system as indicatedby reduced levels of acetylcholinesterase (Imran et al.).The methanolic extract of Otostegia Limbata, a Lamiaceaeplant, is commonly used as an active compound to potentiallytreat epilepsy. As many other (poly)phenol rich plants,O. Limbata demonstrated antioxidant (free-radical and NOscavenging and iron-chelating activities) andanti-inflammatoryproperties (reduced expression of P-NFkB and P-TNFa in thebrain) potentially responsible for the anti-convulsant effectobserved in mice model of epilepsy (Amin et al.).We previously highlighted the necessity to study all themetabolites of each food-derived (poly)phenol and their by-product from microbiota, within various biological models, tobetter characterize the molecular action of these compounds inphysiological conditions. And more specifically, when focusingFrontiers inNeuroscience 02 frontiersin.orgBalland et al. 10.3389/fnins.2022.947761on the brain, it’s important to be able to answer the followingquestions: 1/Whichmetabolite and at what dose does it cross theBBB 2/ Is the metabolite transformed during the uptake process3/ Can brain cells metabolize (poly)phenolic compounds?In conclusion, we need to investigate the specific molecularmechanisms for each (poly)phenol, their derivates and how theycould potentially be metabolized in endothelial cells and diversebrain cells (neurons, astrocyte, tanycytes, and microglial cells),and then what would be the action of the resulting metabolites?Importantly the BBB isn’t the only site of access to the brainfor circulating molecules, circumventricular organs (CVO),highly vascularized structures located around the third andfourth ventricles and characterized by the lack of a classic BBBarchitecture, deserved to be studied along with the tanycytes,the main cellular component of the modified barrier aroundthe CVOs (Langlet et al., 2013). These structures may also beinvolved in (poly)phenols transport and catabolism and couldrepresent an interesting target to access the brain.Author contributionsEB wrote the manuscript. EB, DV, and PL edited themanuscript. All authors contributed to the article and approvedthe submitted version.AcknowledgmentsThe authors would like to thanks all the scientistswho contributed to this Research Topic of articles and allthe reviewers who responded favorably to help improvingthe content. We also extend our acknowledgments to theFrontiers Editorial Board whom reliable help and support isgreatly appreciated.Conflict of interestThe authors declare that the research was conducted in theabsence of any commercial or financial relationships that couldbe construed as a potential conflict of interest.Publisher’s noteAll claims expressed in this article are solely those of theauthors and do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and thereviewers. Any product that may be evaluated in this article, orclaim that may be made by its manufacturer, is not guaranteedor endorsed by the publisher.ReferencesFigueira, I., Garcia, G., Pimpão, R. C., Terrasso, A. P., Costa, I., Almeida, A. F.,et al. (2017). Polyphenols journey through blood-brain barrier towards neuronalprotection. Sci. Rep. 7, 6. doi: 10.1038/s41598-017-11512-6Langlet, F., Mullier, A., Bouret, S. G., Prevot, V., and Dehouck, B.(2013). Tanycyte-like cells form a blood-cerebrospinal fluid barrier in thecircumventricular organs of the mouse brain. J. Comparat. Neurol. 521, 3389–3405.doi: 10.1002/cne.23355Lee, B. K., Hyun, S.W., and Jung, Y. S. (2020). Yuzu and hesperidinameliorate blood-brain barrier disruption during hypoxia via antioxidant activity.Antioxidants 9, 90843. doi: 10.3390/antiox9090843Ramassamy, C. (2006). Emerging role of polyphenolic compounds in thetreatment of neurodegenerative diseases: a review of their intracellulartargets. Eur. J. Pharmacol. 545, 51–64. doi: 10.1016/j.ejphar.2006.06.025Frontiers inNeuroscience 03 frontiersin.org

Editorial: Polyphenols' action on the brain

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Editorial: Polyphenols' action on the brain

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