title: Pomegranate's Neuroprotective Effects against Alzheimer's Disease Are Mediated by Urolithins, Its Ellagitannin-Gut Microbial Derived Metabolites.
abstract: Pomegranate shows neuroprotective effects against Alzheimer's disease (AD) in several reported animal studies. However, whether its constituent ellagitannins and/or their physiologically relevant gut microbiota-derived metabolites, namely, urolithins (6H-dibenzo[b,d]pyran-6-one derivatives), are the responsible bioactive constituents is unknown. Therefore, from a pomegranate extract (PE), previously reported by our group to have anti-AD effects in vivo, 21 constituents, which were primarily ellagitannins, were isolated and identified (by HPLC, NMR, and HRESIMS). In silico computational studies, used to predict blood-brain barrier permeability, revealed that none of the PE constituents, but the urolithins, fulfilled criteria required for penetration. Urolithins prevented β-amyloid fibrillation in vitro and methyl-urolithin B (3-methoxy-6H-dibenzo[b,d]pyran-6-one), but not PE or its predominant ellagitannins, had a protective effect in Caenorhabditis elegans post induction of amyloid β(1-42) induced neurotoxicity and paralysis. Therefore, urolithins are the possible brain absorbable compounds which contribute to pomegranate's anti-AD effects warranting further in vivo studies on these compounds.
authors.affiliation: Bioactive Botanical Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island , Kingston, Rhode Island 02881, United States.
authors.forename: Tao
authors.initials: T
authors.lastname: Yuan
authors.affiliation: Bioactive Botanical Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island , Kingston, Rhode Island 02881, United States.
authors.forename: Hang
authors.initials: H
authors.lastname: Ma
authors.affiliation: Bioactive Botanical Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island , Kingston, Rhode Island 02881, United States.
authors.forename: Weixi
authors.initials: W
authors.lastname: Liu
authors.affiliation: Bioactive Botanical Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island , Kingston, Rhode Island 02881, United States.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Niesen
authors.affiliation: Bioactive Botanical Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island , Kingston, Rhode Island 02881, United States.
authors.forename: Nishan
authors.initials: N
authors.lastname: Shah
authors.affiliation: Nutrition Biomedicine and Biotechnology, Texas State University , San Marcos, Texas 78666, United States.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Crews
authors.affiliation: Bioactive Botanical Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island , Kingston, Rhode Island 02881, United States.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Rose
authors.affiliation: Nutrition Biomedicine and Biotechnology, Texas State University , San Marcos, Texas 78666, United States.
authors.forename: Dhiraj A
authors.initials: DA
authors.lastname: Vattem
authors.affiliation: Bioactive Botanical Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island , Kingston, Rhode Island 02881, United States.
authors.forename: Navindra P
authors.initials: NP
authors.lastname: Seeram
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D001703:Biophysics; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D017173:Caenorhabditis elegans; D002853:Chromatography, Liquid; D003198:Computer Simulation; D003374:Coumarins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D047348:Hydrolyzable Tannins / Q000378:metabolism*; D029561:Lythraceae / Q000737:chemistry*; D013058:Mass Spectrometry; D008954:Models, Biological; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D003374:Coumarins; D047348:Hydrolyzable Tannins; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C013515:ellagitannin; C000595064:urolithin B
keywords: Alzheimer’s disease; Pomegranate; blood-brain barrier; ellagitannins; microbial metabolites; urolithins