title: Brain-targeted proanthocyanidin metabolites for Alzheimer's disease treatment.
abstract: While polyphenolic compounds have many health benefits, the potential development of polyphenols for the prevention/treatment of neurological disorders is largely hindered by their complexity as well as by limited knowledge regarding their bioavailability, metabolism, and bioactivity, especially in the brain. We recently demonstrated that dietary supplementation with a specific grape-derived polyphenolic preparation (GP) significantly improves cognitive function in a mouse model of Alzheimer's disease (AD). GP is comprised of the proanthocyanidin (PAC) catechin and epicatechin in monomeric (Mo), oligomeric, and polymeric forms. In this study, we report that following oral administration of the independent GP forms, only Mo is able to improve cognitive function and only Mo metabolites can selectively reach and accumulate in the brain at a concentration of ∼400 nM. Most importantly, we report for the first time that a biosynthetic epicatechin metabolite, 3'-O-methyl-epicatechin-5-O-β-glucuronide (3'-O-Me-EC-Gluc), one of the PAC metabolites identified in the brain following Mo treatment, promotes basal synaptic transmission and long-term potentiation at physiologically relevant concentrations in hippocampus slices through mechanisms associated with cAMP response element binding protein (CREB) signaling. Our studies suggest that select brain-targeted PAC metabolites benefit cognition by improving synaptic plasticity in the brain, and provide impetus to develop 3'-O-Me-EC-Gluc and other brain-targeted PAC metabolites to promote learning and memory in AD and other forms of dementia.
authors.affiliation: Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Mario G
authors.initials: MG
authors.lastname: Ferruzzi
authors.forename: Lap
authors.initials: L
authors.lastname: Ho
authors.forename: Jack
authors.initials: J
authors.lastname: Blount
authors.forename: Elsa M
authors.initials: EM
authors.lastname: Janle
authors.forename: Bing
authors.initials: B
authors.lastname: Gong
authors.forename: Yong
authors.initials: Y
authors.lastname: Pan
authors.forename: G A Nagana
authors.initials: GA
authors.lastname: Gowda
authors.forename: Daniel
authors.initials: D
authors.lastname: Raftery
authors.forename: Isabel
authors.initials: I
authors.lastname: Arrieta-Cruz
authors.forename: Vaishali
authors.initials: V
authors.lastname: Sharma
authors.forename: Bruce
authors.initials: B
authors.lastname: Cooper
authors.forename: Jessica
authors.initials: J
authors.lastname: Lobo
authors.forename: James E
authors.initials: JE
authors.lastname: Simon
authors.forename: Chungfen
authors.initials: C
authors.lastname: Zhang
authors.forename: Alice
authors.initials: A
authors.lastname: Cheng
authors.forename: Xianjuan
authors.initials: X
authors.lastname: Qian
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Ono
authors.forename: David B
authors.initials: DB
authors.lastname: Teplow
authors.forename: Constantine
authors.initials: C
authors.lastname: Pavlides
authors.forename: Richard A
authors.initials: RA
authors.lastname: Dixon
authors.forename: Giulio M
authors.initials: GM
authors.lastname: Pasinetti
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000627:therapeutic use*; D001682:Biological Availability; D001711:Biotransformation; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D004032:Diet; D016503:Drug Delivery Systems; D005260:Female; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D059808:Polyphenols / Q000737:chemistry / Q000494:pharmacology; D044945:Proanthocyanidins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects; D027843:Vitis / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D017362:Cyclic AMP Response Element-Binding Protein; D059808:Polyphenols; D044945:Proanthocyanidins