In Vivo. Cramp relief stretches of the neuroprotective action of moor. Each brain was then mounted on a cryostat chuck and micrometer thick coronal sections through the hippocampus were cut and collected serially in well plates.

Resveratrol and mood enhancement -

Because aging is associated with greatly diminished hippocampal neurogenesis 11 , 12 , 13 , the proposition that declined neurogenesis contributes to memory and mood dysfunction in the aged population has emerged. This concept has been supported by multiple studies Furthermore, progenitor cells in the hippocampus of depressed patients exhibit decreased proliferation than age-matched controls However, the fraction of quiescent NSCs increases in the aged hippocampus 20 , This is likely due to changes in the DG milieu, as neurotrophic factors and signaling molecules that stimulate the proliferation of NSCs decline in concentration with aging 22 , 23 , 24 , Moreover, other factors that are considered detrimental for neurogenesis also emerge in the aged hippocampus.

These include chronic mild inflammation manifesting in the form of hypertrophy of astrocytes and activation of microglia 26 , 27 , decreased availability of astrocyte-derived pro-neurogenic factors 23 , 28 and decreased microvasculature From this perspective, drugs having ability for restraining inflammation and enhancing microvasculature in the aged hippocampus are likely beneficial for stimulating quiescent NSCs to produce new neurons in the aged hippocampus.

Increased neurogenesis and microvasculature and reduced inflammation may help in the maintenance of adequate memory and mood function in the normal elderly population.

Administration of resveratrol RESV , a naturally occurring polyphenol found in high concentrations in the skin of red grapes, appears suitable for counteracting age-related detrimental changes in the hippocampus because of its pro-angiogenic and antiinflammatory properties with no adverse side effects 30 , 31 , 32 , Indeed, RESV has been shown to mediate a wide range of biological activities including extension of the life span and delayed onset of age related diseases 31 , 34 , 35 , Additionally, recent studies provide evidence that RESV intake in healthy older persons improves memory performance 38 and RESV has antidepressant effects in an animal model of depression To understand mechanisms, we also investigated whether RESV therapy can increase neurogenesis and microvasculature and modulate the hypertrophy of astrocytes and activation of microglia, in the aged hippocampus.

Figure 1 illustrates the time-line of treatment, behavioral tests and other analyses. Characterization using a water maze test WMT revealed that the two groups of months old rats chosen for this study exhibited similar learning and memory ability prior to the commencement of treatment regimen Fig.

Analyses of swim path efficiency i. A cohort of months old rats was examined using a water maze test WMT and animals with normal spatial learning and memory function were chosen and divided into two groups. Both groups underwent a second WMT four weeks after the termination of VEH or RESV treatment followed by a forced swim test FST.

Animals were next euthanized via intracardiac perfusions and brain tissues processed for immunohistochemical staining and various quantifications. PQ NE-Q , platform quadrant northeast quadrant ; SE-Q, southeast quadrant; SW-Q, southwest quadrant; and NW-Q, northwest quadrant.

The two groups of rats described above received either vehicle VEH or RESV for four weeks when they were in the 23 rd month of their life. A month later i. in 25 th month of their life , a second WMT was performed to assess their ability to make new spatial memories. Animals belonging to both VEH and RESV groups learned to locate the position of submerged platform during training sessions.

Thus, RESV-treated rats displayed much superior ability for spatial learning than VEH-treated rats. PQ SW-Q , platform quadrant southwest quadrant ; NW-Q, northwest quadrant; NE-Q, northeast quadrant; SE-Q, southeast quadrant. Analyses of spatial learning data between pre- and post-treatment periods in the VEH group showed that spatial learning ability neither improved nor worsened between 22 and 25 months of age.

In contrast, RESV-treated aged animals displayed improved spatial learning performance. Thus, in the absence of therapeutic treatment, aged rats can maintain their spatial learning ability but lose their capacity for making new spatial memory between 22 and 25 months of age.

In contrast, with RESV treatment, aged rats showed an improved ability for both spatial learning and spatial memory during this period. In contrast, RESV treated rats display improved ability for spatial learning and memory retention in comparison to their pre-treatment performance.

C1—C3 : Comparison of depressive-like behavior in a forced swim test between VEH treated and resveratrol RESV treated aged rats. Note that, RESV treated aged rats displayed reduced depressive-like behavior, in comparison to VEH treated aged rats. To further investigate the improved learning ability displayed by aged animals after RESV-treatment i.

in the second WMT , we compared latencies to reach the platform between the four trials performed on day 1 i. the first learning session. Thus, an improved learning ability of RESV-treated aged rats could be observed in the very first learning session. Furthermore, to examine whether overnight forgetting underlies impaired memory retrieval function in VEH-treated animals, we performed additional analyses on their spatial learning parameters.

First, we compared the last trial trial 4 or T4 latency values in every learning session S with the first trial T1 latency values of the subsequent learning session Table 2 in supplement document.

Next, we compared average latency values of each of sessions 1—6 with T1 latency values of the subsequent learning session T1 of S2—S7, Table 3 in supplement document.

Both of these analyses did not imply the occurrence of overnight forgetting during learning in VEH-treated animals Tables 2 and 3 in supplement document. However, their overall latency values decreased over seven learning sessions as they continuously improved their learning in subsequent learning sessions.

From their behavior, it appeared that RESV-treated animals remembered the logistics involved in finding the hidden platform from the first WMT performed prior to treatment better than VEH-treated animals. This was apparent from their ability to quickly locate the hidden platform by the second learning session, which allowed stronger memory encoding to occur in the remaining learning sessions i.

in learning sessions 3—7, Fig. This is in sharp contrast to VEH-treated rats, which showed progressive decreases in latency values over seven learning sessions but ended up having much higher latency values than RESV treated animals even in the 7 th session of learning Fig.

Thus, VEH-treated animals remained in the learning phase over 7 sessions of learning whereas RESV-treated animals learned to quickly locate the platform within the first two sessions of learning and utilized the remaining sessions of learning for memory encoding.

Thus, VEH or RESV treatment did not significantly alter the motor ability of aged rats. We did not perform visible platform test following spatial learning and memory test in this study as animals belonging to both VEH and RESV groups showed ability for spatial learning in both first and second WMTs.

Hence, it is unknown whether RESV treatment improved vision function of aged rats in this study. Additional studies are needed in the future on possible RESV-mediated vision improvements in aged rats.

Analyses of immobility or floating time in a forced swim test FST was used as a measure of depressive-like behavior in VEH and RESV treated rats, as rats with normal mood function are known to spend reduced amounts of the test time in floating.

When floating times for the entire 10 minutes duration were compared, it was clear that RESV-treated rats displayed decreased tendency for floating Thus, RESV treatment to aged rats resulted in an anti-depressant effect, implying improved mood function.

However, as only FST was used for measuring depressive-like behavior in this study, additional behavioral tests measuring depression will be required in future studies to confirm the anti-depressive effects of RESV in aged rats.

The addition of new cells was increased by 1. Quantification of fractions of newly born cells that differentiate into NeuN-expressing neurons in the SGZ-GCL using dual immunofluorescence and confocal microscopy, Fig.

This analysis showed that RESV treatment to aged rats induced 2. Since BrdU injections were given during the last 7 days of RESV treatment, these results showed the extent of neurogenesis occurring in the 4th week of RESV treatment.

B1 and B2 are magnified views of regions from A1 and B1. We also analyzed neurogenesis through quantification of neurons positive for doublecortin DCX, a marker of newly born neurons in the SGZ-GCL Fig. Since DCX expression in newly born neurons lasts for ~2 weeks after their birth in F rats 40 , this analyses provided a measure of ongoing neurogenesis.

Aged rats treated with RESV exhibited 2. Since these neurons are generated ~6 weeks after the termination of RESV treatment, the results suggest that RESV treatment can trigger sustained increase in neurogenesis in the aged hippocampus even after its termination.

Newly born neurons expressing doublecortin DCX in the subgranular zone-granule cell layer SGZ—GCL of rats treated with vehicle VEH; A1 or resveratrol RESV; B1, C1.

A2, B2 and C2 are magnified views of regions from A1, B1 and C1. DH, dentate hilus; ML, molecular layer. To determine whether RESV treatment improved cerebral blood flow, we measured microvasculature in the hippocampus using rat endothelial cell antigen-1 RECA-1 immunostaining Fig.

Area fraction analyses demonstrated increased microvasculature in RESV-treated rats, in comparison to VEH-treated rats Fig. Distribution of rat endothelial cell antigen-1 RECA-1 -positive microvessels and glial fibrillary acidic protein GFAP -positive astrocytes in vehicle VEH and resveratrol RESV treated groups.

Immunohistochemical staining for glial fibrillary acidic protein GFAP suggested increased occurrence of astrocytes with hypertrophy in VEH-treated rats, in comparison to RESV-treated rats Fig. This quantification revealed reduced astrocyte hypertrophy in the hippocampus of RESV-treated aged rats.

Immunohistochemical characterization using OX CD11b antibody revealed increased occurrence of activated microglia displaying enlarged soma and fewer processes in VEH-treated rats, resulting in larger spaces between microglia Fig.

In contrast, RESV-treated rats showed mostly ramified microglia i. resting microglia exhibiting very extensive fine processes Fig. This measurement suggested increased occurrence of ramified or resting microglia in RESV-treated rats than VEH-treated rats Fig. These results implied that most microglia in RESV-treated rats have highly ramified appearance whereas considerable numbers of microglia in the VEH-treated aged rats have modified into activated microglia with fewer processes.

Collectively, these results confirmed that RESV-treatment in old age reduced the presence of activated microglia in the hippocampus.

Distribution of OX CD11b -positive microglia in the hippocampus of vehicle VEH and resveratrol RESV treated groups. E1 and E2 show representative examples of microglial morphology traced with Neurolucida from VEH treated E1 and RESV treated E2 rats.

Most microglia in VEH-treated aged rats exhibited enlarged soma, shorter processess and reduced ramification of processes arrows in A1, B1, C1 and the cartoon in E1 , implying a tendency towards conversion into amoeboid or activated microglia.

In contrast, most microglia in RESV treated rats maintained longer processes with extensive ramifications arrowheads in A2, B2, C2 and the cartoon in E2 suggestive of resting microglia. Distribution of ED-1 CD68 -positive activated microglia in the dentate hilus DH and granule cell layer GCL of vehicle VEH, A1 and resveratrol RESV, A2 treated groups.

B1 and B2 are magnified views of dentate hilar regions from A1 and B2. Values represent means and standard errors. To ascertain the effects of RESV treatment on hippocampus volume, we measured the volume of hippocampus in animals belonging to both VEH and RESV groups.

Thus, the beneficial effects mediated by RESV did not change the overall volume of hippocampus. The results of this study in a rat model of aging provide new evidence that RESV treatment in late middle age can positively modulate the structure and function of the aged hippocampus. The structural changes that occurred with RESV treatment comprised increased neurogenesis and microvasculature and reduced astrocyte hypertrophy and activation of microglia.

The beneficial functional effects included improved ability for spatial learning, preserved proficiency for making new spatial memory and alleviation of depressive-like behavior associated with aging. Because decreases in neurogenesis and microvasculature and increases in astrocyte hypertrophy and activation of microglia during aging can adversely affect cognitive and mood function, the structural plasticity mediated by RESV in the aged hippocampus have likely contributed greatly towards beneficial functional effects.

Decline in cognitive capacity after middle age is seen in most humans as well as in animal models. In humans, this may manifest in the form of occasional forgetfulness, decreased processing speed and mental flexibility and reduced ability for solving problems or maintaining attentiveness Although these problems in milder forms are typical for the elderly population, progression of these snags into a measurable decline in cognition and memory would result in a clinical condition called MCI.

Because people with MCI have an increased risk for developing AD or other type of dementia 2 , interventions that can improve cognitive and memory function in old age or prevent MCI in old age have immense importance. A multitude of factors including myelin loss, thinning of the cerebral cortex, decreased hippocampus volume, reduced neurotransmitter concentrations, altered neuronal networks associated with decreases in neuron size and synaptic density can contribute to cognitive decline with aging 41 , On the other hand, memory and mood dysfunction in old age has been linked strongly to decreased function of DG in the hippocampus 3 , 4.

There are several structural changes in the aged DG that parallel its diminished function. Greatly reduced neurogenesis is one of the conspicuous alterations attracting the most attention because of its purported role in learning, memory and mood function 6 , 14 , 13 , Additional structural changes in the DG include diminished ability of interneurons to synthesize the inhibitory neurotransmitter gamma-amino butyric acid GABA resulting in compromised inhibitory synaptic transmission 43 , 44 and loss of synapses between DG granule cells and perforant path afferents from the entorhinal cortex However, these changes are likely secondary to multiple primary age-related alterations in the DG.

These include decreased blood flow due to loss of microvasculature, endothelial cell dysfunction or plaques in cerebral blood vessels 29 , increased oxidative stress 45 , chronic low-level inflammation in the form of hypertrophy of astrocytes and activation of microglia 26 , 27 and reduced concentration of astrocyte-derived pro-neurogenic and pro-angiogenic factors and signaling molecules 22 , 23 , 24 , 25 , If the above proposition is true, then, therapeutic interventions that reverse one or more of the primary age-related changes in the brain should improve cognitive and mood function in the aged population.

We chose RESV in this study because of its ability to readily cross the blood-brain barrier following peripheral administration, promote angiogenesis, suppress oxidative stress, inflammation and mitochondrial dysfunction, activate longevity genes and extend life span without adverse side effects 31 , 32 , 33 , 34 , 35 , Moreover, RESV treatment can mimic caloric restriction, a strategy that has been found to exert several beneficial effects on the aging brain 49 , Furthermore, previous studies have shown that RESV treatment can provide protection against neurodegeneration in models of AD 51 , improve cognitive function in adult primates 52 and enhance hippocampal microvasculature in aging mice In addition, recent studies report that RESV treatment can improve memory performance in healthy older persons 38 and promote antidepressant effects in an animal model of depression To understand mechanisms underlying RESV-mediated beneficial effects on learning, memory and mood, we quantified the extent of neurogenesis, microvasculature, astrocyte hypertrophy and activation of microglia in the hippocampus.

These are measures that are known to undergo alterations in old age and substantial changes in them can adversely influence memory and mood. First, it is clear that aging is associated with greatly waned hippocampal neurogenesis and memory and mood dysfunction in aging can be attributed at least partially to greatly decreased neurogenesis.

This is because: i increased hippocampal neurogenesis in middle-aged and aged animals exposed to enriched environment is allied with increased ability for making new spatial memories 17 , 18 ; ii aged rats having ability for forming new spatial memories display higher levels of hippocampal neurogenesis than impaired aged rats 54 , 55 ; iii middle-aged mice exercising on running wheels or having lowered stress hormone levels demonstrate both enhanced hippocampal neurogenesis and better memory ability 15 , 16 ; iv aged rats displaying ability for making new spatial memories exhibit enhanced survival of new cells generated just prior to the onset of learning 56 ; and v progenitor cells in the hippocampus of depressed patients exhibit decreased proliferation than age-matched controls It is believed that these changes in microvasculature contribute to memory dysfunction in aging 29 , Third, chronic low-level inflammation is one of the conspicuous features of the aged rodent and human hippocampus 58 , which can be gauged through changes in the morphology of astrocytes and microglia.

Astrocytes in the aged hippocampus display reactive phenotype and a significant fraction of microglial cells in the aged hippocampus undergoes activation.

This kind of chronic low-level inflammation in the aged hippocampus can adversely affect memory and mood function. For example, systemic inflammation induced pro-inflammatory changes in the hippocampus causes deficits in the hippocampal long-term potentiation LTP, a basis of learning and memory in middle-aged rats and antiinflammatory therapy restores LTP in these rats Interestingly, RESV treatment enhanced net neurogenesis in the last week of RESV treatment and maintained increased neurogenesis and microvasculature when examined at ~25 months of age i.

Furthermore, RESV treatment had antiinflammatory effects in the form of reduced hypertrophy of astrocytes and diminished activation of microglia.

The microvasculature enhancing effects of RESV noted here is consistent with earlier findings that RESV treatment improves endothelial function and cerebral blood flow 60 , 61 , whereas its antiinflammatory effects are in line with a previous study showing that RESV can reduce plasma levels of pro-inflammatory cytokines On the other hand, neurogenesis-enhancing effects of RESV in the aged hippocampus are likely mediated through increased microvasculature and suppression of inflammation in the neurogenic niche i.

Thus, the precise reasons underlying a diminished spatial learning ability and an impaired memory function in VEH-treated aged animals and improved spatial learning and memory ability in RESV-treated aged rats are unknown. However, as age-related memory dysfunction typically occurs between 18 and 24 months of age in male F rats 64 , it is plausible that impaired spatial learning and memory function in VEH-treated animals is linked to multiple adverse changes in the aged hippocampus that are detailed above.

Additional age-related changes observed in earlier studies such as alterations in dendritic morphology, cellular connectivity, gene expression and other factors affecting plasticity and network dynamics of neural ensembles supporting cognition and memory may also be involved On the other hand, improved memory retrieval function in RESV-treated animals is likely owed to multiple RESV-mediated beneficial changes, which may include increased neurogenesis and microvasculature and dampened inflammation described above.

Several molecular mechanisms are expected to be involved in mediating these beneficial changes. These could comprise increased expression of SIRT1 nicotinamide adenine dinucleotide-dependent histone deacetylase , a longevity factor that undergoes upregulation with RESV treatment and is believed to play a role in the maintenance of normal cognitive and mood function and neurogenesis 66 , Indeed, a parallel study in our laboratory has shown that four weeks of oral RESV treatment to aged rats increased the expression of SIRT1 gene as well as its down-stream target FOXO3 68 , a transcription factor that regulates the capacity of cells to cope with endoplasmic reticulum and oxidative stress Furthermore, alteration in the expression of nuclear factor kappa B NF-kB , a transcription factor responsible for the regulation of multiple target genes related to inflammation, could be involved in the suppression of inflammation, as RESV treatment has been shown to modulate NF-kB pathways in several models 70 , In addition, activation of adenosine monophosphate AMP activated protein kinase AMPK , a protein kinase having a major role in neuronal differentiation and mitochondrial biogenesis in neurons, may also be involved, as RESV is known to up-regulate AMPK in a SIRT1-dependent manner Furthermore, mechanisms such as an improved glucose metabolism and enhanced functional connectivity between the posterior hippocampus and the medial prefrontal cortex observed in a recent human study 38 , reduction in serum corticosterone and regulation of the hypothalamus-pituitary-adrenal HPA axis 72 and enhanced brain-derived neurotrophic factor BDNF signaling pathway 39 , 73 may also be contributing to RESV-mediated improved cognitive and mood function.

Studies on these aspects at different time-points after RESV treatment in aging models will be needed in the future to understand their role. Another remarkable attribute of this study is that improved cognitive function in aged rats following RESV treatment differed from an earlier study on the effects of RESV treatment in juvenile 4-weeks old mice This study showed that administration of RESV to juvenile mice reduced hippocampal neurogenesis as well as cognitive function, in association with activation of AMPK and down-regulation of the phosphorylated form of cyclic AMP response element-binding protein pCREB and BDNF in the hippocampus.

The discrepancy reflects divergent effects of RESV on the juvenile vis-à-vis the aged brain. Administration of RESV in the juvenile age corresponds to a time when the hippocampus was still maturing with very high levels of neurogenesis.

This is in sharp contrast to the current study where RESV was administered at a time when the aged hippocampus was exhibiting a greatly declined neurogenesis, reduced cerebral blood flow, chronic low level inflammation and increased oxidative stress.

It is likely that inflammation, oxidative stress and reduced cerebral blood flow in the aged brain contributed to the reduced neurogenesis and impaired cognitive function and RESV treatment enhanced neurogenesis and microvasculature through antiinflammatory, antioxidant and pro-angiogenic effects, which in turn improved cognitive function in aged rats.

On the other hand, since the juvenile brain does not normally display inflammation, increased oxidative stress or decreased cerebral blood flow, RESV-mediated suppression of normal levels of oxidative stress that are believed to be required for neural stem cell NSC proliferation and differentiation 75 may have impaired neurogenesis and interfered with the cognitive function in juvenile mice.

The observed opposing effects of RESV on the juvenile vis-à-vis the aged brain also imply that RESV treatment can have beneficial effects in a background of a disease state or in conditions such as aging, but may adversely affect function of the developing or the young brain Additional longitudinal studies over the lifespan of animals will be useful to comprehend the mechanisms underlying these differences.

Nonetheless, the beneficial effects of RESV treatment for the aged brain is also apparent from a recent human study, which demonstrated that lower dose of RESV intake for 26 weeks can improve memory performance as well as hippocampus functional connectivity in healthy but overweight older individuals Our results in a rat model of aging provide novel evidence that four weeks of daily RESV treatment in late middle age is efficacious for improving cognitive, memory and mood function in old age.

Additional analyses demonstrated that improved cognitive and mood function following RESV treatment is linked with amelioration of several age-related changes such as decreased neurogenesis and microvasculature and low-level chronic inflammation in the hippocampus.

These results suggest that RESV therapy in middle age is beneficial for maintaining normal memory and mood function in old age. Twenty-one month old male Fischer rats acquired from Harlan Sprague-Dawley Indianapolis, IN, USA were used in this study.

All experiments were performed as per the animal protocol approved by the animal studies subcommittee of the Durham Veterans Affairs Medical Center.

Following arrival, animals were allowed to have 7—10 days acclimatization in the vivarium. Figure 1 illustrates the time-line of various treatments and analyses. Animals with normal spatial learning and memory function were chosen and divided into two groups. The dose of RESV was based on findings in our preliminary studies using middle-aged rats, where this dose increased hippocampal neurogenesis.

We chose intraperitoneal injections in this study because we wanted to examine the effects of a relatively lower dose of RESV for a shorter duration 4 weeks.

The drug was injected into areas in the left or right halves of the peritoneal cavity alternatively to minimize repeated injections at one site and peritoneal irritation.

Following injections, animals were closely monitored and no writhing behavior was observed. Thus, animals did not show signs of dermal or peritoneal irritation because of very lower concentration of alcohol used as vehicle in this study.

A month after RESV treatment, a fresh round of WMT was conducted. Following this, the extent of depressive-like behavior was quantified using an FST. In order to determine the production of new cells and the status of hippocampus neurogenesis, stereological quantifications of cells positive for BrdU and DCX were performed for the SGZ-GCL of the DG using serial sections every 10 th immunostained for BrdU or DCX and StereoInvestigator Microbrightfield Inc.

To determine the effects of RESV on other structural changes in different subfields DG, CA1 and CA3 of the hippocampus, we also quantified areas occupied by the microvasculature, astrocytes and microglia through immunohistochemical staining of serial sections every 15th through the hippocampus for RECA-1 a marker of cerebral blood vessels , GFAP a marker astrocytes , OX a marker of microglia and area fraction analyses using J Image.

Moreover, to distinguish any changes in the morphology, we quantified processes of microglia using Neurolucida Microbrightfield. Additionally, to quantify the fraction of microglia that was activated in the vicinity of the neurogenic region, we performed ED-1 immunohistochemistry using serial sections every 15th and quantified the numbers of activated microglia in the DG using StereoInvestigator.

Hippocampus-dependent spatial learning and memory function in aged rats was analyzed using a WMT, as described in our recent studies 77 , The water was rendered opaque by the addition of a white, non-toxic paint and extra-maze cues were positioned on the walls of the room around the tank. A quartz halogen lamp was positioned aiming at the ceiling to indirectly illuminate the water surface.

A video camera was mounted on the ceiling directly above the center of the pool and the movement of rat in the water maze tank was continuously video-tracked and recorded using a computerized ANY-Maze video tracking system Stoelting ANY-maze, Wood Dale, IL, USA.

The rat was trained to find the platform using spatial cues for 7 sessions over 7 days with 4 acquisition trials per session. Each rat was placed in the water, immediately facing the wall of the tank in one of the quadrants in pseudo-random manner and then allowed a maximal time of 90 seconds to locate the platform with an inter-trial interval of seconds.

Each trial commenced from a different start location. When the subject reached the platform it was allowed to stay there for 30 seconds. When the subject failed to find the platform within the ceiling time of 90 seconds, it was guided onto the platform and allowed to stay there for 30 seconds.

The platform was positioned in the same place across all sessions. Data such as the latency and swim path lengths to reach the platform, swim path efficiency the ratio of the shortest possible swim path length to actual swim path length and swim speed were collected using Anymaze software.

Mean latencies to reach the platform were used for assessment of learning curves, as swim speeds did not differ between groups in this study.

A day after the 7-day learning protocol described above, each rat was subjected to a single second probe or memory retrieval test. This involved removal of the platform from the pool and release of rats from the quadrant that is diametrically opposite to the quadrant where the platform was positioned during learning sessions.

Retrieval of learned memory was assessed by comparing dwell time in the PQ with the other three quadrants within the group and also by comparing dwell time in platform quadrant, latency to reach the platform area, dwell time in platform area and platform area crossings across groups. This test was done as detailed in our recent studies 78 , This ensured that the rat could not touch the bottom of the cylinder with its tail or hind paws or escape from the top.

The rat was subjected to a single session of forced swimming lasting ten minutes. We directly performed the forced swimming trial, as this test was conducted two days after the completion of WMT. Since animals have experienced swimming during learning sessions in the WMT, a separate swimming trial was not given prior to testing in an FST.

Animal behavior during the test was monitored and recorded by a video camera. Investigators scored immobility time for each animal using the recorded videos. Animals that exhibited signs of drowning behavior were quickly removed from the cylinder and excluded for FST analyses.

The amount of time spent in immobility also referred to as floating was calculated later. Immobility is defined as the minimal movement necessary to keep the head above the water level. Furthermore, we compared FST data in two separate segments 5 minutes each. This is because typically in the first 5 minutes of the test, normal animals i.

animals having no depression tend to swim continuously with minimal time spent in immobility in contrast to depressed animals spending greater amount of time in immobility. In the last 5 minutes of the test, even a normal rat may display increased immobility due to swimming related fatigue.

Therefore, analysis of two segments of FST time helps to dissociate depression-related immobility from fatigue-related immobility. Each animal was first deeply anesthetized with isoflurane in a Plexiglas chamber until it ceased respiration.

Each brain was then mounted on a cryostat chuck and micrometer thick coronal sections through the hippocampus were cut and collected serially in well plates.

Two sets of serial sections every 10 th through the entire hippocampus were picked from each animal belonging to RESV and VEH control groups and processed for BrdU and DCX immunostaining, as described in our previous studies 12 , 13 , 82 , Furthermore, additional sets of serial sections every 20 th through the hippocampus were processed for immunohistochemical characterization of cells positive for RECA-1 20 , GFAP 23 , OX 22 and ED-1 The primary antibodies comprised monoclonal antibodies against BrdU , BD Biosciences, San Jose, CA, USA or , Serotech, Raleigh, NC, USA , NeuN , EMD Millipore, Darmstadt, Germany , OX , AbD Serotech , RECA-1 and ED-1 , AbD Serotech and polyclonal antibodies against DCX ; Santa Cruz Biotechnology, Santa Cruz, CA, USA and GFAP , Dako, Carpinteria, CA, USA.

For this, we used micrometer thick serial sections every 10 th for BrdU and DCX and every 20 th for ED-1 analyses through the entire hippocampus and the StereoInvestigator system Microbrightfield comprising a color digital video camera Optronics Inc.

A computer driven motorized stage then allowed the cells to be measured at each of the counting frame locations. This plane served as the first point of the counting process. This procedure was repeated for all serial sections. By utilizing parameters such as the initial section thickness i.

at the time of sectioning , the section thickness at the time of cell counting i. The Gundersen coefficient error CE was in the range of 0. The sections processed for BrdU and NeuN dual immunofluorescence were analyzed using a laser scanning confocal microscope FVi, Olympus , as described in our earlier reports Rachal Pugh , Fleshner M , Watkins LR , Maier SF , Rudy JW.

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Witte AV , Kerti L , Margulies DS , Flöel A. Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults J Neurosci.

Köbe T , Witte AV , Schnelle A , et al. Impact of resveratrol on glucose control, hippocampal structure and connectivity, and memory performance in patients with mild cognitive impairment Front Neurosci.

Turner RS , Thomas RG , Craft S , et al. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease Neurology. Wong RH , Nealon RS , Scholey A , Howe PR.

Low dose resveratrol improves cerebrovascular function in type 2 diabetes mellitus Nutr Metab Cardiovasc Dis. Evans HM , Howe PR , Wong RH. Effects of resveratrol on cognitive performance, mood and cerebrovascular function in post-menopausal women; a week randomised placebo-controlled intervention trial Nutrients.

Hirtz D , Thurman DJ , Gwinn-Hardy K , Mohamed M , Chaudhuri AR , Zalutsky R. Mild cognitive decline. A position statement of the Cognitive Decline Group of the European Innovation Partnership for Active and Healthy Ageing EIPAHA Maturitas.

Bidzan M , Bidzan L , Bidzan-Bluma I. Neuropsychiatric symptoms and faster progression of cognitive impairments as predictors of risk of conversion of mild cognitive impairment to dementia Arch Med Sci. Flirski M , Sobow T. The chemical structure of resveratrol is very similar to that of the synthetic estrogen agonist, diethylstilbestrol Figure 2 , suggesting that resveratrol might also function as an estrogen agonist, i.

However, in cell culture experiments, resveratrol was found to act either as an estrogen agonist or as an estrogen antagonist depending on such factors as cell type, estrogen receptor isoform ERα or ERβ , and the presence of endogenous estrogens Most recently, resveratrol was shown to improve endothelial wound healing through an ERα-dependent pathway in an animal model of arterial injury Some compounds are not carcinogenic until they have been metabolized in the body by phase I biotransformation enzymes , especially cytochrome P enzymes 2.

By inhibiting the expression and activity of certain cytochrome P enzymes 25, 26 , resveratrol might help prevent cancer by limiting the activation of procarcinogens.

In contrast, increasing the activity of phase II detoxification enzymes generally promotes the excretion of potentially toxic or carcinogenic chemicals. Resveratrol has been found to increase the expression and activity of NAD P H:quinone oxidoreductase-1 NQO1 in cultured cells 27 and may be a weak inducer of other phase II enzymes Following DNA damage, the cell cycle can be transiently arrested to allow for DNA repair or activation of pathways leading to cell death apoptosis if the damage is irreparable Defective cell cycle regulation may result in the propagation of mutations that contribute to the development of cancer.

Moreover, unlike normal cells, cancer cells proliferate rapidly and are unable to respond to cell death signals that initiate apoptosis. Cancerous cells invade normal tissue aided by enzymes called matrix metalloproteinases.

Resveratrol has been found to inhibit the activity of at least one type of matrix metalloproteinase 30, To fuel their rapid growth, invasive tumors must also develop new blood vessels by a process known as angiogenesis.

Resveratrol has been found to inhibit angiogenesis in vitro and in vivo Inflammation promotes cellular proliferation and angiogenesis and inhibits apoptosis Resveratrol has been found to inhibit the activity of several inflammatory enzymes in vitro , including cyclooxygenases and lipoxygenases 37, Resveratrol may also inhibit pro-inflammatory transcription factors , such as NFκB or AP-1 39, Atherosclerosis is an inflammatory process in which lipids deposit in plaques known as atheromas within arterial walls and increase the risk of myocardial infarction One of the earliest events in the development of atherosclerosis is the recruitment of inflammatory white blood cells from the blood to the arterial wall by vascular cell adhesion molecules Resveratrol has been found to inhibit the expression of adhesion molecules in cultured endothelial cells 43, The proliferation of vascular smooth muscle cells VSMCs plays an important role in the progression of hypertension , atherosclerosis , and restenosis when treated arteries become blocked again.

Resveratrol has been found to inhibit the proliferation of VSMCs in culture , as well as in vivo Resveratrol appeared to reduce VSMC proliferation via an ERα-dependent mechanism, hence preventing the narrowing of vessels in a mouse model of arterial injury Endothelial nitric oxide synthase eNOS is an enzyme that catalyzes the formation of nitric oxide NO by vascular endothelial cells.

NO is needed to maintain arterial relaxation vasodilation , and impaired NO-dependent vasodilation is associated with an increased risk of cardiovascular disease Because physiological concentrations of resveratrol were found to stimulate eNOS activity in cultured endothelial cells , resveratrol might help maintain or improve endothelial function in vivo see Cardiovascular disease.

Platelet aggregation is one of the first steps in the formation of a blood clot that can occlude a coronary or cerebral artery, resulting in myocardial infarction or stroke , respectively.

Resveratrol has been found to inhibit platelet activation and aggregation in vitro Age-related mood alterations and memory deficits result from a decrease in the function of the hippocampus in the elderly. Resveratrol was shown to stimulate neurogenesis and blood vessel formation in the hippocampus of healthy old rats.

These structural changes were associated with significant improvements in spatial learning, memory formation, and mood function Senile plaques are toxic to cells, resulting in progressive neuronal dysfunction and death. Resveratrol was found to facilitate the clearance of β-amyloid peptide and promote cell survival in primary neurons in culture and neuronal cell lines Resveratrol also reduced senile plaque counts in various brain regions of a transgenic AD mouse model Abnormally activated microglia and hypertrophic astrocytes around the senile plaques in AD brains release cytotoxic molecules, such as proinflammatory mediators and ROS , which enhance the formation and deposition of β-amyloid peptides and further damage neurons Resveratrol was found able to inhibit the inflammatory response triggered by β-amyloid peptide-induced microglial activation in microglial cell lines and in a mouse model of cerebral amyloid deposition A decreased occurrence of microglial activation and astrocyte hypertrophy was also reported in healthy aged rats treated with resveratrol Resveratrol counteracted oxidative stress and β-amyloid peptide-induced toxicity in cultured neuroblastoma Resistance against oxidative stress-related damage in primary neuronal cells treated with resveratrol has been associated with the induction of heme oxygenase-1 HO-1 , an enzyme that degrades pro-oxidant heme In an experimental model of stroke , resveratrol limited infarct size during ischemia -reperfusion in wild-type mice but not in mice lacking the HO-1 gene Also, resveratrol was able to correct experimentally induced oxidative stress and the associated cognitive dysfunction in rats Resveratrol has been found to inhibit the proliferation of a variety of human cancer cell lines, including those from breast, prostate , stomach, colon, pancreatic , and thyroid cancers 2.

The anti-cancer effects of resveratrol in rodent models involved the reduction of cell proliferation, the induction of apoptosis , and the inhibition of angiogenesis , tumor growth, and metastasis reviewed in Yet, a few animal studies have reported a lack of an effect of oral resveratrol in inhibiting the development of lung cancer induced by carcinogens in cigarette smoke 70, 71 , and the study of resveratrol administration on colon cancer has given mixed results The low bioavailability of resveratrol reported in human studies limits the clinical evaluation of possible systemic health effects of resveratrol in humans see Metabolism and Bioavailability.

Yet, in a pilot study , unmetabolized resveratrol and conjugates have been detected in colorectal tumor tissues from 20 cancer patients following daily oral supplementation with either 4 g or 8 g of resveratrol for 29 days.

Resveratrol appeared to be well tolerated and significantly, though modestly, reduced cell proliferation compared to baseline A micronized formulation of resveratrol named SRT , which was meant to increase resveratrol delivery to target tissues, was given for 14 days to 6 patients with colorectal cancer and liver metastasis in a small randomized , double-blind , placebo -controlled trial Unmetabolized resveratrol was measurable in the liver of five out of six patients who consumed 5 g of SRT, and SRT administration resulted in an increased detection of the apoptotic marker, cleaved caspase-3, in hepatic tumor tissues.

Yet, in an unrandomized and unblinded trial in patients with multiple myeloma, the administration of SRT was associated with a number of serious adverse effects, including kidney failure, such that the trial was halted Since kidney failure is a frequent complication in myeloma patients, it is unclear whether kidney failure cases should be solely attributed to the use of SRT Nevertheless, there is a need to find safe ways to increase resveratrol bioavailability in humans before exploring its putative benefits in clinical settings 6 , Significant reductions in cardiovascular disease risk have been associated with moderate consumption of alcoholic beverages Red wine contains variable and usually low concentrations of resveratrol see Sources and higher concentrations of flavonoids like procyanidins.

These polyphenolic compounds have displayed antioxidant , anti-inflammatory, and other potentially anti-atherogenic effects in the test tube and in some animal models of atherosclerosis The results of epidemiological studies addressing this question have been inconsistent.

While some large prospective cohort studies found that wine drinkers were at lower risk of cardiovascular disease than beer or liquor drinkers , others found no difference Socioeconomic and lifestyle differences between people who prefer wine and those who prefer beer or liquor may explain part of the additional benefit observed in some studies: people who prefer wine tend to have higher incomes, more education, smoke less, and eat more fruit and vegetables and less saturated fat than those who prefer other alcoholic beverages Although moderate alcohol consumption has been consistently associated with reductions in coronary heart disease risk, it is not yet clear whether red wine polyphenols confer any additional risk reduction.

Interestingly, studies that administered alcohol-free red wine to rodents noted improvements in various parameters related to cardiovascular disease 93, 94 , and a placebo -controlled human study found that heart disease patients administered red grape polyphenol extract experienced acute improvements in endothelial function Endothelial dysfunction is usually associated with the presence of cardiovascular risk factors e.

Endothelial dysfunction is characterized by abnormal vasoconstriction, leukocyte adherence to vascular endothelial cells , platelet activation and aggregation, smooth muscle cell proliferation, vascular inflammation , thrombosis clot formation , impaired coagulation , and atherosclerosis Experimental studies : Resveratrol has been found to exert a number of protective effects on the cardiovascular system in vitro , including inhibition of both platelet activation and aggregation 53 , 98, 99 , promotion of vasodilation by enhancing the production of nitric oxide NO 52 , and control of the production of inflammatory lipid mediators 38 , , However, the concentrations of resveratrol required to produce these effects are often higher than those measured in human plasma after oral consumption of resveratrol 9.

Some animal studies also suggested that high oral doses of resveratrol could decrease the risk of thrombosis and atherosclerosis , , although one study found increased atherosclerosis in animals fed resveratrol Other protective effects of resveratrol in vivo include the reduction of cardiac hypertrophy and the lowering of blood pressure in various models, as well as the limitation of infarct size in post myocardial infarction rats reviewed in Resveratrol supplementation resulted in improved values of flow-mediated dilation FMD of the brachial artery, a surrogate marker of vascular health.

Yet, FMD returned to baseline values within three months after discontinuing resveratrol One study limitation was that the resveratrol formulation contained additional compounds i.

In a few additional studies, resveratrol was shown to improve endothelial function by reducing vascular inflammation and endothelial activation. A randomized, double-blind , placebo-controlled study in 41 healthy subjects found that daily supplementation with resveratrol mg , grapeseed extract mg , and quercetin mg , for one month significantly reduced the expression of interleukin-8 IL-8 and cell adhesion molecules ICAM-1 and VCAM-1 in endothelial cells, suggestive of a protective effect against endothelial dysfunction The daily intake of a resveratrol-rich grape supplement was compared to resveratrol-free grape supplement in a year-long, randomized, double blind, placebo-controlled study in 75 individuals at high risk for cardiovascular disease CVD.

The decreased concentrations of two CVD risk markers, oxidized low-density lipoprotein oxLDL and apolipoprotein B ApoB after six months further suggested a cardioprotective effect of resveratrol Supplementation of patients with stable coronary heart disease with the same regimen also improved the profile of circulating inflammatory markers and reduced the expression of proinflammatory genes in peripheral blood mononuclear cells PBMCs The expression of microRNAs and cytokines specifically involved in atherogenic and pro-inflammatory signals were also found to be downregulated in the PBMCs of supplemented patients While preliminary human studies suggest that resveratrol may have beneficial effects on cardiovascular health, there is currently no convincing evidence that these effects can be achieved in the amounts present in one to two glasses of red wine see Sources.

For more information regarding resveratrol and cardiovascular disease, see Caloric restriction is known to extend the lifespan of a number of species, including yeast, worms, flies, fish, rats, and mice In yeast Saccharomyces cerevisiae , caloric restriction stimulates the activity of an enzyme known as Silent information regulator 2 protein Sir2 or sirtuin Yeast Sir2 is a nicotinamide adenine dinucleotide NAD -dependent deacetylase enzyme that removes the acetyl group from acetylated lysine residues in target proteins see the article on Niacin.

Resveratrol feeding also extended the lifespan of worms Caenorhabditis elegans and fruit flies Drosophila melanogaster by a similar mechanism Additionally, resveratrol dose-dependently increased the lifespan of a vertebrate fish Nothobranchius furzeri Resveratrol was also found to extend the lifespan of mice on a high-calorie diet such that their lifespan was similar to that of mice fed a standard diet Although resveratrol increased the activity of the Sir2 homologous human sirtuin 1 SIRT1 in the test tube , there are no epidemiological data to link resveratrol, SIRT1 activation, and extended human lifespan.

Moreover, the supraphysiological concentrations of resveratrol required to increase human SIRT1 activity were considerably higher than concentrations that have been measured in human plasma after oral consumption. Based on a lack of correlation with baseline inflammatory markers, cardiovascular disease and cancer incidence, and all-cause mortality, the authors concluded that higher versus lower quartiles of urinary resveratrol metabolite concentrations did not predict risk of chronic disease or mortality.

However, key experts identified several limitations regarding the quality of the research , Specifically, the use of single measures of total urinary resveratrol metabolites at baseline has been highlighted as being unlikely to reflect lifetime consumption of wine or exposure to dietary resveratrol Similar to the effect of caloric restriction, resveratrol was found to improve obesity and diabetes -related metabolic deregulations via the activation of metabolic sensors, including SIRT and the AMP-activated protein kinase AMPK , as well as to promote the AMPK-dependent clearance of β-amyloid peptide in the brain of an AD mouse model Resveratrol has also exhibited additional neuroprotective properties in cultured cells and animal models see Biological Activities.

Although resveratrol bioavailability to the brain is uncertain 78 , a randomized , double-blind , placebo -controlled study has reported an increase in cerebral blood flow in the prefrontal cortex of healthy young subjects ages, years following a single oral dose of mg of resveratrol.

However, resveratrol intake did not improve performance in cognitively demanding tasks undertaken during the post-administration period Additional evidence of the potential of resveratrol to mimic the metabolic benefits of caloric restriction on cognitive health may come from ongoing clinical trials in both healthy older individuals and AD patients More than one out of three American adults has impaired glucose tolerance also known as prediabetes , which places them at increased risk of developing type 2 diabetes Impaired glucose tolerance is associated with insulin resistance in skeletal muscle — the major peripheral tissue for insulin -mediated glucose uptake — as well as defective insulin secretion by pancreatic β-cells.

Muscle insulin resistance, which is thought to be the earliest stage in the development of type 2 diabetes, is characterized by excess lipid exposure, impaired insulin receptor signaling , impaired glucose uptake, mitochondrial dysfunction, reduced fatty acid oxidation , and increased expression of pro-inflammatory cytokines.

In humans, short-term supplementation with resveratrol has been associated with beneficial effects on glucose and lipid metabolism in individuals with type 2 diabetes.

Comparison of changes between baseline and end-of-study measures between placebo and intervention groups showed that resveratrol significantly lowered both fasting glucose and fasting insulin concentrations and improved measures of glycemic control HbA1c level and insulin sensitivity HOMA-IR.

In addition, the level of HDL -cholesterol was increased while the level of LDL -cholesterol and systolic blood pressure were significantly reduced. No changes were found in measures of diastolic blood pressure , total cholesterol , triglycerides , and markers of liver function During the three-month study period, changes in biochemical and clinical parameters, including fasting glucose concentration, HbA1c level, systolic and diastolic blood pressure, total cholesterol, and LDL-cholesterol, were significantly improved with resveratrol compared to control i.

A few clinical studies have evaluated the effects of resveratrol on key metabolic variables in overweight or obese subjects with no overt metabolic dysfunction and found little or no metabolic benefits following resveratrol treatment Yet, at present, there is no available evidence to suggest whether overweight or obese individuals with impaired glucose tolerance could benefit from resveratrol supplements and reduce their risk of developing type 2 diabetes Current data suggest that resveratrol could improve specific metabolic variables in individuals with type 2 diabetes , , but more research is needed to assess its effect in individuals at risk for diabetes, including obese subjects with impaired glucose tolerance.

Resveratrol is found in grapes, wine, grape juice, peanuts, cocoa, and berries of Vaccinium species, including blueberries, bilberries, and cranberries In grapes, resveratrol is found only in the skins The amount of resveratrol in grape skins varies with the grape cultivar, its geographic origin, and exposure to fungal infection The amount of fermentation time a wine spends in contact with grape skins is also an important determinant of its resveratrol content.

Because grape skins are removed early during the production process of white and rosé wines, these wines generally contain less resveratrol than red wines 4. Therefore, because of variations between types of wine, vintages, and regions, it is very difficult to provide accurate estimates of resveratrol content in the thousands of wines from worldwide wineries.

Yet, it appears that resveratrol content in wine is usually low, highly variable and unpredictable, and resveratrol is only a minor compound in the complete set of grape and wine polyphenols The predominant form of resveratrol in grapes and grape juice is trans -resveratrolO-β-glucoside trans -piceid , and wines contain significant amounts of resveratrol aglycones, thought to be the result of sugar cleavage during fermentation 3 , Many wines also contain significant amounts of cis -resveratrol see Figure 1 above , which may be produced during fermentation or released from viniferins resveratrol polymers Red wine is a relatively rich source of resveratrol, but other polyphenols are present in red wine at considerably higher concentrations than resveratrol see the article on Flavonoids Estimates of resveratrol content of some beverages and foods are listed in Table 1 and Table 2.

These values should be considered approximate since the resveratrol content of foods and beverages can vary considerably. Most resveratrol supplements available in the US contain extracts of the root of Polygonum cuspidatum , also known as Fallopia japonica , Japanese knotweed, or Hu Zhang Red wine extracts and grape extracts from Vitis vinifera containing resveratrol and other polyphenols are also available as dietary supplements.

Resveratrol supplements may contain anywhere from less than 1 milligram mg to mg of resveratrol per tablet or capsule, but it is not known whether there is a safe and effective dosage for chronic disease prevention in humans also see the section on Safety. Resveratrol is not known to be toxic or cause significant adverse effects in humans, but there have been only a few controlled clinical trials to date reviewed in A trial evaluating the safety of oral trans -resveratrol in 10 subjects found that a single dose of 5, mg resulted in no serious adverse effects Mild diarrhea was also reported in six out of eight individuals who consumed 2, mg of resveratrol twice daily for two periods of eight days in an open-label and within subject-control study The safety of resveratrol-containing supplements during pregnancy and lactation has not been established Because there is no known safe amount of alcohol consumption at any stage of pregnancy , pregnant women should avoid consuming wine as a source of resveratrol.

Until more is known about the estrogenic activity of resveratrol in humans, women with a history of estrogen-sensitive cancers , such as breast, ovarian, and uterine cancers, should avoid resveratrol supplements see Estrogenic and anti-estrogenic activities Resveratrol has been found to inhibit human platelet aggregation in vitro 53 , Theoretically, high intakes of resveratrol i.

Cytochrome P CYP enzymes are phase I biotransformation enzymes involved in the metabolism of a broad range of compounds, from endogenous molecules to therapeutic agents. The most abundant CYP isoform in the human liver and intestines is cytochrome P 3A4 CYP3A4 , which catalyzes the metabolism of about half of all marketed drugs in the US Resveratrol has been reported to inhibit CYP3A4 activity in vitro , and in healthy volunteers Therefore, high intakes of resveratrol i.

Some of the many drugs metabolized by CYP3A4 include HMG-CoA reductase inhibitors statins , calcium channel antagonists felodipine, nicardipine, nifedipine, nisoldipine, nitrendipine, nimodipine, and verapamil , anti-arrhythmic agents amiodarone , HIV protease inhibitors saquinavir , immunosuppressants cyclosporine and tacrolimus , antihistamines terfenadine , benzodiazepines midazolam and triazolam , and drugs used to treat erectile dysfunction sildenafil.

Of note, a recently completed clinical trial NCT examined the potential for single and multiple doses of resveratrol 1, mg to interfere with the metabolism of midazolam in healthy volunteers, and results are soon to be published Other CYP enzymes e.

Finally, resveratrol was found to be a weak inducer of the expression and activity of CYP1A2, which catalyzes the metabolism of several drugs, including acetaminophen paracetamol and the antidepressant drugs, clomipramine and imipramine 28 , This suggests that resveratrol may interfere with CYP1A2-mediated drug metabolism by increasing drug clearance, possibly lowering circulating drug concentrations below therapeutic levels.

Originally written in by: Jane Higdon, Ph. Linus Pauling Institute Oregon State University. Updated in May by: Victoria J.

Drake, Ph. Updated in May by: Barbara Delage, Ph. Reviewed in May by: Juan Carlos Espín, Ph. Soleas GJ, Diamandis EP, Goldberg DM. Resveratrol: a molecule whose time has come? And gone? Clin Biochem. Aggarwal BB, Bhardwaj A, Aggarwal RS, Seeram NP, Shishodia S, Takada Y.

Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res. Romero-Perez AI, Ibern-Gomez M, Lamuela-Raventos RM, de La Torre-Boronat MC. Piceid, the major resveratrol derivative in grape juices. J Agric Food Chem. Siemann EH, Creasey LL. Concentration of the phytoalexin resveratrol in wine.

Am J Enol Vitic. Renaud S, de Lorgeril M. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Walle T. Bioavailability of resveratrol. Ann N Y Acad Sci. Burkon A, Somoza V. Mol Nutr Food Res. Goldberg DM, Yan J, Soleas GJ. Absorption of three wine-related polyphenols in three different matrices by healthy subjects.

Walle T, Hsieh F, Delegge MH, Oatis JE, Jr. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos. Boocock DJ, Faust GE, Patel KR, et al. Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent.

Cancer Epidemiol Biomarkers Prev. Brown VA, Patel KR, Viskaduraki M, et al. Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis.

Cancer Res. Patel KR, Andreadi C, Britton RG, et al. Sulfate metabolites provide an intracellular pool for resveratrol generation and induce autophagy with senescence.

Sci Transl Med. Tome-Carneiro J, Larrosa M, Gonzalez-Sarrias A, Tomas-Barberan FA, Garcia-Conesa MT, Espin JC. Resveratrol and clinical trials: the crossroad from in vitro studies to human evidence. Curr Pharm Des. Vitaglione P, Sforza S, Galaverna G, et al.

Bioavailability of trans-resveratrol from red wine in humans. Vaz-da-Silva M, Loureiro AI, Falcao A, et al. Effect of food on the pharmacokinetic profile of trans-resveratrol. Int J Clin Pharmacol Ther.

la Porte C, Voduc N, Zhang G, et al. Steady-State pharmacokinetics and tolerability of trans-resveratrol mg twice daily with food, quercetin and alcohol ethanol in healthy human subjects.

Clin Pharmacokinet. Leonard SS, Xia C, Jiang BH, et al. Resveratrol scavenges reactive oxygen species and effects radical-induced cellular responses. Biochem Biophys Res Commun. Vlachogianni IC, Fragopoulou E, Kostakis IK, Antonopoulou S.

In vitro assessment of antioxidant activity of tyrosol, resveratrol and their acetylated derivatives. Food Chem. Brito P, Almeida LM, Dinis TC.

The interaction of resveratrol with ferrylmyoglobin and peroxynitrite; protection against LDL oxidation. Free Radic Res. Frankel EN, Waterhouse AL, Kinsella JE. Inhibition of human LDL oxidation by resveratrol.

Thank Eating behaviors and sport performance for visiting nature. Resvetatrol are using a browser version enhancemejt limited support Resveratrkl CSS. Cramp relief stretches obtain the best Psychological tactics for dietary adherence, we recommend you use a more up Cramp relief stretches date browser or turn off compatibility mode Resveratro, Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Greatly waned neurogenesis, diminished microvasculature, astrocyte hypertrophy and activated microglia are among the most conspicuous structural changes in the aged hippocampus. Because these alterations can contribute to age-related memory and mood impairments, strategies efficacious for mitigating these changes may preserve cognitive and mood function in old age. Resveratrol, a phytoalexin found in the skin of red grapes having angiogenic and antiinflammatory properties, appears ideal for easing these age-related changes. Resveratrol 3,4',5-trihydroxystilbene belongs to a class of mood compounds called Psychological tactics for dietary adherence 1. Allergy-safe sports performance plants produce resveratrol and other stilbenoids enhanncement response to Psychological tactics for dietary adherence, injury, fungal Resverarol, or ultraviolet UV radiation 2. Moos is a fat-soluble compound that occurs in both trans and cis molecular configurations Figure 1. Both cis - and trans -resveratrol also occur as glucosidesi. One major resveratrol derivative is resveratrolO-β-glucoside, also called piceid Figure 1 3. Since the early s, when the presence of resveratrol in red wine was established 4the scientific community has been exploring the effects of resveratrol on health.

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