Of all its benefits—including perhaps longer life—one is head over shoulders . . .

Resveratrol Boosts Memory
Exciting research shows that resveratrol can ameliorate
the effects of moderate alcohol consumption and add to its benefits
By Will Block

E

ven though resveratrol was first isolated in 1939 from the roots of white hellebore (Veratrum grandiflorum)1—from which its name was probably derived: res from its molecular class resorcinols; veratr from the plant name Veratrum; and ol for hydroxyl groups, three of which resveratrol posseses—the importance of resveratrol was not recognized until the 1990’s. And only after the widely publicized phenomenon of the “French Paradox,” which is significantly associated with drinking red wine. This led eventually to the discovery that resveratrol, as a plant extract, could extend mean and even maximum longevity in a variety of organisms from certain species of yeast, to roundworms, to fruit flies, to cold water fish, and—most importantly because they’re mammals, and thus closely related to us—mice.

An Amazing Nutrient

Now of all the benefits attributed to this amazing nutrient—resveratrol has been found to protect against degenerative diseases of aging, such as cardiovascular disease, cancer, arthritis, and neurodegenerative diseases—the one that is a clearly above the rest (pun intended) is memory enhancement. Why? Because if we can preserve our minds by maintaining proper memory functioning, we can preserve our determination and will to know. Without these virtues intact, we would not be able to steer our ship toward the greater and greater islands of health. These are most inviting to those who are most cognitively awake.

In the brains of experimental animals, resveratrol has been found to not only protect neural cells from amyloid-beta, the neurotoxic tissue implicated in Alzheimer’s disease, but also to reduce the levels of amyloid-beta in vitro. And while the reduction of amyloid-beta plaques does not necessarily lead to improved cognition, the properties of resveratrol to block inflammation in neural tissue are likely to help protect against cognitive declines that result from Alzheimer’s disease and other aging diseases.

Good for Maze Relief

Have you ever thought that you are caught in a maze, unable to exit from your daily pattern, locked into a repeating script? Point of fact: spatial learning and memory have both been demonstrated to be especially susceptible to the consequences of aging and the effects of alcohol consumption.

Nevertheless, moderate consumption of wine is a good thing, having been shown to decrease dementia. Resveratrol (found in wine, but in very small amounts) has been established to protect neurons against the oxidative stress of alcohol (ethanol), such as that found in wine. Could the moderate consumption of wine, along with adequate amounts of resveratrol help with your maze problem?

Better Spatial Learning and Memory

In a new study study, middle-aged female mice given a combination of resveratrol (44.2 mg/kg)* and a low amount of ethanol (0.71 g/kg) each day for 6 weeks performed better on a Barnes maze tasks for spatial learning and memory than mice consuming only the low concentration of ethanol.2 (See the sidebar, “The Hidden Hole Jackpot of the Barnes Maze.”) The results suggest three conclusions. First, moderate alcohol enhances learning and memory. Second, moderate alcohol and resveratrol together boost learning and memory. Third, resveratrol probably protects spatial learning from the negative effects of alcohol.


*The human equivalent of resveratrol is about 304 mg for a 85 kg (187 lb) human per day.

†The human equivalent of ethanol is about 4.9 g for a 85 kg (187 lb) human per day.


The Hidden Hole Jackpot of the Barnes Maze

The Barnes maze is used to quantify cued (intra-maze cues) and spatial (extra-maze cues) learning and memory in psychological laboratory experiments. It designed to test rodents such as lab mice or rats, which either serve as controls or experimental subjects usually given a test drug, nutrient, or food. The rodents may have some genetic variable or deficiency present that will cause them to react differently to the maze.

Holes Big Enough to Crawl Inside

Circular in shape, the Barnes maze has evenly spaced holes (just big enough to allow the mice or rats to crawl inside) on the circumference. Under each hole is a slot for a box, called the drop box, but only one box has an open top. The maze is elevated from the floor on a table, and the rats or mice are able to escape the brightly lit surface but only by finding and entering the hidden open-topped drop box placed under one of the holes.

Because of the bright light, exposure on the surface of the table serves as negative reinforcement, meaning the test rodent is strongly motivated to seek shelter. Yet, the only shelter available is the drop box. In order to acclimate the rodent (the test subject) to the maze, initially the sheltering hand of a researcher guides it into the drop box. After a number of runs, normally a test subject can rapidly make a beeline for the drop hole. Visual cues set up at fixed points around the platform serve to orient the rodent during the trials.

In the Ranney et al. study, performance was measured by number of errors the mice made, such as repeated poking into or hovering oven false holes (those not containing the drop box). Also measured was the speed of learning from trial to trial, called escape latency, and episodes of freezing, where the mice remained immobile, except for respiration, for 10 seconds. The study was divided into tests for cued learning and special learning. In the cued learning the mice were given four consecutive days of cued training, four trials per day. The intra-maze cue, a blue-capped aerosol paint can, was placed behind the appropriate escape hole. It’s placement randomly changed with each trial.

Spatial learning and memory utilized extra-maze cues—large, colored shapes of poster board—placed on the surrounding walls. The researcher, in a lab coat, was positioned in the same corner of the test room, wearing no perfumed scents. Using these distal cues to orient themselves, the mice were required to locate the escape box. Finally, the location of the escape hole was randomized by mouse, contrasting with the cued training locations. Yet they remained constant for that mouse over the 4 days. Training began 2 days after the cued training ended. In all, the mice received four training trials per day for 4 days completing 16 spatial learning trials.

Smelly and Squeezy

There are problems to be avoiding using the Barnes test. When nervous, most rodents will pee and poop on the table, requiring the researcher to clean up the entire table with disinfectant. Test subjects cannot be allowed to witness the experiment in action, for the obvious reasons that it would give them an upper edge. Witnessing the experiment also makes the subjects anxious, thereby increasing stress, and making it harder for the researcher to pick up the animal without squeezing it too much.

Resveratrol Protects Against Alcohol Damage

Other studies have suggested the same. One study—while wary that ethanol consumption impairs neurological function primarily because of oxidative injury—found that resveratrol has neuroprotective effects against the oxidative injury of ethanol.3 Another study found that the moderate consumption of red wine (which contains both ethanol and small amounts of resveratrol) decreases the incidence of cognitive decline associated with aging.4 Also, red wine consumption has been associated with reduced risk of developing Alzheimer’s disease.

Returning to the maze study, the overall conclusion reached by Ranney, et al. showed that the negative effects of chronic low-dose ethanol consumption on spatial and reference memory are countered by resveratrol. Nonetheless, resveratrol did not provide additional benefit for what is known as cue memory. The middle-aged mice (consuming resveratrol) were unable to do any better than controls (consuming just water) in their ability to learn the spatial cues in the Barnes maze. Also, although ethanol consumption impaired spatial learning, it enhanced cued learning in the mice. Other studies have shown similar results, i.e., ethanol more strongly affects the ability of rats to perform spatial reference memory tasks than non-spatial reference memory tasks, meaning that special performance is more sensitive to ethanol than non-spatial reference memory.5,6,7

Different Brain Regions for Different Skills

Spatial learning requires a healthy hippocampus, while cued learning requires a healthy striatum. During learning, the striatum and the hippocampus actually compete with one another in what is called bidirectional competition.8 When the striatum is disrupted, cued learning is impaired, while spatial learning is enhanced. On the other hand, hippocampal processing disruption leads to spatial learning impairment and cued association enhancement.


The mice fed resveratrol
together with ethanol were found to
have fewer errors after locating the
cued target hole.


In the Barnes maze study, the same relationship between cued and spatial learning was shown in the mice receiving only ethanol. They had improved cued learning but impaired spatial learning. The mice fed resveratrol together with ethanol were found to have fewer errors after locating the cued target hole. The controls found the hole, as indicated by dipping their heads into it, but then explored the other holes before finally entering the escape box. The alcohol mice did the same, though to a lesser extent. Therefore, resveratrol seems to improve the mouse’s ability to recognize and correctly respond to appropriate proximal cues to escape an aversive stimulus.

Resveratrol’s Antioxidant Effects on Learning and Memory

Mice fed ethanol showed an impaired ability to use extra-maze spatial cues to learn the location of the escape hole. The controls or the ethanol plus resveratrol mice were not impaired. Ethanol has been shown to increase oxidative stress on cells and tissues,9 and oxidative stress adds to the neurodegenerative damage associated with Alzheimer’s disease.10


Improved cognitive performance of
middle-aged female mice
receiving both resveratrol and ethanol
may be due in part to
the effect of resveratrol on
estrogen receptor activity.


Germane to the mechanism of action, resveratrol has been found to possess antioxidative properties.11 Consequently, spatial learning and memory deficits from the oxidative effects of ethanol at the level of the hippocampus are likely countered by resveratrol.

Resveratrol’s Estrogenic Effects on Learning and Memory

But there’s another possible mechanism. Resveratrol possesses estrogen-like activity.12 The use of estrogen in hormone replacement therapy has been associated with improved memory.13 and spatial reference memory is sensitive to reduced estrogen during the estrus cycle,14 after ovariectomy,15 and because of aging.16 What’s more. the ability to switch easily from one learning strategy to another may be affected by estrogen.15

The Ranney, et al. study used middle-aged female mice as subjects for whom resveratrol, in the cued task test, helped to improve response after finding the correct hole. The mice entered it more quickly than the ethanol-only or water-only mice.

Yet, after the intra-maze cue was removed for the spatial learning task, the resveratrol mice responded more rapidly. They were immobile and able to switch quickly to an extra-maze cue strategy than was the case with the ethanol mice. Curiously, while ethanol biased an animal’s strategy to the use of nearby cues, resveratrol seems to augment the use of distanced cues.

In summation, resveratrol is likely to oppose the negative effects of ethanol on hippocampal-related spatial memory in middle-aged female mice. And while part of this may be due its antioxidative effects—which would protect neurons of the hippocampus from ethanol-induced oxidative damage—improved cognitive performance of middle-aged female mice receiving both resveratrol and ethanol may be due in part to the effect of resveratrol on estrogen receptor activity.

So if you find yourself caught in a maze and forgetting how you got there, you might want to add some more resveratrol to your supplement program. It could prove to be your drop box to better memory.

References

  1. Takaoka M, Resveratrol, a new phenolic compound, from Veratrum grandiflorum. J Chem Soc Japan 1939;60:1090-100.
  2. Ranney A, Petro MS. Resveratrol protects spatial learning in middle-aged C57BL/6 mice from effects of ethanol. Behav Pharmacol 2009 Jul;20(4):330-6.
  3. Kasdallah-Grissa A, Mornagui B, Aouani E, Hammami M, El May M, Gharbi N, Kamoun A, El-Fazaâ S. Resveratrol, a red wine polyphenol, attenuates ethanol-induced oxidative stress in rat liver. Life Sci 2007 Feb 20;80(11):1033-9.
  4. Luchsinger JA, Tang MX, Siddiqui M, Shea S, Mayeux R. Alcohol intake and risk of dementia. J Am Geriatr Soc 2004;52:540–6.
  5. Matthews DB, Ilgen M, White AM, Best PJ. Acute ethanol administration impairs spatial performance while facilitating nonspatial performance in rats. Neurobiol Learn Mem 1999;72:169–79.
  6. Matthews DB, Simson PE, Best PJ. Ethanol impairs spatial processing of hippocampal place cells: a mechanism for impaired navigation when intoxicated. Alcohol Clin Exp Res 1996;20:404–7.
  7. White AM, Elek TM, Beltz TL, Best PJ. Spatial performance is more sensitive than nonspatial performance regardless of cue proximity. Alcohol Clin Exp Res 1998;22:2102–7.
  8. Lee AS, Duman RS, Pittenger C. A double dissociation revealing bidirectional competition between striatum and hippocampus during learning. Proc Natl Acad Sci U S A 2008;105:17163–8.
  9. Koop DR. Alcohol metabolism’s damaging effects on the cell: a focus on reactive oxygen generation by the enzyme cytochrome P450 2E1. Alcohol Res Health 2006;29:274–80.
  10. Beal MF. Oxidative metabolism. Ann N Y Acad Sci 2000;924:164–9.
  11. Robb EL, Winkelmolen L, Visanji N, Brotchie J, Stuart JA. Dietary resveratrol administration increases MnSOD expression and activity in mouse brain. Biochem Biophys Res Commun 2008;372:254–9.
  12. Pervaiz S. Resveratrol: from grapevines to mammalian biology. FASEB J 2003:17:1975–85.
  13. Duff SJ, Hampson E. A beneficial effect of estrogen on working memory in postmenopausal women taking hormone replacement therapy. Horm Behav 2000;38:262–76.
  14. Frick KM, Berger-Sweeney J. Spatial reference memory and neocortical neurochemistry vary with the estrous cycle in C57BL/6 mice. Behav Neurosci 2001;115:229–37.
  15. Korol DL, Malin EL, Borden KA, Busby RA, Couper-Leo J. Shifts in preferred learning strategy across the estrous cycle in female rats. Horm Behav 2004;45:330–8.
  16. Frick KM, Fernandez SM, Bulinski SC. Estrogen replacement improves spatial reference memory and increases hippocampal synaptophysin in aged female mice. Neuroscience 2002;115:547–58.


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

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