An all-purpose health benefactor . . . perhaps no other nutrient hits so many targets

Resveratrol Elevates
Memory and Cognition

A new study has found that resveratrol can improve memory
in diabetics by decreasing the activity of acetylcholinesterase
By Will Block


Japanese knotweed crowds out other species by virtue of survival advantages offered by resveratrol.

eality is often stranger than fiction. Did you know that resveratrol—that exceedingly bright star of the nutritional world—is actually a natural antibiotic (a phytoalexin) produced by certain plants when under attack by pathogens such as bacteria or fungi? Although it can be made by chemical synthesis and is found in grapes and red wine, the resveratrol you typically find in a nutritional supplement is derived from Japanese knotweed (Polygonum cuspidatum). Curiously, in the United States and Europe, Japanese knotweed is widely considered one of the worst of invasive exotic species. It can completely crowd out any other herbaceous species. How does this conquistador plant achieve the upper hand? By virtue of its ability to produce resveratrol. But surviving at the expense of others (plants), is not a model for human behavior. Strangely, though, we are its beneficiaries . . . and more so every day.

Able to tolerate a wide range of soil types, pH, and salinity as well as stay alive under extreme weather conditions, the Japanese knotweed survives and thrives. This adaptive behavior is reflected in resveratrol’s universality with regard to diverse established biological activities—such as its use as an antioxidant, anti-inflammatory, cardioprotector, and anticarcinogenic agent.1-2 Its “street-wise” toughness, garnered from its role in the plant kingdom, undoubtedly helps to explain the large array of treatment findings attributed to it—including life extension (it has extended the lifespan of yeast, fruit flies, short-lived fish, and mice), cancer prevention, enhanced athletic performance (it has increased the athletic aerobic time to exhaustion in mice by a factor of two), radiation protection, and neurodegenerative disease.*


*See “The Universal Cause of Aging” in the February issue, “Resveratrol Combats Age-Related Diseases” in the September 2008 issue, “Promoting Survival with Resveratrol” in the May 2008 issue, “Resveratrol Mimics Caloric Restriction” in the April 2008 issue, and “Resveratrol Boosts Strength and Endurance in Mice” in the February 2007 issue.


Resveratrol for Neuroprotective Benefits

Recent studies have revealed resveratrol’s neuroprotective effects and its value for the central nervous system (CNS), including its ability to boost memory and cognition. These studies demonstrate that this compound can lessen amyloid-β peptide-induced toxicity,3-4 protect against cerebral ischemic injury,5-6 and shield neurons from induced excitotoxicity.7 Several neuroprotective properties of resveratrol have been attributed to its potent antioxidant activity that in many studies has been shown to protect the neural tissue against a variety of neurodegenerative conditions caused by oxidative stress.8-11 And now, a new study has found that resveratrol can improve memory in diabetics by decreasing the activity of acetylcholinesterase (AChE), thereby boosting cholinergic memory function while enhancing cognition.12 AChE is an enzyme that degrades acetylcholine, albeit sometimes too rapidly before it is wisely “spent” in your brain.

Diabetes is Thought to Cause Memory Loss

It has been known for some time that diabetes mellitus is associated with cognitive dysfunction and that it causes the CNS to undergo a series of neurochemical, neurophysiological, and structural abnormalities, producing a condition called diabetic encephalopathy. In addition, cognitive function impairments have been noted in diabetic patients as well as animal models for the disease. These impairments are characterized by moderate deficits in learning and memory, psychomotor slowing such as reduced eye-hand coordination, and loss of mental flexibility. Last, but not least, diabetes appears to double the probability of developing Alzheimer’s disease and other dementias.

The mechanisms of brain damage in diabetes are not fully understood, but at this time these are thought to involve changes in the blood glucose level, along with metabolic and vascular disruption (such as reduced cerebral blood flow), and cellular calcium homeostasis dysfunction. As well, hyperglycemia induces oxidative stress in various brain regions, altering enzymes activities considered crucial for normal CNS functioning. A few studies using experimental diabetes have found an increase in AChE activity, which can alter cholinergic function and thus be associated to cognitive impairments observed in diabetes.12

The Rationale Behind the New Resveratrol Study

Cholinergic neurons and their protrusions are vastly distributed in the CNS, where they evolved to help regulate many vital functions. These include not only memory and learning, but movement and cerebral blood flow control. The enzyme AChE has been found to be one of the most important mechanisms for correct cholinergic function, through its ability to hydrolyse the neurotransmitter acetylcholine in cholinergic synapses and neuromuscular junctions. Interestingly, AChE responds to oxidative stress, which is related to a variety of CNS disorders, such as stroke, Alzheimer’s disease, and diabetes mellitus.

Considering that diabetes affects memory and cognitive function and that resveratrol has important neuroprotective actions, the researchers decided to investigate the effects of resveratrol on learning and memory and on the activity of AChE in the brain and blood of diabetes-induced rats in order to explore and verify resveratrol’s actions and effects on the cholinergic system.

Memory Impairment Prevented

In the research—conducted at Federal University of Santa Maria in Brazil—the animals were divided into six groups (six to thirteen rats per group), three of which were controls given saline (control/saline), resveratrol at 10 mg/kg of body weight (control/Res-10), and resveratrol at 20 mg/kg of body weight (control/Res-20), respectively. The other three groups were initially streptozotocin-induced to become diabetic and then given saline (diabetic/saline), resveratrol at 10 mg/kg of body weight (diabetic/Res-10), and resveratrol at 20 mg/kg of body weight (diabetic/Res-10), respectively. All amounts given were per day. After 30 days of treatment with resveratrol, the animals were behaviorally tested and then analyzed for brain structural and blood changes. Resveratrol at both levels (10 and 20 mg/kg) was found to prevent the impairment of memory induced by diabetes.*


*Resveratrol was injected intraperitoneally (into the abdominal cavity). You might wonder why the researchers chose injection rather than oral administration, when the latter would have been much easier and more directly relevant to human health concerns. The answer is simple: they wanted to keep the experiments as biochemically clean as possible by bypassing the messy gastrointestinal tract. This entails a tradeoff, however: although the results can be easier to interpret and the conclusions drawn can be more definitive, the conclusions are less relevant than if the experiments had simulated real-life conditions.


Behavioral Testing

To measure the rats behaviorally, three tests were employed: an inhibitory avoidance test, an open field test, and a foot shock sensitivity test. These tests are designed to measure learning and memory retention, motor disabilities, and insulin sub-sensitivity, respectively.

In the inhibitory avoidance test, the rats were subjected to a single training session in which they were taught how they could behaviorally avoid getting a mild shock. Statistical analysis of the results of this test revealed that treatment with resveratrol reversed the impairment of memory induced by diabetes.


A new study has found that
resveratrol can improve memory
in diabetics by decreasing
the activity of acetylcholinesterase
(AChE), thereby boosting
cholinergic memory function
while enhancing cognition.


In the open field test—given immediately after the inhibitory avoidance test to discount any disparities that could cause differences in inhibitory avoidance—experiments were performed to assess whether diabetes or resveratrol affected shock threshold or locomotor ability. In this test, the animals were transferred to an open field where an observer—blinded to which rats had received resveratrol—recorded the number of the rat’s activities on a grid, including crossing and rearing responses, manually. The idea of this test was to identify motor disabilities, which might influence inhibitory avoidance performance, and thus confound the prior test. But there were none. Statistical analysis found that pharmacological treatment did not alter the number of crossing or rearing responses suggesting that neither streptozotocin-induced diabetes nor resveratrol caused motor disabilities that would invalidate the prior test.

Finally, in the foot shock sensitivity test, the animal’s reaction to shock was evaluated with the same apparatus used for inhibitory avoidance. Here the idea was to determine the flinch and jump thresholds in experimentally naive animals (without training). A flinch response was defined as withdrawal of one paw from the grid floor, and a jump response was defined as withdrawal of three or four paws. Two measurements of each threshold (flinch, and jump) were made, and the mean score was calculated for each animal. Diabetes did not alter foot shock sensitivity, again strongly suggesting that neither the diabetic state nor treatment with resveratrol administered before training of inhibitory avoidance caused motor disabilities or altered foot shock sensitivity.

Brain Analysis

Following the behavioral testing, the rats were examined for any indication of changes in AChE activity.

In the cerebral cortex, there was a significant increase in AChE activity in the diabetic/saline group compared to the control/saline group. However, treatment with resveratrol significantly prevented the increase in AChE activity in diabetic/Res-10 and diabetic/Res-20 groups. And treatment with resveratrol significantly inhibited AChE activity in control/Res-10 and control/Res-20 groups when compared to control/saline group.

In the hippocampus, a significant increase in AChE activity in the diabetic/saline group was observed when compared to the control/saline group, as would be expected. But treatment with resveratrol prevented this increase in AChE activity in diabetic/Res-10 and diabetic/Res-20 groups. As well, treatment with resveratrol significantly inhibited AChE activity in control/Res-10 and control/Res-20 groups when compared to the control/saline group.

In the striatum, the results were similar to the cortex and the hippocampus, where a significant increase in AChE activity was observed in the diabetic/saline group when compared with the control/saline group, while treatment with resveratrol prevented this rise in AChE activity in diabetic/Res-10 and diabetic/Res-20 groups. Treatment with resveratrol per se significantly inhibited AChE activity in control/Res-10 and control/Res-20 groups when compared to the control/saline group.

In the cerebellum and the hypothalamus, the results were similar: AChE activity in these two cerebral regions was significantly increased in diabetic/saline group when compared to control/saline group. Treatment with resveratrol also prevented the increase in AChE activity in control/Res-10 and control/Res-20 groups. However, when resveratrol was given, no significant differences in AChE activity were observed in control/Res-10 and control/Res-20 groups when compared to the control/saline group. This was the only exception to the findings for other brain areas.


Diabetes appears to double the
probability of developing Alzheimer’s
disease and other dementias.


Blood Analysis

As in the brain regions, AChE activity in the blood was also increased in the diabetic/saline group when compared to the control/saline group. But treatment with resveratrol prevented this rise in AChE activity in the diabetic/Res-10 and diabetic/Res-20 groups. Treatment with resveratrol per se significantly inhibited AChE activity in control/Res-10 and control/Res-20 groups when compared to control/saline group. There was a statistically significant positive correlation between brain and blood analysis.

Resveratrol Boosts Memory and Cognition

Remember that cognitive dysfunctions associated with diabetes correspond to neurophysiological and structural changes in the CNS. In other studies, polyphenolic compounds (such as resveratrol) have been shown to protect neurons against a variety of neurodegenerative conditions, including cognitive deficits associated with diabetes. While resveratrol has been investigated in diabetes animal models, no research has previously focused on the effects of this compound on cholinergic neurotransmission.

In the Brazilian study, when the diabetic rats were treated with resveratrol, their physical performance in the inhibitory avoidance test was similar to that found for rats from the control group. These findings indicate that treatment with resveratrol was able to prevent learning and memory impairment induced by diabetes. What is usually a concern in tests of this sort—that pharmacological treatment might affect locomotor activity or motivational aspects of learning, such as shock sensitivity—was overruled through the determination that there was no motor disability, which might influence inhibitory avoidance performance. The researchers also demonstrated that streptozotocin-induced diabetic rats did not demonstrate altered shock sensitivity adding to the certainty that pharmacological treatment was of no concern.

Although the precise mechanism through which diabetes alters cognitive functions is still not fully understood, it is clear from the research that: 1) AChE has a fundamental role in learning and memory and 2) that alterations in its activity as well as in the acetylcholine neurotransmitter level are neurochemically associated with cognitive deficits observed in patients and in animal models of diabetes.


Resveratrol at both levels
(10 and 20 mg/kg) was found to
prevent the impairment of memory
induced by diabetes.


Diabetes Degrades Acetylcholine

Also, it is clear that there was an increase in AChE activity in diabetic rats in all brain regions evaluated (cerebral cortex, hippocampus, striatum, cerebellum and hypothalamus) but with less pronunciation in the cerebellum and hypothalamus. AChE activation causes fast acetylcholine degradation and consequently the down-stimulation of acetylcholine receptors causing undesirable effects on cognitive functions. An increase in AChE activity caused by diabetes leads to a reduction of cholinergic neurotransmission efficiency due to a decrease in acetylcholine levels in the synaptic cleft, thus contributing to progressive cognitive impairment and other neurological dysfunctions seen in diabetic patients.


Resveratrol per se was found to inhibit AChE activity in the cerebral cortex, hippocampus and striatum.
The effect of diabetes on AChE activity could be one of the mechanisms involved on the memory impairment observed in the inhibitory avoidance test in this study. Altered brain membrane functions in diabetes occurs due to free radical formation, which in turn promotes increased lipid peroxidation. Because AChE is a significant biological component of the membrane—contributing to its integrity and changes in permeability during synaptic transmission and conduction—alterations in the lipid membrane could lead to damage to AChE, which would explain changes in the activity of this enzyme. Thus, AChE activation in diabetes is probably precipitated by free radical generation and consequent oxidative stress in the various brain regions.

Resveratrol Prevents Excessive AChE Activity

Treatment with resveratrol prevents increases in AChE activity in various regions of the brain, similar to findings in studies with other antioxidants such as vitamin E and turmeric. These antioxidants have also been found to prevent the rise in AChE activity and consequently reduce cognitive deficits caused by diabetes. The antioxidant property of resveratrol may be responsible for preventing cholinergic dysfunction in diabetic rats.

Several studies have shown that resveratrol protects against oxidative stress, decreasing membrane lipid peroxidation and increasing the antioxidant defensive capacity in the diabetic animal brain. But in the Brazilian study, resveratrol per se inhibits AChE activity in the cerebral cortex, hippocampus and striatum, which are structures rich in cholinergic pathways. Consequently, AChE inhibitors (such as galantamine) are important therapeutic tools for the treatment of many neurological diseases. These compounds increase the efficiency of cholinergic transmission by preventing the hydrolysis of released ACh through the inhibition of AChE, thus making more ACh available at the cholinergic synapse.


Treatment with resveratrol
reversed the impairment of memory
induced by diabetes.


Resveratrol Increases Acetylcholine Levels

A decrease of AChE activity by resveratrol can increase levels of ACh and consequently improve cognitive functions, such as learning and memory, suggesting an interaction between resveratrol and cholinergic neurotransmission. Interestingly, along with its antioxidants properties, there are several other properties of resveratrol that may be of causal value, including its structural similarity to estrogens. Its ability to bind to estrogen receptors may account, at least in part, for its anti-inflammatory activity.

Unlike Conquistador Plants

In conclusion, impairment in memory and learning in diabetic rats is associated with a marked increase in AChE activity in all brain structures and in the blood, and treatment with resveratrol was found able to prevent this increase. Consequently, in cognitive impairment in diabetic rats, resveratrol can modulate cholinergic neurotransmission and consequently improves cognition. These results may contribute to a better understanding of the neuroprotective role of resveratrol, emphasizing the influence of this polyphenol and other antioxidants in the diet for human health, and possibly help to prevent brain disorders associated with cognitive impairments such as diabetes.

And unlike the invasiveness exercised by resveratrol-bearing plants, we can exercise our benevolence and enhance our health by supplementing with resveratrol.

References

  1. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006 Nov 16;444(7117):337-42. Epub 2006 Nov 1.
  2. Saiko P, Szakmary A, Jaeger W, Szekeres T. Resveratrol and its analogs: defense against cancer, coronary disease and neurodegenerative maladies or just a fad? Mutat Res. 2008 Jan-Feb;658(1-2):68-94. Epub 2007 Aug 17. Review.
  3. Han YS, Zheng WH, Bastianetto S, Chabot JG, Quirion R. Neuroprotective effects of resveratrol against beta-amyloid-induced neurotoxicity in rat hippocampal neurons: involvement of protein kinase C. Br J Pharmacol 2004 Mar;141(6):997-1005.
  4. Anekonda TS, Reddy PH. Neuronal protection by sirtuins in Alzheimer's disease. J Neurochem 2006 Jan;96(2):305-13. Epub 2005 Oct 7. Review.
  5. Wang Q, Xu J, Rottinghaus GE, Simonyi A, Lubahn D, Sun GY, Sun AY. Resveratrol protects against global cerebral ischemic injury in gerbils. Brain Res 2002 Dec 27;958(2):439-47.
  6. Uguralp S, Mizrak B, Bay Karabulut A. Resveratrol reduces ischemia reperfusion injury after experimental testicular torsion. Eur J Pediatr Surg 2005 Apr;15(2):114-9.
  7. Wang Q, Yu S, Simonyi A, Rottinghaus G, Sun GY, Sun AY. Resveratrol protects against neurotoxicity induced by kainic acid. Neurochem Res 2004 Nov;29(11):2105-12.
  8. Ates O, Cayli S, Altinoz E, Gurses I, Yucel N, Sener M, Kocak A, Yologlu S. Neuroprotection by resveratrol against traumatic brain injury in rats. Mol Cell Biochem 2007 Jan;294(1-2):137-44.
  9. Ates O, Cayli SR, Yucel N, Altinoz E, Kocak A, Durak MA, Turkoz Y, Yologlu S. Central nervous system protection by resveratrol in streptozotocin-induced diabetic rats. J Clin Neurosci 2007 Mar;14(3):256-60.
  10. Mokni M, Elkahoui S, Limam F, Amri M, Aouani E. Effect of resveratrol on antioxidant enzyme activities in the brain of healthy rat. Neurochem Res 2007 Jun;32(6):981-7.
  11. Quincozes-Santos A, Andreazza AC, Nardin P, Funchal C, Gonçalves CA, Gottfried C. Resveratrol attenuates oxidative-induced DNA damage in C6 Glioma cells. Neurotoxicology 2007 Jul;28(4):886-91.
  12. Schmatz R, Mazzanti CM, Spanevello R, Stefanello N, Gutierres J, Corrêa M, da Rosa MM, Rubin MA, Schetinger MR, Morsch VM. Resveratrol prevents memory deficits and the increase in acetylcholinesterase activity in streptozotocin-induced diabetic rats. Eur J Pharmacol 2009 Mar 18. [Epub ahead of print]


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

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