Oxidative stress, cognitive function and pterostilbene

Pterostilbene is a natural compound first isolated from blueberries. It is a phytoalexin similar in structure to resveratrol, but with a much longer half-life in the body. Pterostilbene has been shown to have cholesterol and blood glucose lowering abilities and an anti-inflammatory function. It can also protect against oxidative stress and slow or reverse age-related declines in cognitive function.

Pterostilbene can improve cognitive function

During the aging process, gradual impairment of memory and cognitive function occurs in most organisms. Accumulation of damage due to oxidative stress is thought to be the major cause of this process. Diets rich in natural anti-oxidants can slow down or even reverse this process. In the laboratory, blueberry extracts rich in pterostilbene have been shown to be highly effective in reversing age-related declines in memory, cognitive function, and motor neuron function in rats (1). In a mouse model of Alzheimer‘s disease, a diet rich in blueberry extracts was able to prevent the onset of cognitive impairment as the mice aged (2). Further studies in rats and mice found that blueberry-supplemented animals had higher levels of hippocampal neuroplasticity, neurogenesis, and extracellular kinase receptor activation (3). Damage to the hippocampus is strongly associated with declines in memory associated with Alzheimer‘s disease.

Pterostilbene is the active ingredient in blueberry extracts

pterostilbene oxidative stress

In order to identify the neuroprotective agent in blueberry extract, a laboratory cell culture experiment was performed. Human cells grown in culture had a type of muscarinic receptor that is known to be particularly susceptible to oxidative stress introduced. After introduction of this receptor, when the cells were exposed to oxidative stress by first depolarizing them with oxotremorine and then incubating them with dopamine, their calcium levels dropped. Recovery from the oxidative stress could easily be measured via an intracellular calcium level assay. When the cells were incubated with blueberry extract before dopamine treatment, the cells were able to return to almost normal calcium levels, indicating a strong protective effect against oxidative stress. Then, a number of different purified stilbenoid compounds were used instead of the blueberry extract (4). Resveratrol was unable to reproduce the blueberry extract effect, but purified pterostilbene worked as well as the blueberry extract in protecting the cells [see figure 1a].

pterostilbene oxidative stress 2The researchers then went on to feed pterostilbene to aged rats for 8 weeks (4). The brains of the rats were removed and exposed in vitro to oxidative stress (by exposure to hydrogen peroxide). When the striatal cells of the brain are exposed to oxidative stress, it is well-known that they release large amounts of dopamine. Alterations in dopamine release during aging are associated with defects in memory and motor neuron function. The brains of the pterostilbene-fed rats released significantly less dopamine in response to oxidative stress than did control rats [see Figure 1b].

Pterostilbene improves memory and learning ability

The researchers then went on to feed purified pterostilbene to aged rats and tested their memory (4). A widely-accepted test of the rat’s memory is the Morris Water Maze, where rats have to remember the location of a platform hidden under water. Rats fed high doses of pterostilbene showed significantly improved performance on the Morris Water Maze in comparison to control rats [see Figure 2a and 2b].

pterostilbene oxidative stress 3

After the experiments, the brains of the rats were removed and the amount of pterostilbene located within the hippocampus was measured. There was a strong correlation between the amount of pterostilbene in the brain and the rat’s performance on the Morris Water Maze test [see Figure 3a and 3b].

pterostilbene oxidative stress 4

Pterostilbene has direct anti-oxidant activity

One mechanism whereby pterostilbene improves cognitive function is through its ability to act directly as an anti-oxidant. In in vitro assays, pterostilbene is a very effective scavenger of free radicals. In these assays, a molecule called Trolox is used as the reference anti-oxidant agent. Trolox can scavenge two free radicals per molecule. Pterostilbene is more effective than Trolox, able to scavenge at least 3 free radicals per molecule (5). Therefore, during oxidative stress in the brain, pterostilbene can directly remove free radicals and reduce damage to neurons.

Pterostilbene affects the expression of multiple genes

In addition to its direct anti-oxidant activity, pterostilbene protects neurons by altering the expression of more than 1000 genes. Researchers exposed yeast to pterostilbene and then analyzed the changes in their gene expression patterns with a genomic profiling assay. They found that 1007 genes were up-regulated and 182 were down-regulated as a consequence of exposure to pterostilbene (6). Many of the up-regulated genes were found to be involved in natural defenses against oxidative stress, indicating that pterostilbene induces higher levels of natural protection against oxidative stress in addition to acting as a free radical scavenger. In addition, some of the up-regulated genes are involved in the function of mitochondria. Mitochondria are organelles inside cells that are responsible for providing energy to the cell. Malfunction of mitochondria has been shown to be linked to both aging and Alzheimer’s disease. Therefore, part of pterostilbene’s effect on cognitive function may be mediated through stabilization of mitochondrial function.

In summary, pterostilbene improves memory and cognitive function through several different mechanisms. It accumulates in the brain and acts as a free radical scavenger to protect the neurons against oxidative damage. It also alters the gene expression patterns of cells, naturally up-regulating their ability to protect against oxidative stress. In addition, it stabilizes and protects mitochondrial function. Intriguingly, in addition to protecting against age-related cognitive decline, it may also be able to improve cognitive function in younger individuals. Studies in both children and young rats report that blueberry extracts are able to improve memory (7, 8).


(1) J Neurosci. 1999 Sep 15;19(18):8114-21.
(2) Nutr Neurosci. 2003 Jun;6(3):153-62.
(3) Nutr Neurosci. 2004 Oct-Dec;7(5-6):309-16.
(4) J Agric Food Chem. 2008 Nov 26;56(22):10544-51. doi: 10.1021/jf802279h.
(5) J Agric Food Chem. 2002 Jun 5;50(12):3453-7.
(6) BMC Med Genomics. 2008 Mar 20;1:7. doi: 10.1186/1755-8794-1-7.
(7) Nutrition. 2015 Mar;31(3):531-4. doi: 10.1016/j.nut.2014.09.013. Epub 2014 Oct 18.
(8) Psychopharmacology (Berl). 2012 Oct;223(3):319-30. doi: 10.1007/s00213-012-2719-8. Epub 2012 May 9.

11 Comments on Oxidative stress, cognitive function and pterostilbene

  1. Allan Silliphant | 11 October 2015 at 6 h 40 min | Reply

    I am a U.S. Veteran and a diagnosed type2 diabetes patient. For over 13 years
    I have been taking metformin, Present dosage 1500 Mg. Daily. I have been taking 500 mg. of resveratrol for two years, I now take 100 mg of pterostilbenem as well. I take it with 2 oz. of live blueberries, with a dipping in coconut oil with each cap of pterostilbene. My 140 finger-stick value dropped a month ago from an average fasting value of 134 down 40 points to a 30 day 98 fasting result! In the last 40 days I have also lost
    12 lbs. My blood pressure has stable-ized at a 115 over 68. Urination voiding interval has more than tripled, from a max of one hour interval
    that effected me for over a year. I’m 74 and can do twice the number of exercise repetions. I am tying to form a veteran group on metformin for
    human research with a clinical test doctor a free pterostilbe and free suppky of research blueberries. Maybe ten L.A. CA vets could join my informal group. E-mail sharper3d@yahoo,com

  2. Allan Silliphant | 29 October 2015 at 2 h 18 min | Reply

    A quick up-date on my 1500mg metformin personal experiment with 100mmg
    pterostilbene, plus 500mg resveratrol, to reduce diabetes 2, finger-stick
    numbers. For 14 months I was a placebo (I surmised) in a metformin clinical
    trial with a very major “pharma” giant. As a presumed placebo, after 14 months,I asked to quit the study,as my average finger-sick after fasting was 134. I was advised that unless I continued for a 30 day period, I would
    probably be dropped from future trials. I had to find a way to drop the number…radically. I was taking resveratrol during the test, (500mg) daily. I still continue that, but I stumbled across pterostilben in the
    online articles that I surf. They suggested that this molecule would be
    far longer in my bloodstream, (105 minute half life) I added this at once.
    Within 3 days the blood numbers began to plummet. Now 50 days later I am
    down in the 90s, 80s, and even middle seventies with no sign of symptoms of hypoglycemia! I have at the same time put myself on a 1300 to 1500 cal.
    CR related diet. I feel great. I’m just at 195 lbs. and heading lower. I
    have certifiable proof from VA medical records of the loss in body wt. I
    had severe frequent urination problems, now I can go 4 hours plus. I’m able
    to do 3 times as many reps.in simple exercises. I have had diabetes for 16 years. And I’m noting all the promising trials with cancer, in lab-rats!

  3. Allan Silliphant | 6 November 2015 at 7 h 24 min | Reply

    A further update from post of 29 October 2015. I am now at 192 in naked body weight. Finger-stick today, after 8hr. fasting…86! I mostly wanted to point out in this post, that my weight loss on the 1300 to 1500 cal. was greatly helped by the reduction of my hunger pangs. I have not seen this noted elsewhere in other online discussion of human testing of pterostilbene. If I’m wrong on this opinion, please advise me of an instance elsewhere. I find the combination of ptereostilbene 100 mg, resveratrol 500,plus live blueberries, AND freezed-dried blue-berry powder
    blended into to cottage cheese, or other low fat nourishment, may perhaps
    fool the digestive system to prolonging the bio availability half-life of
    105 minutes, perhaps extending it to perhaps DOUBLE the 105 minutes. I had the move my last belt hole to 3 inches tighter!!! 38 inches down to 35. I still take the established 1500 mg of slow release metformin. I feel great,
    & now can almost move like some kind of an NINJA… with 7 more lbs. to go!

  4. Quick comment: I pulled up my recent medical records at the VA. In April of 2015, my A1c was 7.9 on the non-VA pharma test with 1000 mg of metformin and the test investigation medication, although I assume I was in fact a placebo. I went on pterostilbene in July, and added the 15 LIVE Blueberries with each of the 2 50mg caps taken daily. Finely powdered blueberry was added to the mix, after a week more. It is mixed with the
    two oz. of low fat cottage cheese, and some cut up strawberries.Continued on the 1500 mg of slow release metformin, and just yesterday cut down to
    just 1000 mg of that medication. The purpose of the lie berries is to try to fool the very complex digestive nervous network. Tht it bigger than your spinal cord…WHO KNEW! The resveratrol (2) 250 mm was discontinued today, because the COSCO resver. caps failed to dissolve while passing through the digestive system. With the pterostilbene, being encapsulated in a much thinner gel cap, the 4 of us on the experiment poke 6 tiny holes in the ends of the capsules with gluco-meter lancets. My A1c
    was drawn a week or so ago. The 7.9 number had come down to 6.2. and the
    Average estimated glucose down to just 131, whre it had been 180 in April.
    Since the pterostilbene seems to curb most of the hunger pangs, I have been able to lose 23 lbs. in about 70 days, & 3 inches in the waist. It
    appears that the fat with the abdomen was the first to go…amazingly!
    My diet is meant to have some CR benefits, at around a 1500 cal max. I’m
    190.4 today, and hope to reach my 186 goal in about a week. When I do, I’ll
    probably raise the intake to about 1800 for a month, and then take stock of the wight stability. By all means…get a good accurate digital scale, if you ant to try this plan on your own.

  5. It is now Sunday,December 13 of 2015. I have now lost 30 lbs, down from 215 87 days ago. My diabetes numbers have come down from a1C of 7.9% on December 23, 2014 to a1C of 5.8%. I have also started 200 mg. of Niagen for NAD+, along with 1500 mg of slow release metformin, and the U.S.D.A. patented version of pterostilbene, which was developed in Oxford, MS at the State University, School of Pharmacy. It is 99+% pure stuff. It is chemically identical to the stuff in blueberries. To hopefully, trick my digestive tract, I am eating a combination of 1 Oz. of tasty live blueberries, a finely ground powder from blue-berries (small pinch), mixed in with 2 Oz. of low fat cottage cheese, eaten along with taking my pills. This is my breakfast starter, & again taken with the pre-dinner meds. I cannot state all of the beneficial changes that have taken place. Some of the highlights: Bladder irritation gone! 55 minute interval has morphed into 4 hours plus interval. PK on my face is 90% better. I can do 300 reps of leg and upper body work. I can walk extremely fast, like a college kid!
    I have give away my 40 in. waist Levis, slacks , and I now comfortable with just 34 inch pants. The internal belly fat is gone, the external layer, almost so. Skin is tightening, especially under my jaw. I’m getting a certain amount of CR effect also, since, during the diet phase I’m only
    eating about 1500 cals. I’m talking with Congressional Staffers of the several members of the VA medical oversight sub-committee, and getting positive feedback. I hope and pray that my brother Vets can get some of this stuff to ward off diabetes , cardio-vascular, dementia, and cancers that are being seen in tests at a raft of university labs. Please, Vets out there, talk to the doctors about this stuff. The whole world will be helped.

  6. pterostilbene.com | 19 December 2015 at 19 h 45 min | Reply

    Impressive results ! Thanks for sharing !

  7. It is now Dec 27, 2015. I presently weigh 183 lbs. That represents a 31 lb.
    loss in about 92 days. I am taking 3 key things to control my type2 diabetes.1: Metformin 1500 mg slow release a prescription I have been on with the U.S. VA medical program for seven years, having used the regular metformin, which is hard on my GI tract, for nine years prior to that. This is,of course, a prescription drug. I suggest that most people with
    even pre-diabetes should take at least 500 mg, if your doctor approves the idea. 2: Pterostilbene (the USDA patented version) which is a very pure synthetic compound. The word “pure” is in the name of the better version.
    Natural pterostilbene, contains a lot of other filler material, I’ve read.
    One of the good things about pterostilbene is that it seems to greatly
    enhance your ability to control your hunger pangs. It also gives you more
    stamina to increase your workout level (important). I have observed that
    the P.K. (pre-non-melanoma cancer lesions) have gone inactive, as has a little rosacea on my cheeks. Memory seems to have improved, especially now
    that I am also taking Niagen, a precursor to NAD+ , which is believed to
    enhance gene expression in the communication chemically between the several
    mitochondria and the DNA at the nucleus of each cell. This is the substance, that Dr. David Sinclair was discussing in his statement published in the bio journal “CELL” in December of 2013. Another gentleman
    in my little informal VA research group is also taking the 200 mg of Niagen
    We are very convinced that our recall of forgotten detail knowledge has
    seemingly improved…make us laugh a lot about it…it is almost a level of
    glee sometimes. Please Vets…talk to your endocrinologists at the VA. We
    really need this stuff as part of our fight against amputations & blindness. Cancers of all sorts and Alzheimers are also under research in
    scores of university labs…go for it!

  8. I’ll be brief. As of February 18th 2016, I now weigh just 175 lbs. My A1C is now 5, down from 7.9 a year ago. In addition to extended release metformin, which hopefully you can get through your doctor, at least 500 mg for pre-t2diabetes. Then, I suggest you take at least 100 mg in two caps of 50mg of the synthetic, but bio-identical version of pterostilbene, developed by the USDA scientists, & tested in human trials at the U. of Mississippi, several years back, Also take Niagen (NR) the precursor to NAD+ which was developed at Dartmouth U. and finally Quercetin, which is
    a natural substance found in apples, which is being researched at Mayo Clinic, and the Scrips Inst. of Medical Research, in Jupiter FL. These are
    all very promising substances which improve mitochodrial gene expression in
    commenication with the DNA in the nucleus of your body cells. My waist size is down to 32 inches now, & I have given away 5 good over-sized suits. Because I can now workout my arms with 8 lb. weights my strength
    & stamina are greatly improved. I’ve agree to a left side clean-out of my
    occluded carotid arteries…the right was cleared in 2013. I’m hoping to
    out live my pioneer vitamin manufacturing uncle who lived to 97, & his sister Lucy who worked at 95 as head nurse in a Burbank CA hospital & passed away in the 1970s, at 100. I think this stuff should be made available to my fellow veterans, as it seems to have a very powerful impact on T2 diabetes, as all of these things are being tested in multiple
    universities & research clinics. I am so pleased with my agility & sense
    of vitality now…Please consider what I’m suggesting for you & yours!

  9. So, basically, the perfect mix is 100mg of pterostilbene, together with some blueberry powder all mixed with low fat dairy? Once or twice a day? This is amazing!

  10. It is now October 23, 2016. This is an update, on my weight, A1C values, and certain additions to our informal “testing”. I weigh just 175 now…DOWN 47lbs. from my starting weight about 13 months ago. My A1C is 5.7 approx. I eat a maintenance diet of about 1900 calories, daily. My facial skin is now fully free of pink (rosaca) blotches. I am taking 1500 mg of metformin EXTENDED release version…way better on the GI tract!!! I am taking Ptero-pure, synthetic tperostilbene, which was developed and human tested by the USD of Agriculture scientists, work with the Univ. of Mississippi Pharma lab. I am also taking optimized Trans-resveratrol, from Life Extension, Optimized quercetin, and also special vitamin E substance, called tocotrienols. These two are shown in studies by Mayo Clinic and Scrips Institute of Medical Research, to greatly extend the life span of specially bred short lived rats, when taken with a prescription med called dasinatib. But testing elsewhere has shown these two substances stimulate the immune system to return to carrying out apoptosis of the senescent cells with the thin endotheilum cell layer of the arterial system. This is very gone for the health of mammals and hopefully for mankind! These tired, non-replicating cell give off very nasty toxins!Purge these nasty cells very selectively…much like the effect of “culling a heard” grazing animals! Are little group of 4 are also testing Niagen, the precursor to NAD+ which inhances comunication between the DNA in the nuclei, and the many mitochondria in our cells. Folks, and especially our brother and sister VETS…
    this stuff seems to work, because my regular medical records reflect the improvement. I’m hoping to be given a hugely important “cleanout” of my left side carotid arterial branch point which is badly occluded. The VA docs were unwilling to do this proceedure until I was able to pass a nuclear imaging stress test with treadmill. Losing 47 lbs. has made this possible….wish me well, I might happen before Christmas! I’m going to be 76 in April…Hope to be alive and kicking well past 90 if this procedure goes well, and will have far less risk of stroke or even Alzheimer’s! It sure feels great to lose the diabetes symptoms, and look maybe 10 or 12 years younger, at least from a short distance…really a fact…love it!

  11. Well I finally got the VA/UCLA vascular surgeons to clean out my 95% blocked left carotid arteries, 23 days ago. All is healing up well. Of course I have continued to take my metformin, along with the pterostilbene, & also Niagen (nr) the precursor to NAD+, as well as twice daily doses of quercetin & tocotrienols , which help the body to apply the
    natural process of apoptosis to remove moribund (senescent)arterial endothelial cells, to make room for health cells that can take their place.
    Your body does that until your sixties, in most cases. The combination of
    metformin, which is now seen as a likely anti-aging medicine by the NIofH,
    & to some extent by the FDA, on a wait & see approach. A 5 year study called: T.A.M.E. will use 3000 subjects between 70 & 80 to find out if the
    established diabetic drug will kill some of the cancers, & even might delay
    the onset of dementia. The significance of my endarterectomy proceedure, is
    connected…BIGTIME, to my medicinal tests. Here’s the best news, so far:
    As a result of getting both sides finished…after a 3 1/2 year delay…
    I’m seeing dramatically better, in terms of focus, light levels, & pupil
    functions. My ears are working better, my middle ear is giving me better
    balance & agility. My facial skin is a healthy color now, & free of 8 years
    of rosaea. My teeth are getting a good blood supply now. My brain is working better, faster, & forgotten names, words, & memories have surfaced
    again. I beg you to look into these cutting edge substances, & urge you to
    have your carotids checked for blockage. Every morning I awake to a sense
    of having been physically “reborn”. I thank my friends for their prayers
    & supportive energy. Please feel free to contact me on my facebook page, or
    my flickr.com sub-site: sharper3d. I’ll be 76 in April…I aspire to pass
    106, before I’m elsewhere!

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