What could be more important for memory?

Resveratrol May Enhance Neurogenesis
And benefit a spectrum of highly prevalent diseases

By Will Block

Among the most important tasks of neuroscience is the search for molecules capable of restoring hippocampal plasticity. That’s because debilitating conditions such as highly prevalent Alzheimer’s disease, depression, anxiety, stroke, diabetes, and chemotherapy-induced cognitive impairment, can be improved by nutraceuticals that enhance neural plasticity. This benefit refers to the ability of the nervous system to adaptively respond to changes in the environment. While neural plasticity is improved by stimuli such as an enriched environment and increased physical activity, it is also bolstered by certain pharmaceuticals and nutrients.

The Need for Generating New Functional Neurons

Enhancement is especially important for psychiatric and neurological conditions where it is well established that neural plasticity, such as the ability of the postnatal hippocampus to continuously generate newly functional neurons throughout life. This process, called adult hippocampal neurogenesis (AHN), can be modulated not only by pharmacological agents, physical exercise, and environmental enrichment, but also by “nutraceutical” agents.

Neurogenesis is the creation of new neurons from neural stem or progenitor cells in the brain. Until recently, it was considered that the number of neurons was fixed and that they did not replicate after maturity of the brain. It wasn’t until the 1990’s that neurogenesis was observed in the brains of humans, other primates, and a number of other species that led to its widespread scientific acceptance.

Does Resveratrol Exceed It’s Known Benefits?

In a new review researchers focused on resveratrol (RES), a phenol and phytoalexin found in the skin of grapes and red berries, as well as in nuts. Resveratrol has been reported to have antioxidant and antitumor properties, but its effects as a neural plasticity-inducer are still not clear.

The new review examines recent evidence implicating resveratrol in regulating hippocampal neural plasticity and in mitigating the effects of various disorders and diseases on this important brain structure. Overall, findings show that RES can improve cognition and mood and enhance hippocampal plasticity and AHN. However, some studies report opposite effects, with RES inhibiting aspects of AHN. Therefore, while resveratrol use is safe, further investigation is needed to resolve these controversies before RES can be established as a coadjuvant in preventing and treating neuropsychiatric conditions.

The researchers examined the role of nutrition and especially resveratrol as a potential enhancer of AHN. A number of studies have shown that total calorie intake, as well as meal frequency, texture, and content are able to alter AHN. A growing number of reports point to polyphenols—compounds widely found in certain fruits, spices, and tea leaves—as capable of inducing important antioxidant responses in the brain, as well as protecting or enhancing AHN levels.

Remember that RES is a polyphenol and thought to exert part of its actions through the activation of the histone deacetylase enzyme sirtuin 1. Also, its neuroprotective effects appear to be mediated by an increase in the activation of AMP-activated kinase, leading to neurite outgrowth and stimulation of mitochondrial biogenesis. RES’s antioxidant, anti-inflammatory, and antitumor activities are well documented.

Increased Lifespan, Too

RES is also known for its ability to promote increased lifespan, similar to the effects exerted by caloric restriction. However, with regard to AHN enhancement, studies show opposing and contradictory results, and therefore it is still vigorously argued whether RES can be considered a proplasticity-inducer in the context of AHN.

Bibliographic Search

A bibliographical search was carried out in Medline/PubMed and Web of Science/ISI collected studies about RES, hippocampal neurogenesis, and hippocampal plasticity. Original papers published in English from 2000 to 2015 directly assessing hippocampal neurogenesis or other hippocampal plasticity markers accompanied by treatment with RES were selected.


Resveratrol is also known for its
ability to promote increased lifespan,
similar to the effects exerted by
caloric restriction.


Eleven articles adhering to those criteria were identified, both in vivo and in vitro. Seven papers that did not appear in the original search-engine results were further identified manually to comply with the inclusion criteria, and were added to the selected literature.

Resveratrol and Stress

Stress has been widely attributed to depression. Rodents submitted to unpredictable chronic mild stress (UCMS) display depressive-related phenotypes, including reduced consumption of sucrose, increased immobility time in the forced swimming test (FST), impairment of coat state and of hippocampal-dependent learning.

Interestingly, the behavioral changes triggered by exposition to stressful events are often followed by a number of hippocampal alterations, including reduced levels of AHN and brain-derived neurotrophic factor (BDNF). RES can exert antidepressant effects and restore the hippocampal plasticity markers found to be decreased in stress-induced models of depression. For instance, intraperitoneal injections of RES (mainly at 80 mg/kg) had similar effects to those of the antidepressant desipramine, both in normalizing behavior and serum corticosterone levels in rats exposed to UCMS for 5 weeks. The review also revealed that RES could restore the levels of BDNF and other aspects of neuronal plasticity, and an element-binding protein involved in enhancing the transcription of the BDNF gene.

Similarly, the same regimen of RES prevented the cognitive deficits caused by UCMS in the Morris water maze (MWM) and in the novel object recognition task, also accompanied by restoration of pERK, and pCREB levels, in addition to BDNF. In another report, RES at a dose of just 20mg/kg prevented UCMS-induced cognitive impairments in the MWM, and also in the passive-avoidance test, a test designed to assess emotional memory.

Restored Levels of Hippocampal BDNF

The neuroprotective effects of RES against the deficits induced by UCMS were proposed to be mediated by restored levels of hippocampal BDNF. Furthermore, the reduction in c-Fos protein expression following UCMS was prevented by RES, suggesting that the effects of this polyphenol can include changes in target gene expression. Furthermore, the study reports anti-inflammatory effects of RES, in that it normalized the UCMS-induced higher circulating levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β).


Resveratrol could contribute to
preserving neurogenesis and,
therefore, protecting
cognitive function.


Considering the detrimental effects of both TNF-α and IL-1β over parameters of hippocampal neurogenesis, it is plausible to reason that, by decreasing the levels of these proinflammatory cytokines, RES could contribute to preserving neurogenesis and, therefore, protecting cognitive function. Also in the context of inflammation, another study showed that RES could prevent the decrease in antioxidant defenses and the increase in inflammatory responses (as measured by the levels of TNF-α and IL-1β) in hippocampal astrocyte cultures of adult and aged Wistar rats. Although the study did not investigate parameters of hippocampal neurogenesis, it is well known that astrocytes play an important role in the regulation of a number of neural plasticity events, including neurogenesis.

Therefore, a potential protection of AHN by RES through astrocytic regulation should not be discarded. Besides UCMS, another way to induce depressive-like behaviors in rodents is by repeated administration of corticosterone (CORT).

In the context of stress, a study investigated the potential neuroprotective effects of RES (10 mg/kg body weight) orally administered throughout pregnancy in the offspring of female rats subjected to restraint stress in either the early or late gestational periods. The study demonstrated that prenatal administration of RES was neuroprotective for the offspring at postnatal day 40 from the deleterious effects of prenatal stress on anxiety (as measured in the open field test) and on cognitive function (as assessed in the MWM).


Astrocytes play an important role in
the regulation of a number of neural
plasticity events, including
neurogenesis.


Considering the involvement of the hippocampus in both anxiety and cognitive regulation, it is of great interest to further investigate hippocampal-related plasticity markers in a similar experimental design, and a subsequent study attempted to address this issue. Using the same prenatal stress and RES regimen, the authors found that this polyphenol was able to improve the number of doublecortin (DCX) neurons in the dentate gyrus (DG), as well as hippocampal BDNF expression, of PND40 pups whose dams have been exposed to prenatal stress. Interestingly, it is not only in stress-induced models of dysfunctional phenotypes that RES has been shown to exert positive effects.

In Wistar-Kyoto rats, an inbred strain of rodents that displays depressive-like behavior even in the absence of aversive stimuli, RES intraperitoneally administered acutely for 7 days reduced immobility time in the FST. The chronic regimen, at two doses, also increased sucrose intake. Interestingly, at one-week posttreatment, behavioral effects could no longer be observed, suggesting that sustained consumption of RES might be necessary for antidepressant effects. With regard to plasticity markers, following 7 days of RES treatment, BDNF has been found to be increased in the hippocampus, an effect not observed in other brain areas involved in the neurobiology of depression, such as the frontal cortex.

RES and Ethanol-Induced Toxicity

Ethanol exposure in utero is well-recognized as an important risk factor in abnormal brain development and function. Indeed, a number of adverse outcomes at the cognitive, physical, and behavioral levels have been described as a result of prenatal ethanol exposure, giving rise to a continuum of conditions known as Fetal Alcohol Spectrum Disorders (FASD).

The detrimental effects of alcohol to the brain and hippocampal plasticity are not restricted to exposure during the prenatal period. In the rat DG, for instance, ethanol administered at the end of the first postnatal week was capable of significantly reducing the pool of neural stem cells (NSCs) and neural progenitor cells (NPCs), a finding that may have subsequent consequences for AHN. In order to investigate the role of RES in protecting the neonatal hippocampus against the deleterious effects of ethanol, a recent report of pretreated C57/BL6 mice at age postnatal day 6 with RES (20 mg/kg), subsequently exposing them to 20% ethanol (total of 5 g/kg) at postnatal day 7.

The study investigated a number of hippocampal neurogenesis markers, as well as other aspects of neural plasticity. For instance, using bromodeoxyuridine (BrdU) to detect proliferating cells in living tissues at postnatal day 8, it was found that RES could protect the neonatal DG, reversing the ethanol-induced reduction in cell proliferation.

Neuroprotective effects of RES were also observed with regard to lessening the decreased pool of hippocampal neural precursor cells, as shown by the number of glial fibrillary acidic protein, and brain lipid-binding protein cells in the DG. RES was also found to reverse the anti-neurogenic effects of ethanol at postnatal day 14, as measured by the number of cells expressing both BrdU and DCX. Also, pretreatment with this polyphenol could promote the reversal of the reduced spine density of granule neurons in mice also exposed to ethanol. In fact, not only was the density of spines augmented as a result of RES treatment prior to ethanol exposure, but the proportion of more mature, mushroom shaped spines was also found to be higher in RES-treated groups.


BDNF has been found to be increased
in the hippocampus, an effect not
observed in other brain areas
involved in the neurobiology of
depression, such as the frontal cortex.


Hippocampal levels of proteins involved in the proliferation, maintenance, and fate determination of NPCs, such as pERK, Hes 1 (hairy and enhancer of split-1), and Sirt1, were also verified to be increased in the RES + Ethanol group. Interestingly, the findings of RES treatment in vivo on cell proliferation were also consistent with those of in vitro assays.

Using NPC cells, the same study reported that pretreatment with RES could lessen the detrimental effects of ethanol on the number of Ki-67+ cells, a cellular marker for proliferation, as well as reducing apoptosis and preventing the cell cycle arrest mediated by ethanol exposure.

Resveratrol and Chronic Fatigue

Another condition whose pathophysiology has been found to include hippocampal abnormalities is chronic fatigue syndrome (CFS). For instance, reduced levels of N-acetylaspartate, a marker of neuronal metabolism, were found in the right hippocampus of CFS patients. Other lines of evidence linking the hippocampus and CFS come from studies reporting a particular reduction in serotonin 5-HT1A receptor binding potential in this brain structure in these individuals, as well as a significant increase in blood oxygen level dependent (BOLD) activity in brain regions including the hippocampus of CFS subjects during a fatiguing cognitive task.

In the context of RES, another study found that daily doses of orally administered RES (40mg/kg) for 4 weeks could rescue the decreased daily activity of an animal model of CSF. At the hippocampal level, this behavioral effect was accompanied by an increase in cell proliferation in the DG, as measured by BrdU labeling, and a decrease in the levels of apoptosis, as measured by a labeling assay in the DG.


In stroke, quiescent NSCs can
become active, a phenomenon that is
being actively investigated in the field
of neural repair and regeneration.


Resveratrol and Stroke

In stroke, quiescent NSCs can become active, a phenomenon that is being actively investigated in the field of neural repair and regeneration. Also, in stroke, RES has emerged as a potential plasticity inducer, with evidence pointing to an antiapoptotic action in hippocampal neurons after focal cerebral ischemia in rats, and by attenuation of the cerebral ischemic injury through upregulation of transcription factor nuclear factor erythroid 2-related factor 2 (Nrf-2) and enzyme heme oxygenase 1 implicated in oxidative stress responses.

With regard to hippocampal neurogenesis, in an in vitro model of stroke using oxygen-glucose deprivation/ reoxygenation, pretreatment with RES was able to increase NSCs survival and proliferation. Furthermore, RES administered prior to the insult was associated with upregulation of protein patched homolog 1, smoothened and Gli-1 proteins, and mRNA, indicating that RES effects in this condition were mediated by sonic hedgehog signaling (a signaling pathway that transmits information to embryonic cells required for proper development).

Another recent study analyzed the rat hippocampus following global cerebral ischemia and previous treatment with RES. The authors found that RES (at 1 and 10 mg/kg) could protect CA1 neurons found in the hippocampus from the ischemic insult at both 7 and 85 days after surgery.

This latter finding deserves special attention, considering the association between local angiogenesis and normal levels of AHN. Specifically, with regard to AHN, another study found that RES treatment prior to the global cerebral ischemia was associated with reduced number of DCX-PSA-NCAM colabeling cells at both doses and intervals studied. According to the authors, one possible explanation for this intriguing finding is that RES can decrease microglia and astrocyte activation 7 days after the ischemic insult, which can therefore inhibit glial released trophic factor-induced neurogenesis.

However, despite the reduction in AHN, increased swimming time in the target quadrant during the probe trial of the MWM was found in RES-treated ischemic rats.

Some of the most interesting findings relating RES to hippocampal plasticity within the context of ischemia come from measures of post-stroke depression. A recent study showed that oral administration of RES (20 and 40 mg/kg) was able to significantly reduce the infarction volume of the brain 22 hours following middle cerebral artery occlusion and exerted antidepressant effects 13 days after insult.

The noted antidepressant effects included increased sucrose preference and decreased immobility time in the FST to levels comparable to those elicited by the antidepressant imipramine. At the hippocampal level, the authors found that the aforementioned doses of RES decreased the levels of corticotropin-releasing factor (CRF) as well as increased the expression of glucocorticoid receptors (GR), both measures indicating normalized activation of the hypothalamic-pituitary-adrenal (HPA) axis. Moreover, hippocampal levels of BDNF protein were increased in the rats treated with RES.

Resveratrol and Diabetes

Due to its association with cognitive deficits, the link between diabetes and hippocampal changes has received growing attention in the past few years.

Patients with type-2 diabetes (T2D) exhibit cognitive deficits, which are associated with changes in left hippocampal metabolism. Animal models of diabetes also display a number of hippocampal changes such as synaptic integrity loss, as measured by a decrease in the levels of postsynaptic density protein 95 and synaptosomal-associated protein 25 in the hippocampus of T2D mice.

RES reduces a number of diabetes-induced neurodegenerative markers. One study used the streptozotocin-induced diabetes model and found that the number of degenerative neurons among certain hippocampal neurons was increased, along with astrocytic activation in other hippocampal neurons. All these parameters were significantly restored following oral administration of RES (0.75 mg/kg) 3 times per day for 4 weeks.

Resveratrol Normalizes Hippocampal Neurogenesis Genes

Supporting evidence from another study was found where 6 weeks of RES supplementation (50 mg/kg) in mice resulted in normalization of expression of genes implicated with hippocampal neurogenesis and synaptic plasticity, which had been previously found to be altered as a consequence of the diabetic state.

Resveratrol Protects Cognition from Impaired Glucose Metabolism

Also, reinforcing the idea that RES can potentially protect cognitive function in the context of impaired glucose metabolism, another study used the Senescence-accelerated prone mouse model [SAMP8, a model of glucose hypometabolism characteristic of aging and Alzheimer’s disease (AD)] and showed that RES added to a high-fat diet (HF) for 15 weeks could prevent the behavioral deficits observed in SAMP8 mice subjected to HF. In particular, it was shown that RES could prevent the deleterious effects of HF-induced metabolic stress on the novel object recognition test (NORT) and the probe trial of the MWM. The study also showed that RES could restore mitochondrial function and reduce oxidative stress and parameters of AD, such as Tau hyperphosphorylation. Moreover, the authors showed that in HF-fed SAMP8 mice, RES promoted action of the Wnt pathway, which is known to be important for AHN.

Resveratrol, Aging, and Alzheimer’s

AD is one of the most incapacitating of neuropsychiatric impairments, posing important emotional, social, and financial burdens on patients, caregivers, and society in general. The population shift to a higher proportion of older people means more AD so effective ways to intervene and interrupt its progression are needed. Although the search for effective pharmaceuticals is the basis of this endeavor, nutritional supplementation also arises as a potential coadjuvant for both prevention and treatment of AD.

In order to investigate the potential neuroprotective effects of RES in the context of AD, a recent in vitro study pretreated rat hippocampal neuronal cells with RES (75 mM) for 2 h followed by 24 hours of incubation with Ab (25 mM). RES was able to reduce lipid peroxidation in Ab-treated cells and restore a number of other oxidative damage markers, improving the levels of ascorbic acid, glutathione reductase, superoxide dismutase, among others. Pretreatment with RES was also able to improve the hippocampal levels of various synaptic proteins.

Healthy aging practices could be one of the ways to prevent or delay the onset of AD. Within the context of healthy aging, a recent report showed that a 4-week treatment with RES (40 mg/kg) at the age of 21 months brought a series of beneficial effects at 25 months of age in rats, both at the behavioral and hippocampal levels, in comparison with same-age vehicle-treated rats.

Among the behavioral effects, RES-treated rodents displayed decreased latency to reach the hidden platform of the MWM, as well as having improved memory in the probe trial. Antidepressant effects were also identified, as shown by the decreased floating time in the FST.

These cognition- and mood-related behavioral outcomes were accompanied by improvements in hippocampal plasticity markers, such as increased number of BrdU+ and DCX cells in the SGZ-granule cell layer (GCL), increased net neurogenesis (defined as the number of BrdU+ cells with the percentage of newborn cells also expressing neuronal nuclei protein, NeuN), and enhanced microvasculature, as shown by rat endothelial cell antigen-1 (RECA-1) immunostaining in CA1 and entire hippocampus. Furthermore, the authors demonstrated that the hippocampi of RES-treated aged rats displayed reduced hypertrophy of astrocytes and reduced microglia activation, suggesting that this polyphenol is able to diminish the chronic low-level inflammation found in the aging rat brain. Although the focus of the study was not on dementia, considering the interplay between neuroinflammation and AD, the findings by other scientific researchers suggest that further testing of RES in animal models of AD could be valuable.

Resveratrol and the Healthy Brain

Not many studies have investigated the effects of RES consumptions under nonpathological conditions. This is particularly important, considering the need to better understand under which circumstances this polyphenol could exert beneficial effects to brain health and plasticity.

Resveratrol Increases Cell Proliferation in the Dentate Gyrus

In this regard, dietary supplementation with RES leads to increased cell proliferation in the DG, as well as to an increase in the expression of presenilin 1, a regulator of AHN and also involved in AD pathogenesis. Also of interest to hippocampal plasticity and AHN, the authors found that dietary supplementation with RES was associated with increased expression of the transcriptional repressor Hes 1, involved in stem cell maintenance through the Notch homolog 1 (NOTCH1) signaling pathway.

At the behavioral level, 18-month treatment with RES (200 mg/kg/day) improved working memory in the spontaneous alternation task in nonhuman primates to levels comparable with those of CR-treated animals. In addition, supplementation with RES—but not the CR regimen—led to increased spatial memory in the circular platform task.

Also at the behavioral level, RES (10 and 20 mg/kg, orally administered in conjunction with 2.5mg/kg piperine—an alkaloid that enhances the bioavailability of RES in vivo) exerted antidepressant effects in model mice, as measured by the reduced immobility time in both FST and TST.

As was noted by the researchers, the majority of studies in healthy rodents are descriptive investigations showing possible associations between a certain RES treatment regimen and behavioral and hippocampal changes. In one of the most interesting reports in the RES literature that tried to bridge this gap, the authors reported that oral administration of RES (20 mg/L) once daily for 3 weeks induced insulin-like growth factor 1 production in the hippocampus, increased AHN and angiogenesis, and improved spatial learning and memory in the MWM.

Mice administered either 1 or 10mg/kg RES for two weeks had reduced numbers of both NPCs and newly-generated neurons in the DG of the hippocampus relative to a vehicle-treated control group, in a dose-dependent manner. Furthermore, they also found a reduction in BDNF and pCREB (a cellular transcription factor) in the hippocampus and impaired spatial learning in the MWM of the RES-treated animals relative to controls.

What About Healthy Individuals?

One of the key aspects in any attempt to determine how RES affects hippocampal plasticity relates to the controversial roles of this polyphenol’s receptor, Sirt1. For example, in one study, RES antagonized the detrimental effects of ethanol on NPCs and neurogenesis, a finding accompanied by the rescue of hippocampal levels of markers.

The reviewers point to the involvement of these proteins in the regulation of NPCs; however, Sirt1 signaling negatively regulates neuronal differentiation in the adult hippocampus, with Sirt1 knockdown increasing the neurogenic potential of NPCs in vivo and in vitro.

In their discussion, the authors also claim that previous studies have reported that Sirt1 and Hes 1 interact and repress downstream targets, probably including those involved in inhibiting neuronal differentiation. Similarly, another paper reported increased neurogenesis in the adult hippocampus with Sirt1 knockout mice.

In this same respect, it is worth noting the need for randomized controlled trials investigating the effects of RES supplementation with either capsules or diet on the behaviors and brain functions discussed here.


For the neuropsychiatric conditions
discussed in the review—depression,
anxiety, stroke, diabetes, ethanol
administration, chronic fatigue, and
AD—resveratrol appears to be an
effective agent in promoting
neuroprotection, neurogenesis and
hippocampal plasticity.


Resveratrol Improves Memory in Humans

Addressing this issue, a recent double-blind placebo-controlled study showed that intake of RES capsules for 26 weeks (200 mg per day) improved memory (retention of words) and enhanced hippocampal functional connectivity in healthy overweight older individuals. It will be interesting to see in the future if these encouraging results could also be observed in other age and body mass index populations, especially considering that another recent randomized double-blind placebo-controlled study found that, when administered in conjunction with piperine, RES can augment cerebral blood flow in young healthy adults.

Resveratrol and Cerebral Blood Flow in Young Healthy Adults

Nevertheless, the study failed to demonstrate that RES could improve mood and cognition in this population. These negative results could be due to the relatively short regimen applied: only three doses of RES (250 mg) at least a week apart.

Also concerning the use of RES by humans, a recent report showed that a single dose of this polyphenol (500 mg tablet taken orally by healthy adults) was able to promote relevant pharmacological activities comparable to those reported by in vitro studies. It was also promising that the study revealed that besides being well absorbed, RES was also well tolerated by all participants.

Another useful line of investigation for the field of RES and neural plasticity could be to examine if this polyphenol administered in conjunction with other beneficial strategies (such as CR, physical exercise, EE, and even other polyphenols) could exert synergistic effects capable of amplifying the potential enhancement of hippocampal plasticity observed in most of the RES studies.

In conclusion, for the neuropsychiatric conditions discussed in the review—depression, anxiety, stroke, diabetes, ethanol administration, chronic fatigue, and AD—RES appears to be, at least in rodents, an effective agent in promoting neuroprotection and hippocampal plasticity, including aspects of AHN.

Reference
  1. Dias GP, Cocks G, do Nascimento Bevilaqua MC, Nardi AE, Thuret S. Resveratrol: A Potential Hippocampal Plasticity Enhancer. Oxid Med Cell Longev. 2016;2016:9651236. doi: 10.1155/2016/9651236. Epub 2016 May 25. Review. PubMed PMID: 27313836; PubMed Central PMCID: PMC4897722.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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