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

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.