Novel application of brain-targeting polyphenol compounds in sleep deprivation-induced cognitive dysfunction

Abstract

Sleep deprivation produces deficits in hippocampal synaptic plasticity and hippocampal-dependent memory storage. Recent evidence suggests that sleep deprivation disrupts memory consolidation through multiple mechanisms, including the down-regulation of the cAMP-response element-binding protein (CREB) and of mammalian target of rapamycin (mTOR) signaling. In this study, we tested the effects of a Bioactive Dietary Polyphenol Preparation (BDPP), comprised of grape seed polyphenol extract, Concord grape juice, and resveratrol, on the attenuation of sleep deprivation-induced cognitive impairment. We found that BDPP significantly improves sleep deprivation-induced contextual memory deficits, possibly through the activation of CREB and mTOR signaling pathways. We also identified brain-available polyphenol metabolites from BDPP, among which quercetin-3-O-glucuronide activates CREB signaling and malvidin-3-O-glucoside activates mTOR signaling. In combination, quercetin and malvidin-glucoside significantly attenuated sleep deprivation-induced cognitive impairment in -a mouse model of acute sleep deprivation. Our data suggests the feasibility of using select brain-targeting polyphenol compounds derived from BDPP as potential therapeutic agents in promoting resilience against sleep deprivation-induced cognitive dysfunction.

The Role of the Gut Microbiota in the Metabolism of Polyphenols as Characterized by Gnotobiotic Mice

“…Recent work from our group found that several polyphenol metabolites from grape seed extract (GSPE), concord grape juice (CGJ) and resveratrol (RSV), were able to protect against neuropathology and cognitive impairment in neurodegenerative disorders such as AD [35, 102, 103, 109–112] and related tau-mediated neurodegenerative disorders [113–116]. These studies led to the identification of 26 polyphenol metabolites from GSPE, CGJ, and RSV and each were found to accumulate in blood, and a subset in the brain, which had potential to modulate biological activitis in vivo [30, 31, 117–120] Moreover we found polyphenol metabolites that were present in the brain such as 3′-O-Me-epicatechin-5-glucuronide [32] and quercetin glucuronide [31]. 3-hydroxybenzoic acid and 3-(3′-hydroxyphenyl) propionic acid were primarily responsible for inhibiting the onset and progression of AD-type pathophysiology [18].…”

“…The compounds exerted their nuroprotective effects by interfering with the generation of neurotoxic AD-type amyloid-β peptides, which can interfere with neuroplasticity and memory consolidation. In addition to interfering with AD mechanisms, studies demonstrated that multiple biologically available microbiota-derived phenolic acids including 3,4-dihydroxypenylacetic acid, 3-(3′-hydroxyphenyl) propionic acid, 3,4-dihydroxyhydrocinnamic acid and homovanillic acid from a bioactive dietary polyphenol preparation (BDPP), composed of GSPR, CGJ, and RSV, were able to modulate biological mechanisms associated with inflammation and synaptic plasticity [18, 30, 121]. These processes are known to influence psychological and cognitive resilience in, for example, animal models of social defeat and sleep deprivation.…”

“…Ongoing studies support the hypothesis that the gut microbiota’s influence on brain function is mediated through metabolic processing of certain dietary compounds such as polyphenols [15–18] and synthetic drugs [19–22] by the resident bacteria. Studies from our group and others suggest that the polyphenol metabolites produced by the microbiota modulate immune-inflammatory cascades [23–29], synaptic maladaptation [30–32], mood disorders [33, 34] as well as age-related neurodegenerative disorders [18, 31, 32, 35]. Given this ability of the microbiota to generate unique bioactive compounds, efforts have been made to manipulate the gut microbiota to improve the delivery and efficacy of orally consumed compounds, including phyto-drugs [36–38].…”

Dietary polyphenols enhance optogenetic recall of fear memory in hippocampal dentate gyrus granule neuron subpopulations

“…The modulation of CaMKII-CREB signaling by specific bioavailable phenolic metabolites suggests that upregulation of IEGs, including c-Fos, may be among the mechanisms through which dietary polyphenols promote memory function 7,28 . Based in part on this, we utilized an inducible c-fos-tTA/TRE-ChR2 optogenetics model to identify subpopulations of DG granule neurons that are influenced by polyphenol treatment and recapitulate learned behavior in the same animal 19,20 .…”

A Comprehensive Database and Analysis Framework To Incorporate Multiscale Data Types and Enable Integrated Analysis of Bioactive Polyphenols

“…We found BDPP to be highly effective in protecting against the onset and/or progression of multiple, diverse neurological, psychological, and metabolic disorders in animal models. 25–27 BDPP is composed of a select Concord grape juice (CGJ), a select grape seed polyphenol extract (GSPE), and trans -resveratrol (RSV), 25–27 which provides a complex mixture of diverse naturally occurring polyphenols. 17,18,25 We have gathered extensive published 25–27 and unpublished information on the effects of oral BDPP administration in modulating multiple pathologic behavioral phenotypes and/or cellular/molecular pathways across diverse animal models of cognitive, psychological, and metabolic disorders.…”