Dietary polyphenols promote resilience against sleep deprivation-induced cognitive impairment by activating protein translation.

Previous evidence has suggested that dietary supplementation with a bioactive dietary polyphenol preparation (BDPP) rescues impairment of hippocampus-dependent memory in a mouse model of sleep deprivation (SD). In the current study, we extend our previous evidence and demonstrate that a mechanism by which dietary BDPP protects against SD-mediated cognitive impairment is via mechanisms that involve phosphorylation of the mammalian target of rapamycin complex 1 and its direct downstream targets, including the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and the ribosomal protein S6 kinase ß-1 (p70S6K). In additional mechanistic studies in vitro, we identified the brain bioavailable phenolic metabolites derived from the metabolism of dietary BDPP that are responsible for the attenuation of SD-mediated memory impairments. On the basis of high-throughput bioavailability studies of brain bioavailable metabolites after dietary BDPP treatment, we found that select polyphenol metabolites [ e.g., cyanidin-3'- O-glucoside and 3-(3'-hydroxyphenyl) propionic acid] were able to rescue mTOR and p70S6K phosphorylation in primary cortico-hippocampal neuronal cultures, as well as rescue 4E-BP1 phosphorylation in response to treatment with 4EGI-1, a specific inhibitor of eIF4E-eIF4G interaction. Our findings reveal a previously unknown role for dietary polyphenols in the rescue of SD-mediated memory impairments via mechanisms involving the promotion of protein translation.-Frolinger, T., Smith, C., Cobo, C. F., Sims, S., Brathwaite, J., de Boer, S., Huang, J., Pasinetti, G. M. Dietary polyphenols promote resilience against sleep deprivation-induced cognitive impairment by activating protein translation.

In Silico Modeling of Novel Drug Ligands for Treatment of Concussion Associated Tauopathy.

The objective of this study was to develop an in silico screening model for characterization of potential novel ligands from commercial drug libraries able to functionally activate certain olfactory receptors (ORs), which are members of the class A rhodopsin-like family of G protein couple receptors (GPCRs), in the brain of murine models of concussion. We previously found that concussions may significantly influence expression of certain ORs, for example, OR4M1 in subjects with a history of concussion/traumatic brain injury (TBI). In this study, we built a 3-D OR4M1 model and used it in in silico screening of potential novel ligands from commercial drug libraries. We report that in vitro activation of OR4M1 with the commercially available ZINC library compound 10915775 led to a significant attenuation of abnormal tau phosphorylation in embryonic cortico-hippocampal neuronal cultures derived from NSE-OR4M1 transgenic mice, possibly through modulation of the JNK signaling pathway. The attenuation of abnormal tau phosphorylation was rather selective since ZINC10915775 significantly decreased tau phosphorylation on tau Ser202/T205 (AT8 epitope) and tau Thr212/Ser214 (AT100 epitope), but not on tau Ser396/404 (PHF-1 epitope). Moreover, no response of ZINC10915775 was found in control hippocampal neuronal cultures derived from wild type littermates. Our in silico model provides novel means to pharmacologically modulate select ubiquitously expressed ORs in the brain through high affinity ligand activation to prevent and eventually to treat concussion induced down regulation of ORs and subsequent cascade of tau pathology. J. Cell. Biochem. 117: 2241-2248, 2016. © 2016 Wiley Periodicals, Inc.

Delirium: A Marker of Vulnerability in Older People.

Delirium is an acute neuropsychiatric syndrome and one of the most common presenting symptoms of acute medical illnesses in older people. Delirium can be triggered by a single cause, but in most cases, it is multifactorial as it depends on the interaction between predisposing and precipitating factors. Delirium is highly prevalent in older patients across various settings of care and correlates with an increased risk of adverse clinical outcomes. Several pathophysiological mechanisms may contribute to its onset, including neurotransmitter imbalance, neuroinflammation, altered brain metabolism, and impaired neuronal network connectivity. Several screening and diagnostic tools for delirium exist, but they are unfortunately underutilized. Additionally, the diagnosis of delirium superimposed on dementia poses a formidable challenge - especially if dementia is severe. Non-pharmacological approaches for the prevention and multidomain interventions for the treatment of delirium are recommended, given that there is currently no robust evidence of drugs that can prevent or resolve delirium. This article aims to review the current understanding about delirium in older people. To achieve this goal, we will describe the epidemiology and outcomes of the syndrome, the pathophysiological mechanisms that are supposed to be involved, the most commonly used tools for screening and diagnosis, and prevention strategies and treatments recommended. This review is intended as a brief guide for clinicians in hospital wards to improve their knowledge and practice. At the end of the article, we propose an approach to improve the quality of care provided to older patients throughout a systematic detection of delirium.

Prophylactic effect of flavanol rich preparation metabolites in promoting resilience to a mouse model of social stress.

Major depressive disorder (MDD) is a leading cause of disability, and there is an urgent need for new therapeutics. Stress-mediated induction of pro-inflammation in the periphery contributes to depression-like behaviors both in humans and in experimental models. Inflammatory cytokine interleukin-6 (IL-6) has emerged as a potential therapeutic target. Our studies demonstrated that metabolism of flavanol rich cocoa preparation (FRP) led to the accumulation of select phenolic acids that may contribute to its anti-inflammatory activity. Using a repeated social defeat stress (RSDS) model of depression, we showed that oral administration of FRP attenuates susceptibility to RSDS-mediated depression, supporting the further development of FRP as a novel therapeutic for the treatment of stress disorders and anxiety in humans.

Heterogeneity in gut microbiota drive polyphenol metabolism that influences α-synuclein misfolding and toxicity.

The intestinal microbiota actively converts dietary flavanols into phenolic acids, some of which are bioavailable in vivo and may promote resilience to select neurological disorders by interfering with key pathologic mechanisms. Since every person harbors a unique set of gut bacteria, we investigated the influence of the gut microbiota's interpersonal heterogeneity on the production and bioavailability of flavonoid metabolites that may interfere with the misfolding of alpha (α)-synuclein, a process that plays a central role in Parkinson's disease and other α-synucleinopathies. We generated two experimental groups of humanized gnotobiotic mice with compositionally diverse gut bacteria and orally treated the mice with a flavanol-rich preparation (FRP). The two gnotobiotic mouse groups exhibited distinct differences in the generation and bioavailability of FRP-derived microbial phenolic acid metabolites that have bioactivity towards interfering with α-synuclein misfolding or inflammation. We also demonstrated that these bioactive phenolic acids are effective in modulating the development and progression of motor dysfunction in a Drosophila model of α-synucleinopathy. Lastly, through in vitro bacterial fermentation studies, we identified select bacteria that are capable of supporting the generation of these bioavailable and bioactive phenolic acids. Outcomes from our studies provide a better understanding of how interpersonal heterogeneity in the gut microbiota differentially modulates the efficacy of dietary flavanols to protect against select pathologic mechanisms. Collectively, our findings provide the basis for future developments of probiotic, prebiotic, or synbiotic approaches for modulating the onset and/or progression of α-synucleinopathies and other neurological disorders involving protein misfolding and/or inflammation.

Suppression of Presymptomatic Oxidative Stress and Inflammation in Neurodegeneration by Grape-Derived Polyphenols.

Neurodegenerative disorders constitute a group of multifaceted conditions characterized by the progressive loss of neurons and synaptic connections consequent to a combination of specific genetic predispositions and stochastic stressors. The neuropathologies observed in both Alzheimer's and Parkinson's disease are in part attributed to compounding intrinsic and extrinsic environmental stressors, which we propose may be limited by the administration of specific grape derived phytochemicals and their metabolized derivatives, specifically polyphenols isolated from grape botanicals. Current therapies for neurodegenerative disorders are limited as they solely target the final disease pathologies including behavioral changes, cognitive deficits, proteinopathies and neuronal loss; however, this strategy is not a sustainable approach toward managing disease onset or progression. This review discusses the application of grape derived polyphenols as an adjunctive treatment paradigm for the prevention of neuropathologies associated with Alzheimer's disease, Parkinson's disease and Chronic Traumatic Encephalopathy by simultaneously ameliorating two stochastic stressors that facilitate their disease pathologies: inflammation and oxidative stress. The biophysical attributes of grape-derived polyphenols buffer against redox potential dependent peripheral and neuroinflammation and down regulate the activation of inflammasomes in microglia and astrocytes, which could provide a novel mechanism through which grape-derived polyphenols simultaneously suppress risk factors across pathologically distinct neurodegenerative conditions. This approach therefore offers a prophylactic mode, not feasible through current pharmacological agents, to target activity dependent risk factors for neurodegenerative disorders that manifest over an individual's lifetime.

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

Grape-derived polyphenols have been investigated for their role in promoting memory in model systems of stress, but little is known about select subpopulations of neurons that are influenced by polyphenols to improve memory performance. Granule neurons in the hippocampal dentate gyrus are vulnerable to stressors that impair contextual memory function and can be influenced by dietary polyphenols. We utilized a c-fos-tTA/TRE-ChR2 optogenetics model in which neurons activated during fear learning are labeled with ChR2-mCherry and can be optically reactivated in a different context to recapitulate the behavioral output of a related memory. Treatment with dietary polyphenols increased fear memory recall and ChR2-mCherry expression in dentate gyrus neurons, suggesting that dietary polyphenols promote recruitment of neurons to a fear memory engram. We show that dietary polyphenols promote memory function and offer a general method to map cellular subpopulations influenced by dietary polyphenols, in part through the mechanism of c-Fos expression enhancement.

Association Between Preoperative Malnutrition and Postoperative Delirium After Hip Fracture Surgery in Older Adults.

OBJECTIVES: To determine whether poor nutritional status can predict postoperative delirium in elderly adults undergoing hip fracture surgery. DESIGN: Prospective observational cohort study. SETTING: Italian orthogeriatric unit. PARTICIPANTS: Individuals aged 70 and older (mean age 84.0 ± 6.6, 74.5% female) consecutively admitted for surgical repair of a proximal femur fracture between September 2012 and April 2016 (N = 415). MEASUREMENTS: Participants underwent a comprehensive geriatric assessment including nutritional status, which was evaluated using the Mini Nutritional Assessment Short Form (MNA-SF). The MNA-SF-based three-class stratification was tested using multivariable logistic regression to assess its role in predicting postoperative delirium (outcome). RESULTS: Seventy-eight malnourished individuals (MNA-SF score 0-7), 185 at risk of malnutrition (MNA-SF score 8-11), and 152 who were well nourished (MNA-SF score 12-14) were compared. On average, individuals with poor nutritional status were more disabled and more cognitively impaired than those who were well nourished and those at risk of malnutrition. Moreover, those who were malnourished were more likely to have postoperative delirium. Multivariate regression analysis adjusted for age, sex, comorbidity, functional impairment, preoperative cognitive status, and American Society of Anesthesiologists score showed that those who were at risk of malnutrition (odds ratio (OR) = 2.42, 95% confidence interval (CI) = 1.29-4.53) and those who were overtly malnourished (OR = 2.98, 95% CI = 1.43-6.19) were more likely to develop postoperative delirium. CONCLUSION: This is the first study in a Western population showing that risk of malnutrition and overt malnutrition, as assessed using the MNA-SF, are independent predictors of postoperative delirium. Accordingly, nutritional status should be assessed in individuals with hip fracture before surgery to determine risk of developing delirium.