This loss of brain volume, measured by brain imaging, may be due to a reduction in inflammation but it is usually indicative of degeneration.

Based on this trial, it is unclear whether resveratrol will help or harm patients in the long term. Several small clinical trials report no serious side effects for daily doses of resveratrol between 20 mg and 2 g. In a clinical trial of Alzheimer's patients, one year of use starting at mg and going up to 2 g per day was reported to be safe and well-tolerated [14].

However, there is no reliable information on the safety of long-term use of high doses [15]. Other trials did report diarrhea or gastrointestinal discomfort at doses above 1 g per day [15].

One trial reported moderately serious side effects from 1 g per day in postmenopausal women, including liver enzyme changes and severe skin rash [16]. And yet another trial reported serious risk of kidney failure with resveratrol plus standard medical treatment for multiple myeloma cancer patients [17] , though again most small clinical trials have not reported serious side effects [9].

Resveratrol may interact in dangerous ways with common drugs such as blood thinners, anti-inflammatory drugs, and anti-hypertensive drugs [18].

NOTE: This is not a comprehensive safety evaluation or complete list of potentially harmful drug interactions. It is important to discuss safety issues with your physician before taking any new supplement or medication.

The highest concentration of dietary resveratrol is found in the skin of red grapes. One 5-ounce glass of red wine contains around µg of resveratrol.

It would take approximately 20 bottles of red wine a day to equal the level of resveratrol used in even the lowest-dose clinical trials. To achieve any potential benefit, a high dose of resveratrol would likely be necessary, but long-term use of such high doses has not been studied.

Daily doses between 20 mg and 2 g have been used in short clinical trials, with gastrointestinal side effects more common above 1 g per day [15] [19]. Download full scientific report. AlzForum reports on resveratrol research: "Dietary Resveratrol Makes Little Difference to Health" "Resveratrol Improves Memory in Overweight Adults".

Potential Benefit. For Dementia Patients Evidence regarding resveratrol's impacts for dementia patients is mixed. Download full scientific report AlzForum reports on resveratrol research: "Dietary Resveratrol Makes Little Difference to Health" "Resveratrol Improves Memory in Overweight Adults".

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Sahebkar A, Serban C, Ursoniu S et al. International journal of cardiology , 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 In brief, microscopic images from different regions of the hippocampus were digitized using 20× objective lens in a Nikon E microscope equipped with a digital video camera connected to a computer.

The overall morphology of microglia were compared between RESV and VEH treated groups by measuring processes of randomly selected but well stained OX microglial cells from both groups.

These measurements were made using a semiautomatic neuron tracing system Neurolucida; Microbrightfield linked to a Nikon microscope. To measure the extent of process growth away from the soma and the branching of processes at different distances from the soma, the concentric circle analysis of Sholl was performed using NeuroExplorer component of the Neurolucida program.

A semiautomatic tracing system Neurolucida, Microbrightfield linked to a Nikon microscope was employed for these measurements. All statistical analyses were done using Prism software.

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Hippocampus 21, — Aging Cell 7, — Download references. This study was supported by grants from the National Institutes of Health National Center for Complementary and Alternative Medicine R21 award, AT to AKS , State of Texas Emerging Technology Funds to AKS and Department of Veterans Affairs VA Merit Award to AKS.

Present address: Department of Radiation Oncology, Univ California Irvine,. Research Service, Olin E. Teague Veterans Affairs Medical Center, Central Texas Veterans Health Care System, Temple, Texas, USA. Department of Surgery Neurosurgery and Research Service, Duke University and Veterans' Affairs Medical Centers, Durham, North Carolina, USA.

Vipan K. You can also search for this author in PubMed Google Scholar. and V. contributed equally to this work. performed statistical analyses of behavioral tests, stereological cell counts, immunohistochemistry, J imaging and Neurolucida tracing to quantify cognitive and mood function, hippocampus neurogenesis, microvasculature and microglia, prepared figure composites and the first version of the manuscript text.

performed water maze and forced swim tests, administration of resveratrol, initial analyses of behavioral data and some experiments for neuronal differentiation of newly born cells. contributed to the experimental design, analyses and interpretation of behavioral data, analyses of neuronal differentiation of newly born cells using confocal microscopy, immunohistochemistry, photomicrography and preparation of composite figures.

performed GFAP immunohistochemistry, J Imaging of astrocytes and the associated statistical analyses.

performed animal perfusions, tissue processing, cryostat sectioning, histology and BrdU and DCX immunohistochemistry. conceived the study, conceptualized the research design, interpreted all behavioral and immunohistochemical results and prepared the final version of manuscript text and figures.

All authors gave input to the manuscript text and approved the final version of the manuscript. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material.

Reprints and permissions. Kodali, M. Resveratrol Prevents Age-Related Memory and Mood Dysfunction with Increased Hippocampal Neurogenesis and Microvasculature and Reduced Glial Activation.

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