Effects of a polyphenol-rich grape and blueberry extract (Memophenol™) on cognitive function in older adults with mild cognitive impairment: A randomized, double-blind, placebo-controlled study.

Background: Polyphenols are naturally occurring organic compounds found in plants. Research suggests that their intake reduces the risk of cognitive decline and related dementias. Grapes and blueberries are polyphenol-rich foods that have attracted attention for their potential cognitive-enhancing effects. Purpose: Examine the effects of supplementation with a standardized and patented polyphenol-rich grape and blueberry extract (Memophenol™) on cognitive function in older adults with mild cognitive impairment. Study design: Two-arm, 6 month, parallel-group, randomized, double-blind, placebo-controlled trial. Methods: One hundred and forty-three volunteers aged 60 to 80 years with mild cognitive impairment were supplemented with either 150 mg of Memophenol™, twice daily or a placebo. Outcome measures included computer-based cognitive tasks, the Behavior Rating Inventory of Executive Function (BRIEF-A), the Cognitive Failures Questionnaire, and the CASP-19. Results: Compared to the placebo, Memophenol™ supplementation was associated with greater improvements in the speed of information processing (p = 0.020), visuospatial learning (p = 0.012), and the BRIEF-A global score (p = 0.046). However, there were no other statistically significant between-group differences in the performance of other assessed cognitive tests or self-report questionnaires. Memophenol™ supplementation was well-tolerated with no reports of significant adverse reactions. Conclusion: The promising results from this trial suggest that 6-months of supplementation with Memophenol™ may improve aspects of cognitive function in adults with mild cognitive impairment. Further research will be important to expand on the current findings and identify the potential mechanisms of action associated with the intake of this polyphenol-rich extract.

Dietary Marine Hydrolysate Improves Memory Performance and Social Behavior through Gut Microbiota Remodeling during Aging.

Aging is characterized by a decline in social behavior and cognitive functions leading to a decrease in life quality. In a previous study, we show that a fish hydrolysate supplementation prevents age-related decline in spatial short-term memory and long-term memory and anxiety-like behavior and improves the stress response in aged mice. The aim of this study was to determine the effects of a fish hydrolysate enriched with EPA/DHA or not on the cognitive ability and social interaction during aging and the biological mechanisms involved. We showed for the first time that a fish hydrolysate enriched with EPA/DHA or not improved memory performance and preference for social novelty that were diminished by aging. These changes were associated with the modulation of the gut microbiota, normalization of corticosterone, and modulation of the expression of genes involved in the mitochondrial respiratory chain, circadian clock, neuroprotection, and antioxidant activity. Thus, these changes may contribute to the observed improvements in social behavior and memory and reinforced the innovative character of fish hydrolysate in the prevention of age-related impairments.

Neuronal morphology and synaptic plasticity in the hippocampus of vitamin A deficient rats.

Vitamin A (retinol) and related retinoids are micronutrients provided by food. Retinol derivatives are growth factors important for development, cell differentiation and tissue homeostasis, especially in the brain.Objective: The hippocampus is a pivotal brain structure for learning and memory and hippocampal-dependent memory is highly sensitive to retinoids action. However, the underlying mechanisms are still unclear. In this study, we characterized the impact of vitamin A deficiency on memory and neuronal plasticity, focusing on the CA1 region of the hippocampus in rats.Methods: Weaned male Wistar rats were fed a control (5 UI/g) or deficient vitamin A diet (0 UI/g) for 10 weeks. The effect of vitamin A supplementation (20 UI/g) for 3 weeks was also tested. Memory performances were assessed in the Y-maze (n = 24-30/group), retinoic acid levels were measured (LC-MS/MS) in the serum and in the hippocampus (n = 5/group), CA1 neuronal architecture was analyzed with Golgi staining (n = 17-20 neurons/group) and electrophysiological patch-clamp recordings were performed on hippocampal brain slices (n = 6-11/group).Results: Vitamin A deficiency from weaning significantly lowered hippocampal levels of retinoic acid, reduced dendritic length and branching of CA1 pyramidal neurons and decreased spontaneous glutamatergic synaptic events and synaptic plasticity. When replenishment with moderate dose of dietary vitamin A for 3 weeks was done, most of the synaptic and morphological alterations were absent.Conclusion: This study provides new mechanistic insight to understand the critical role of retinoic acid in hippocampal function.

Dietary Fish Hydrolysate Improves Memory Performance Through Microglial Signature Remodeling During Aging.

Brain aging is characterized by a chronic low-grade inflammation, which significantly impairs cognitive function. Microglial cells, the immunocompetent cells of the brain, present a different phenotype, switching from a homeostatic signature (M0) to a more reactive phenotype called "MGnD" (microglial neurodegenerative phenotype), leading to a high production of pro-inflammatory cytokines. Furthermore, microglial cells can be activated by age-induced gut dysbiosis through the vagus nerve or the modulation of the peripheral immune system. Nutrients, in particular n-3 long chain polyunsaturated fatty acids (LC-PUFAs) and low molecular weight peptides, display powerful immunomodulatory properties, and can thus prevent age-related cognitive decline. The objective of this study was to investigate the effects of n-3 LC-PUFAs and low molecular weight peptides contained in a marine by-product-derived hydrolysate on microglial phenotypes and intestinal permeability and their consequences on cognition in mice. We demonstrated that the hydrolysate supplementation for 8 weeks prevented short- and long-term memory decline during aging. These observations were linked to the modulation of microglial signature. Indeed, the hydrolysate supplementation promoted homeostatic microglial phenotype by increasing TGF-ß1 expression and stimulated phagocytosis by increasing Clec7a expression. Moreover, the hydrolysate supplementation promoted anti-inflammatory intestinal pathway and tended to prevent intestinal permeability alteration occurring during aging. Therefore, the fish hydrolysate appears as an interesting candidate to prevent cognitive decline during aging.

Role of Retinoid X Receptors (RXRs) and dietary vitamin A in Alzheimer's disease: Evidence from clinicopathological and preclinical studies.

BACKGROUND: Vitamin A (VitA), via its active metabolite retinoic acid (RA), is critical for the maintenance of memory function with advancing age. Although its role in Alzheimer's disease (AD) is not well understood, data suggest that impaired brain VitA signaling is associated with the accumulation of ß-amyloid peptides (Aß), and could thus contribute to the onset of AD. METHODS: We evaluated the protective action of a six-month-long dietary VitA-supplementation (20 IU/g), starting at 8 months of age, on the memory and the neuropathology of the 3xTg-AD mouse model of AD (n = 11-14/group; including 4-6 females and 7-8 males). We also measured protein levels of Retinoic Acid Receptor ß (RARß) and Retinoid X Receptor γ (RXRγ) in homogenates from the inferior parietal cortex of 60 participants of the Religious Orders study (ROS) divided in three groups: no cognitive impairment (NCI) (n = 20), mild cognitive impairment (MCI) (n = 20) and AD (n = 20). RESULTS: The VitA-enriched diet preserved spatial memory of 3xTg-AD mice in the Y maze. VitA-supplementation affected hippocampal RXR expression in an opposite way according to sex by tending to increase in males and decrease in females their mRNA expression. VitA-enriched diet also reduced the amount of hippocampal Aß40 and Aß42, as well as the phosphorylation of tau protein at sites Ser396/Ser404 (PHF-1) in males. VitA-supplementation had no effect on tau phosphorylation in females but worsened their hippocampal Aß load. However, the expression of Rxr-ß in the hippocampus was negatively correlated with the amount of both soluble and insoluble Aß in both males and females. Western immunoblotting in the human cortical samples of the ROS study did not reveal differences in RARß levels. However, it evidenced a switch from a 60-kDa-RXRγ to a 55-kDa-RXRγ in AD, correlating with ante mortem cognitive decline and the accumulation of neuritic plaques in the brain cortex. CONCLUSION: Our data suggest that (i) an altered expression of RXRs receptors is a contributor to ß-amyloid pathology in both humans and 3xTg-AD mice, (ii) a chronic exposure of 3xTg-AD mice to a VitA-enriched diet may be protective in males, but not in females.

Fish Hydrolysate Supplementation Containing n-3 Long Chain Polyunsaturated Fatty Acids and Peptides Prevents LPS-Induced Neuroinflammation.

Neuroinflammation constitutes a normal part of the brain immune response orchestrated by microglial cells. However, a sustained and uncontrolled production of proinflammatory factors together with microglial activation contribute to the onset of a chronic low-grade inflammation, leading to neuronal damage and cognitive as well as behavioral impairments. Hence, limiting brain inflammatory response and improving the resolution of inflammation could be particularly of interest to prevent these alterations. Dietary n-3 long chain polyunsaturated fatty acids (LC-PUFAs) and low molecular weight peptides are good candidates because of their immunomodulatory and proresolutive properties. These compounds are present in a fish hydrolysate derived from marine-derived byproducts. In this study, we compared the effect of an 18-day supplementation with this fish hydrolysate to a supplementation with docosahexaenoic acid (DHA) on lipopolysaccharide (LPS)-induced inflammation in mice. In response to peripherally injected LPS, the fish hydrolysate supplementation decreased the hippocampal mRNA expression of the proinflammatory cytokines IL-6 (p < 0.001), IL-1ß (p = 0.0008) and TNF-α (p < 0.0001), whereas the DHA supplementation reduced only the expression of IL-6 (p = 0.004). This decline in proinflammatory cytokine expressions was associated with an increase in the protein expression of IκB (p = 0.014 and p = 0.0054 as compared to the DHA supplementation and control groups, respectively) and to a modulation of microglial activation markers in the hippocampus. The beneficial effects of the fish hydrolysate could be due in part to the switch of the hippocampal oxylipin profile towards a more anti-inflammatory profile as compared to the DHA supplementation. Thus, the valorization of fish byproducts seems very attractive to prevent and counteract neuroinflammation.

Dietary vitamin A supplementation prevents early obesogenic diet-induced microbiota, neuronal and cognitive alterations.

BACKGROUND: Early consumption of obesogenic diets, rich in saturated fat and added sugar, is associated with a plethora of biological dysfunctions, at both peripheral and brain levels. Obesity is also linked to decreased vitamin A bioavailability, an essential molecule for brain plasticity and memory function. METHODS: Here we investigated in mice whether dietary vitamin A supplementation (VAS) could prevent some of the metabolic, microbiota, neuronal and cognitive alterations induced by obesogenic, high-fat and high-sugar diet (HFSD) exposure from weaning to adulthood, i.e. covering periadolescent period. RESULTS: As expected, VAS was effective in enhancing peripheral vitamin A levels as well as hippocampal retinoic acid levels, the active metabolite of vitamin A, regardless of the diet. VAS attenuated HFSD-induced excessive weight gain, without affecting metabolic changes, and prevented alterations of gut microbiota α-diversity. In HFSD-fed mice, VAS prevented recognition memory deficits but had no effect on aversive memory enhancement. Interestingly, VAS alleviated both HFSD-induced higher neuronal activation and lower glucocorticoid receptor phosphorylation in the hippocampus after training. CONCLUSION: Dietary VAS was protective against the deleterious effects of early obesogenic diet consumption on hippocampal function, possibly through modulation of the gut-brain axis.

Chronic Supplementation with a Mix of Salvia officinalis and Salvia lavandulaefolia Improves Morris Water Maze Learning in Normal Adult C57Bl/6J Mice.

Background: Two different species of sage, Salvia officinalis and Salvia lavandulaefolia, have demonstrated activities in cognitive function during preclinical and clinical studies related to impaired health situations or single administration. Different memory processes have been described to be significantly and positively impacted. Objective: Our objective is to explore the potential of these Salvia, and their additional activities, in healthy situations, and during prolonged administration, on memory and subsequent mechanisms of action related to putative effects. Design: This mouse study has implicated four investigational arms dedicated to control, Salvia officinalis aqueous extract, Salvia lavandulaefolia-encapsulated essential oil and a mix thereof (Cognivia™) for 2 weeks of administration. Cognitive functions have been assessed throughout Y-maze and Morris water maze models. The impact of supplementation on lipid peroxidation, oxidative stress, neurogenesis, neuronal activity, neurotrophins, neurotrophin receptors, CaM kinase II and glucocorticoid receptors has been assessed via post-interventional tissue collection. Results: All Salvia groups had a significant effect on Y-maze markers on day 1 of administration. Only the mix of two Salvia species demonstrated significant improvements in Morris water maze markers at the end of administration. Considering all biological and histological markers, we did not observe any significant effect of S. officinalis, S. lavandulaefolia and a mix of Salvia supplementation on lipid peroxidation, oxidative stress and neuronal plasticity (neurogenesis, neuronal activity, neurotrophins). Interestingly, CaM kinase II protein expression is significantly increased in animals supplemented with Salvia. Conclusion: The activities of Salvia alone after one intake have been confirmed; however, a particular combination of different types of Salvia have been shown to improve memory and present specific synergistic effects after chronic administration in healthy mice.

n-3 Polyunsaturated Fatty Acids and Their Derivates Reduce Neuroinflammation during Aging.

: Aging is associated to cognitive decline, which can lead to loss of life quality, personal suffering, and ultimately neurodegenerative diseases. Neuroinflammation is one of the mechanisms explaining the loss of cognitive functions. Indeed, aging is associated to the activation of inflammatory signaling pathways, which can be targeted by specific nutrients with anti-inflammatory effects. Dietary n-3 polyunsaturated fatty acids (PUFAs) are particularly attractive as they are present in the brain, possess immunomodulatory properties, and are precursors of lipid derivates named specialized pro-resolving mediators (SPM). SPMs are crucially involved in the resolution of inflammation that is modified during aging, resulting in chronic inflammation. In this review, we first examine the effect of aging on neuroinflammation and then evaluate the potential beneficial effect of n-3 PUFA as precursors of bioactive derivates, particularly during aging, on the resolution of inflammation. Lastly, we highlight evidence supporting a role of n-3 PUFA during aging.

Normalization of hippocampal retinoic acid level corrects age-related memory deficits in rats.

Dietary micronutrients constitute a major environmental factor influencing aging processes. Vitamin A (vit. A) is the precursor of retinoic acid, a bioactive molecule that controls the expression of several genes involved in brain function. Evidence suggests a reduction of vit. A bioavailability with aging, but its impact on neuronal network is poorly understood. We investigated the mechanisms linking memory impairments with specific alterations of retinoic acid metabolism in the hippocampus. We compared young (10 weeks) and aged (16 months) rats, supplemented or not with dietary vit. A (20 IU retinol/g) for 4 weeks. Our study reveals that aging induced dysregulation of gene expression involved in vit. A and retinoic acid metabolism in the liver. Furthermore, vit. A supplementation restored the integrity of the hippocampal neuronal morphology altered by aging. Importantly, we found a high correlation between hippocampal levels of retinoic acid and memory performance. The present work establishes the link between collapse of retinoid metabolism and age-related cognitive decline, highlighting the role of vit. A in maintaining memory through aging.

Reduction of acute mild stress corticosterone response and changes in stress-responsive gene expression in male Balb/c mice after repeated administration of a Rhodiola rosea L. root extract.

Rhodiola rosea L. (R. rosea) is an adaptogenic plant increasing body resistance to stress. Its efficacy has been evidenced mainly in chronic stress models, data concerning its effect in acute stress and underlying mechanisms being scarce. The objective was to investigate the effect of repeated doses of a R. rosea hydroethanolic root extract (HRE) on hypothalamic pituitary adrenal response in a murine model of acute mild stress and also the mechanisms involved. Stress response was measured in Balb/c mice having received by gavage HRE (5 g/kg) or vehicle daily for 2 weeks before being submitted to an acute mild stress protocol (open-field test then elevated plus maze). Corticosterone was measured in plasma from mandibular vein blood drawn before and 30, 60, and 90 min after initiation of the stress protocol. Mice were sacrificed at 90 min, and the hippocampus, prefrontal cortex, and amygdala were excised for high-frequency RT-PCR gene expression analysis. At 30 min after acute mild stress induction, corticosterone level in mice having received the HRE was lower than in control mice and comparable to that in nonstressed mice in the HRE group. HRE administration induced brain structure-dependent changes in expression of several stress-responsive genes implicated in neuronal structure, HPA axis activation, and circadian rhythm. In the acute mild stress model used, R. rosea HRE decreased corticosterone level and increased expression of stress-responsive genes, especially in the hippocampus and prefrontal cortex. These findings suggest that R. rosea HRE could be of value for modulating reactivity to acute mild stress.

Vitamin A deficiency impairs contextual fear memory in rats: Abnormalities in the glucocorticoid pathway.

Vitamin A and its active metabolite, retinoic acid (RA), play a key role in the maintenance of cognitive functions in the adult brain. Depletion of RA using the vitamin A deficiency (VAD) model in Wistar rats leads to spatial memory deficits in relation to elevated intrahippocampal basal corticosterone (CORT) levels and increased hippocampal 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity. All of these effects are normalised by vitamin A supplementation. However, it is unknown whether vitamin A status also modulates contextual fear conditioning (CFC) in a glucocorticoid-associated fear memory task dependent on the functional integrity of the hippocampus. In the present study, we investigated the impact of VAD and vitamin A supplementation in adult male rats on fear memory processing, plasma CORT levels, hippocampal retinoid receptors and 11ß-HSD1 expression following a novelty-induced stress. We also examined whether vitamin A supplementation or a single injection of UE2316, a selective 11ß-HSD1 inhibitor, known to modulate local glucocorticoid levels, had any beneficial effects on contextual fear memory and biochemical parameters in VAD rats. We provide evidence that VAD rats exhibit a decreased fear conditioning response during training with a poor contextual fear memory 24 hours later. These VAD-induced cognitive impairments are associated with elevated plasma CORT levels under basal conditions, as well as following a stressful event, with saturated CORT release, altered hippocampal retinoid receptors and 11ß-HSD1 expression. Vitamin A supplementation normalises VAD-induced fear conditioning training deficits and all biochemical effects, although it cannot prevent fear memory deficits. Moreover, a single injection of UE2316 not only impairs contextual fear memory, but also reduces plasma CORT levels, regardless of the vitamin A status and decreases slightly hippocampal 11ß-HSD1 activity in VAD rats following stress. The present study highlights the importance of vitamin A status with respect to modulating fear memory conditioning in relation to plasma CORT levels and hippocampal 11ß-HSD1.

Polyphenols From Grape and Blueberry Improve Episodic Memory in Healthy Elderly with Lower Level of Memory Performance: A Bicentric Double-Blind, Randomized, Placebo-Controlled Clinical Study.

Polyphenols are promising nutritional bioactives exhibiting beneficial effect on age-related cognitive decline. This study evaluated the effect of a polyphenol-rich extract from grape and blueberry (PEGB) on memory of healthy elderly subjects (60-70 years-old). A bicentric, randomized, double-blind, placebo-controlled trial was conducted with 215 volunteers receiving 600 mg/day of PEGB (containing 258 mg flavonoids) or a placebo for 6 months. The primary outcome was the CANTAB Paired Associate Learning (PAL), a visuospatial learning and episodic memory test. Secondary outcomes included verbal episodic and recognition memory (VRM) and working memory (SSP). There was no significant effect of PEGB on the PAL on the whole cohort. Yet, PEGB supplementation improved VRM-free recall. Stratifying the cohort in quartiles based on PAL at baseline revealed a subgroup with advanced cognitive decline (decliners) who responded positively to the PEGB. In this group, PEGB consumption was also associated with a better VRM-delayed recognition. In addition to a lower polyphenol consumption, the urine metabolomic profile of decliners revealed that they excreted more metabolites. Urinary concentrations of specific flavan-3-ols metabolites were associated, at the end of the intervention, with the memory improvements. Our study demonstrates that PEGB improves age-related episodic memory decline in individuals with the highest cognitive impairments.

Polyphenol-rich extract from grape and blueberry attenuates cognitive decline and improves neuronal function in aged mice.

Ageing is characterised by memory deficits, associated with brain plasticity impairment. Polyphenols from berries, such as flavan-3-ols, anthocyanins, and resveratrol, have been suggested to modulate synaptic plasticity and cognitive processes. In the present study we assessed the preventive effect of a polyphenol-rich extract from grape and blueberry (PEGB), with high concentrations of flavonoids, on age-related cognitive decline in mice. Adult and aged (6 weeks and 16 months) mice were fed a PEGB-enriched diet for 14 weeks. Learning and memory were assessed using the novel object recognition and Morris water maze tasks. Brain polyphenol content was evaluated with ultra-high-performance LC-MS/MS. Hippocampal neurotrophin expression was measured using quantitative real-time PCR. Finally, the effect of PEGB on adult hippocampal neurogenesis was assessed by immunochemistry, counting the number of cells expressing doublecortin and the proportion of cells with dendritic prolongations. The combination of grape and blueberry polyphenols prevented age-induced learning and memory deficits. Moreover, it increased hippocampal nerve growth factor (Ngf) mRNA expression. Aged supplemented mice displayed a greater proportion of newly generated neurons with prolongations than control age-matched mice. Some of the polyphenols included in the extract were detected in the brain in the native form or as metabolites. Aged supplemented mice also displayed a better survival rate. These data suggest that PEGB may prevent age-induced cognitive decline. Possible mechanisms of action include a modulation of brain plasticity. Post-treatment detection of phenolic compounds in the brain suggests that polyphenols may act directly at the central level, while they can make an impact on mouse survival through a potential systemic effect.

Maternal n-3 polyunsaturated fatty acid dietary supply modulates microglia lipid content in the offspring.

The brain is highly enriched in long chain polyunsaturated fatty acids (LC-PUFAs) that are esterified into phospholipids, the major components of cell membranes. They accumulate during the perinatal period when the brain is rapidly developing. Hence, the levels of LC-PUFAs in the brains of the offspring greatly depend on maternal dietary intake. Perinatal n-3 PUFA consumption has been suggested to modulate the activity of microglial cells, the brain's innate immune cells which contribute to the shaping of neuronal network during development. However, the impact of maternal n-3 PUFA intake on microglial lipid composition in the offspring has never been studied. To investigate the impact of maternal dietary n-3 PUFA supply on microglia lipid composition, pregnant mice were fed with n-3 PUFA deficient, n-3 PUFA balanced or n-3 PUFA supplemented diets during gestation and lactation. At weaning, microglia were isolated from the pup's brains to analyze their fatty acid composition and phospholipid class levels. We here report that post-natal microglial cells displayed a distinctive lipid profile as they contained high levels of eicosapentaenoic acid (EPA), more EPA than docosahexaenoic acid (DHA) and large amount of phosphatidylinositol (PI) / phosphatidylserine (PS). Maternal n-3 PUFA supply increased DHA levels and decreased n-6 docosapentaenoic acid (DPA) levels whereas the PI/PS membrane content was inversely correlated to the quantity of PUFAs in the diet. These results raise the possibility of modulating microglial lipid profile and their subsequent activity in the developing brain.

Vitamin A, endocrine tissues and hormones: interplay and interactions.

Vitamin A (retinol) is a micronutrient critical for cell proliferation and differentiation. In adults, vitamin A and metabolites such as retinoic acid (RA) play major roles in vision, immune and brain functions, and tissue remodelling and metabolism. This review presents the physiological interactions of retinoids and endocrine tissues and hormonal systems. Two endocrine systems have been particularly studied. In the pituitary, retinoids targets the corticotrophs with a possible therapeutic use in corticotropinomas. In the thyroid, retinoids interfere with iodine metabolism and vitamin A deficiency aggravates thyroid dysfunction caused by iodine-deficient diets. Retinoids use in thyroid cancer appears less promising than expected. Recent and still controversial studies investigated the relations between retinoids and metabolic syndrome. Indeed, retinoids contribute to pancreatic development and modify fat and glucose metabolism. However, more detailed studies are needed before planning any therapeutic use. Finally, retinoids probably play more minor roles in adrenal and gonads development and function apart from their major effects on spermatogenesis.

Retinoic acid increases glucocorticoid receptor phosphorylation via cyclin-dependent kinase 5.

Glucocorticoid receptor (GR) function is modulated by phosphorylation. As retinoic acid (RA) can activate some cytoplasmic kinases able to phosphorylate GR, we investigated whether RA could modulate GR phosphorylation in neuronal cells in a context of long-term glucocorticoid exposure. A 4-day treatment of dexamethasone (Dex) plus RA, showed that RA potentiated the (Dex)-induced phosphorylation on GR Serine 220 (pSer220GR) in the nucleus of a hippocampal HT22 cell line. This treatment increased the cytoplasmic ratio of p35/p25 proteins, which are major CDK5 cofactors. Roscovitine, a pharmacological CDK5 inhibitor, or a siRNA against CDK5 prevented RA potentiation of GR phosphorylation. Furthermore, roscovitine counter-acted the effect of RA on GR sensitive target proteins such as BDNF or tissue-transglutaminase. These data help understanding the interaction between RA- and glucocorticoid-signalling pathways, both of which have strong influences on the adult brain.

Diabetes and Insulin Injection Modalities: Effects on Hepatic and Hippocampal Expression of 11ß-Hydroxysteroid Dehydrogenase Type 1 in Juvenile Diabetic Male Rats.

BACKGROUND: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is often encountered in diabetes, leading to several clinical complications. Our recent results showing an elevated tetrahydrocortisol/tetrahydrocorticosterone ratio in morning urine of diabetic children compared to that of controls suggest an increased nocturnal activity of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) in the former. QUESTION: We hypothesized that these observations could be explained by a reduced inhibition of hepatic 11ß-HSD1 activity by exogenous insulin owing to its subcutaneous (SC) administration and absence of first hepatic passage. Additionally, we hypothesized that hippocampal 11ß-HSD1 activity might also be impaired by diabetes. METHODS: We therefore measured HPA axis activity and 11ß-HSD1 expression and activity in liver and hippocampus in streptozotocin-induced diabetic juvenile rats treated with SC or intraperitoneal (IP) insulin. RESULTS: Plasma corticosterone levels were elevated in untreated diabetic rats during the resting phase and restored by both types of insulin treatment. The mRNA expression and activity of 11ß-HSD1 were increased in the untreated diabetic group in liver. Although diabetes was controlled equally whatever the route of insulin administration, liver 11ß-HSD1 gene expression and activity was decreased only in the IP group, suggesting that a first hepatic pass is needed for 11ß-HSD1 hepatic inhibition. In hippocampus, 11ß-HSD1 activity was elevated in the untreated diabetic group but restored by both types of insulin treatment. Thus, these data extend our findings in diabetic children by showing impairment of hippocampal 11ß-HSD1 in diabetes and by demonstrating that IP is preferable to SC insulin administration to restore 11ß-HSD1 activity in liver.

EPA/DHA and Vitamin A Supplementation Improves Spatial Memory and Alleviates the Age-related Decrease in Hippocampal RXRγ and Kinase Expression in Rats.

Studies suggest that eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and vitamin A are critical to delay aged-related cognitive decline. These nutrients regulate gene expression in the brain by binding to nuclear receptors such as the retinoid X receptors (RXRs) and the retinoic acid receptors (RARs). Moreover, EPA/DHA and retinoids activate notably kinase signaling pathways such as AKT or MAPK, which includes ERK1/2. This suggests that these nutrients may modulate brain function in a similar way. Therefore, we investigated in middle-aged rats the behavioral and molecular effects of supplementations with EPA/DHA and vitamin A alone or combined. 18-month-old rats exhibited reference and working memory deficits in the Morris water maze, associated with a decrease in serum vitamin A and hippocampal EPA/DHA contents. RARα, RXRß, and RXRγ mRNA expression and CAMKII, AKT, ERK1/2 expression were decreased in the hippocampus of middle-aged rats. A combined EPA/DHA and vitamin A supplementation had a beneficial additive effect on reference memory but not in working memory in middle-aged rats, associated with an alleviation of the age-related decrease in RXRγ, CAMKII, AKT, and ERK1 expression in the hippocampus. This study provides a new combined nutritional strategy to delay brain aging.

Dietary Polyphenol Supplementation Prevents Alterations of Spatial Navigation in Middle-Aged Mice.

Spatial learning and memory deficits associated with hippocampal synaptic plasticity impairments are commonly observed during aging. Besides, the beneficial role of dietary polyphenols has been suggested as potential functional food candidates to prevent this memory decline. Indeed, polyphenols could potentiate the signaling pathways of synaptic plasticity underlying learning and memory. In this study, spatial learning deficits of middle-aged mice were first highlighted and characterized according to their navigation patterns in the Morris water maze task. An eight-week polyphenol-enriched diet, containing a polyphenol-rich extract from grape and blueberry (PEGB; from the Neurophenols Consortium) with high contents of flavonoids, stilbenes and phenolic acids, was then successful in reversing these age-induced effects. The use of spatial strategies was indeed delayed with aging whereas a polyphenol supplementation could promote the occurrence of spatial strategies. These behavioral results were associated with neurobiological changes: while the expression of hippocampal calmodulin kinase II (CaMKII) mRNA levels was reduced in middle-aged animals, the polyphenol-enriched diet could rescue them. Besides, an increased expression of nerve growth neurotrophic factor (NGF) mRNA levels was also observed in supplemented adult and middle-aged mice. Thus these data suggest that supplementation with polyphenols could be an efficient nutritional way to prevent age-induced cognitive decline.