Thursday, 7 February 2019

Pterostilbene for Neuromodulation – worth a look?

Google have just discontinued Google+

Many people followed this blog via Google+ 

You can either follow by email (just to right of the blueberries), or follow by Blogger


A common criticism of this blog is that it is mainly about prescription drugs rather than OTC supplements.
Today’s post is about a supplement that is highly regarded by our reader Ling.
Pterostilbene is like a super potent version of resveratrol.  

Resveratrol is quite well known and has long been put forward as having some potentially highly beneficial health effects, but in practise it is just too poorly absorbed to have much effect in humans.
Pterostilbene is found in blueberries.  Also found in blueberries is Anthocyanin, which is worth a mention in this post, it is what gives blueberries their colour; very often it is the colour in a food that underlies part of its health benefit. This is why eating a mixed colour diet is a wise idea.
Aronia is extremely rich in anthocyanins and Aronia juice is very common where I live. We even have a bottle of the dark coloured juice in the kitchen.
The purple colour in beetroot is betanin, a so-called betacyanin and may well have anti-Alzheimer’s effects, inhibiting plaque formation.
Anthocyanin is put forward as one reason certain Japanese who eat large amounts of purple sweet potato do not suffer much cancer or dementia and live a very long time.

Today we are mainly looking at pterostilbene, but if you want Anthocyanins, to avoid dementia, just eat blue and purple coloured fruit and vegetables on a very regular basis.
Ling has proposed pterostilbene as a PDE4 inhibitor, but as is often the case, it has numerous other effects, so it would be hard to know which is the main reason it might be therapeutic.  

Known biological effects of Pterostilbene                                                                                   
Here is an excellent graphic that highlights many of the effects of Pterostilbene, other than on PDE4.

The regular readers of this blog will note that the great majority of the above signalling molecules are implicated in autism.

The proposed effects on the brain are highlighted in the next graphic

The source paper is here: -  


Based on the evidence presented, PTE (Pterostilbene) is more bioavailable and better at evoking molecular and functional events than RES (Resveratrol) in vivo

Although clinical trials are underway to assess the effects of RES in diseases such as dementia and AD, pre-clinical and clinical studies on PTE have yet to be conducted. Furthermore, the biological effects of many of the structural analogues of RES and PTE are unknown, and no studies have identified the metabolites of RES or PTE in brain tissues. There is a need for future studies to identify means of enhancing the efficacy and bioavailability of these compounds and to analyse the metabolites of these compounds in thebrain. Altogether, the evidence from a variety of studies strongly suggests the potential of RES and PTE as promising bioactive agents to improve brain health and prevent neurodegeneration

Most research, but not all, concerns aging and dementia. 

Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene) is a natural dietary compound and the primary antioxidant component of blueberries. It has increased bioavailability in comparison to other stilbene compounds, which may enhance its dietary benefit and possibly contribute to a valuable clinical effect. Multiple studies have demonstrated the antioxidant activity of pterostilbene in both in vitro and in vivo models illustrating both preventative and therapeutic benefits. The antioxidant activity of pterostilbene has been implicated in anticarcinogenesis, modulation of neurological disease, anti-inflammation, attenuation of vascular disease, and amelioration of diabetes. In this review, we explore the antioxidant properties of pterostilbene and its relationship to common disease pathways and give a summary of the clinical potential of pterostilbene in the prevention and treatment of various medical conditions.

Resveratrol is a natural phytoestrogen with neuroprotective properties. Polyphenolic compounds including resveratrol exert in vitro antioxidant, anti-inflammatory, and antiamyloid effects. Resveratrol and its derivative pterostilbene are able to cross the blood-brain barrier and to influence brain activity. The present short review summarizes the available evidence regarding the effects of these polyphenols on pathology and cognition in animal models and human subjects with dementia. Numerous investigations in cellular and mammalian models have associated resveratrol and pterostilbene with protection against dementia syndromes such as Alzheimer's disease (AD) and vascular dementia. The neuroprotective activity of resveratrol and pterostilbene demonstrated in in vitro and in vivo studies suggests a promising role for these compounds in the prevention and treatment of dementia. In comparison to resveratrol, pterostilbene appears to be more effective in combatting brain changes associated with aging. This may be attributed to the more lipophilic nature of pterostilbene with its two methoxyl groups compared with the two hydroxyl groups of resveratrol. The findings of available intervention trials of resveratrol in individuals with mild cognitive impairment or AD do not provide evidence of neuroprotective or therapeutic effects. Future clinical trials should be conducted with long-term exposure to preparations of resveratrol and pterostilbene with high bioavailability.

Low-dose pterostilbene, but not resveratrol, is apotent neuromodulator in aging and Alzheimer's disease.

Recent studies have implicated resveratrol and pterostilbene, a resveratrol derivative, in the protection against age-related diseases including Alzheimer's disease (AD). However, the mechanism for the favorable effects of resveratrol in the brain remains unclear and information about direct cross-comparisons between these analogs is rare. As such, the purpose of this study was to compare the effectiveness of diet-achievable supplementation of resveratrol to that of pterostilbene at improving functional deficits and AD pathology in the SAMP8 mouse, a model of accelerated aging that is increasingly being validated as a model of sporadic and age-related AD. Furthermore we sought to determine the mechanism of action responsible for functional improvements observed by studying cellular stress, inflammation, and pathology markers known to be altered in AD. Two months of pterostilbene diet but not resveratrol significantly improved radial arm water maze function in SAMP8 compared with control-fed animals. Neither resveratrol nor pterostilbene increased sirtuin 1 (SIRT1) expression or downstream markers of sirtuin 1 activation. Importantly, markers of cellular stress, inflammation, and AD pathology were positively modulated by pterostilbene but not resveratrol and were associated with upregulation of peroxisome proliferator-activated receptor (PPAR) alpha expression. Taken together our findings indicate that at equivalent and diet-achievable doses pterostilbene is a more potent modulator of cognition and cellular stress than resveratrol, likely driven by increased peroxisome proliferator-activated receptor alpha expression and increased lipophilicity due to substitution of hydroxy with methoxy group in pterostilbene                                                                                                        

Effect of resveratrol and pterostilbene on aging and longevity.

Over the past years, several studies have found that foods rich in polyphenols protect against age-related disease, such as atherosclerosis, cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes (T2D), hypertension and Alzheimer's disease. Resveratrol and pterostilbene, the polyphenol found in grape and blueberries, have beneficial effects as anti-aging compounds through modulating the hallmarks of aging, including oxidative damage, inflammation, telomere attrition and cell senescence. In this review, we discuss the relationship between resveratrol and pterostilbene and possible aging biomarker, including oxidative stress, inflammation, and high-calorie diets. Moreover, we also discuss the positive effect of resveratrol and pterostilbene on lifespan, aged-related disease, and health maintenance. Furthermore, we summarize a variety of important mechanisms modulated by resveratrol and pterostilbene possibly involved in attenuating age-associated disorders. Overall, we describe resveratrol and pterostilbene potential for prevention or treatment of several age-related diseases by modulating age-related mechanisms.

One area of autism research concerns targeting mTOR signalling. This is covered in the paper below

and was the subject of this blog post from 2015

Targeting the PI3K/Akt/mTOR signaling pathway by pterostilbene attenuates mantle cell lymphoma progression.

Mantle cell lymphoma (MCL) is an aggressive and mostly incurable B-cell malignancy with frequent relapses after an initial response to standard chemotherapy. Therefore, novel therapies are urgently required to improve MCL clinical outcomes. In this study, MCL cell lines were treated with pterostilbene (PTE), a non-toxic natural phenolic compound primarily found in blueberries. The antitumor activity of PTE was examined by using the Cell Counting Kit-8, apoptosis assays, cell cycle analysis, JC-1 mitochondrial membrane potential assay, western blot analysis, and tumor xenograft models. PTE treatment induced a dose-dependent inhibition of cell proliferation, including the induction of cell apoptosis and cell cycle arrest at the G0/G1 phase. Moreover, the PI3K/Akt/mTOR pathway was downregulated after PTE treatment, which might account for the anti-MCL effects of PTE. Synergistic cytotoxicity was also observed, both in MCL cells and in xenograft mouse models, when PTE was administered in combination with bortezomib (BTZ). The antitumor effects of PTE shown in our study provide an innovative option for MCL patients with poor responses to standardized therapy. It is noteworthy that the treatment combining PTE with BTZ warrants clinical investigation, which may offer an alternative and effective MCL treatment in the future.

And finally, PDE4
Inhibiting PDE4 has some very useful anti-inflammatory benefits. It may also improve myelination and indeed cognition.  PDE4 inhibitors are currently used to treat severe asthma and in clinical trials for Multiple Sclerosis (MS) and cognitive enhancement.
There are different sub-types of PDE4.
Inhibiting one of the subtypes has the tendency to make you want to vomit.  This is currently the drawback that limits the use of PDE4 inhibiting drugs.
A selective PDE4 inhibitor is required.
As Ling has found, research does indeed show that pterostilbene is a PDE4 inhibitor.

The molecular basis for the inhibition of phosphodiesterase-4D by three natural resveratrol analogs. Isolation, molecular docking, molecular dynamics simulations, binding free energy, and bioassay.

The phosphodiesterase-4 (PDE4) enzyme is a promising therapeutic target for several diseases. Our previous studies found resveratrol and moracin M to be natural PDE4 inhibitors. In the present study, three natural resveratrol analogs [pterostilbene, (E)-2',3,5',5-tetrahydroxystilbene (THSB), and oxyresveratrol] are structurally related to resveratrol and moracin M, but their inhibition and mechanism against PDE4 are still unclear. A combined method consisting of molecular docking, molecular dynamics (MD) simulations, binding free energy, and bioassay was performed to better understand their inhibitory mechanism. The binding pattern of pterostilbene demonstrates that it involves hydrophobic/aromatic interactions with Phe340 and Phe372, and forms hydrogen bond(s) with His160 and Gln369 in the active site pocket. The present work also reveals that oxyresveratrol and THSB can bind to PDE4D and exhibits less negative predicted binding free energies than pterostilbene, which was qualitatively validated by bioassay (IC50=96.6, 36.1, and 27.0μM, respectively). Additionally, a linear correlation (R(2)=0.953) is achieved for five PDE4D/ligand complexes between the predicted binding free energies and the experimental counterparts approximately estimated from their IC50 values (≈RT ln IC50). Our results imply that hydrophobic/aromatic forces are the primary factors in explaining the mechanism of inhibition by the three products. Results of the study help to understand the inhibitory mechanism of the three natural products, and thus help the discovery of novel PDE4 inhibitors from resveratrol, moracin M, and other natural products.

Based on Ling’s recommendation, I have ordered some Pterostilbene and I am curious to see its effects. It is another substance that might be helpful for older adults, if not for your case of autism.
It is clear that in most cases resveratrol is a substance whose effect is limited to the test tube rather than humans. As a “super-resveratrol” we should take a closer look at Pterostilbene.
Eating large amounts of fruits, vegetables and berries with anthocyanins and betacyanins is going to do you no harm and does look a way to possibly secure a long healthy future, like those Japanese centenarians in Okinawa.


  1. A couple other things about Pterostilbene and Resveratrol should be mentioned which suggests they may be more like apples and carrots than apples and oranges to use an analogy.

    First off, reveratrol has a very short half-life in vivo, however, there was one paper I read a while back that suggested the immediate resveratrol metabolite called resveratrol sulfate was even more potent than resveratrol itself and stayed around in the body much longer before being broken down into something else and excreted.

    Secondly, much of the pooly absorbed resveratrol may exert it's positive health effects, not directly in the body but instead on its interaction with the microbiome. Figuring out which species of bacteria metabolize resveratrol to something else used on the body or else another metabolite used by another bacteria species, etc. is like trying to find a needle in a haystack, but researchers in this space seem to be rapidly improving their abilities in finding needles in haystacks. So at this time I can't say how or if there is a strong connection, but there has been strong speculation that microbiome interactions are one of the primary benefits or oral resveratrol.

    When people talk about Pterostilbene being a superior form of Resveratrol, they are really just talking about their relative effects on SIRT1. The molecules really seem to do many different things in vitro with resveratrol doing a lot more, probably because it has been studied more aggressively.

    My advice is they are both good general purpose supplements with no real downsides and taking both could very well be synergistic, though I have yet to see a study looking at this possibility since all of them to date I have seen merely compare and contrast the two polyphenols.

    There is a strong synergy between resveratrol and spermidine on mTOR inhibition so who knows what synergies pterostilbene has with resveratrol or any other molecule dealing with cellular metabolism.

  2. My own list of all the possible effects of pterostilbene is probably even longer than the one you provided in the picture above Peter, and they are only partly overlapping. It's hard to tell exactly which ones are most important in our case, but I think PDE4 inhibition and enhanced production of certain heat shock proteins might be the answer here.

    We have used it for.. I don't know, 9 months perhaps, without any downsides. Eventually we saw a small change in appetite (less), but that was enhanced before so maybe pterostilbene just normalized things. I haven't heard about anyone vomiting from pterostilbene, so I guess it is more selective regarding the PDE4 effect than rolipram.

    I have tried pterostilbene myself, but I didn't experience any notable effect. For my daughter, it really deserves its place in her daily polypill. So for some it makes a big cognitive change, and for others it will eventually just contribute to a longer healthspan.

    It should be good for both diabetes, colorectal cancer and proteinopathies, and eventually for some hypo-NMDA states. It is a calorie restriction mimetic too.


    1. Ling, it would be useful if you could provide some further information.

      How would you describe the beneficial cognitive effects? What dose are you using? Did you try different doses, if so what was the effect? How long did it take to show effect? Have you tried making a pause to see if the beneficial effect is then lost? Did you also try Resveratrol? Since once effect is against ROS, have you tried other antioxidants like NAC?

    2. @Ling,

      I know resveratrol does preconditioning for NMDA receptors, blocking NMDA receptors with an antagonist actually prevented the protective effect of resveratrol against excitoxicity.

      Here is some info:

      It seems to have a regulatory effect on NMDA and NR2B receptors. Most people tend to think that NMDA is like an on/off switch, it is far more than that. Disease states such as ASD/shizo and god knows what cannot flip the switch and the genetic expression for synaptic nmda transmission. It is actually faulty transmission with crappy receptor binding that is excitoxic.

      Once again im not sure how this extends to pterostilbene.

      Heres another interesting paper on pterostilbene (compared to bromocriptine, a well known dopaminergic and prolactin inhibitor).

      Effects of pterostilbene on treating hyperprolactinemia and related mechanisms

      As you can see it is not as easy as high dopamine would be bad in asd/autism, ratios and brain areas do matter.
      FYI the study showed that the higher dose of pterostilbene was actually nearly as good of a prolactin supressor as bromocriptine, which is pretty impressive. This shows however though that pterostilbene has dopaminergic activity, its something that parents whos kids do clearly have high dopamine levels should be aware of.

  3. I've actually reported on Pterostilbene twice here in this blog, first time at
    and second time here:
    I found a third report in my notes, that I don't think I ever published here:
    "The dose was increased after 5 months of use:
    Age: 3y 5m Weight: 16 kg
    Changing the dose to once daily and upping it to 12.5 mg after several months of use. Saw once again a small cognitive lift within first three weeks. More interest in surroundings and wants to explore more. Started to have an interest in playing board games, which is way above her cognitive level. Plays and plays and plays and wants us to participate. While there still are very few speech sounds, she is using her voice and signs to us more frequently. No obvious side effects at this dose.”

    What I want to add to these reports is that the side effect I mention with toe walking could be something else - last time I saw this I thought it was due to another intervention but in the end it turned out to be teething issues.

    To be honest, I am not sure which dose would be the best. As low as ½ mg/kg and day gave an effect. Upping the dose gives better results, at least short term. I have used as much as 1 mg/kg and day. There was one very unreliable Internet source that I used telling that the cognitive effect of pterostilbene should be at doses between 0.4mg-1.5mg/kg and day, and at least part of that statement seems true.

    We haven't tried Resveratrol and I don't think I will. Ibudilast however could have an additional effect with regards to PDE inhibition.

    Fisetin is the best antioxidant we've used so far, better than Sulforaphane and I think ALA too. Didn't try NAC yet long enough to tell.


    1. Thanks for all the updates Ling.

      Some people do trawl through this blog looking for information, so to make it easier, here are links and the full text of Ling's previous reports on Pterostilbene.

      30 January 2018 at 15:19

      And here is my report on Pterostilbene.

      The brand was Life Extension PteroPure 50 mg and my daughter is 2½ year and weighs around 15 kg.

      We started out with a dose of 2 * 5 mg daily, morning and evening. It was not very easy to get out one tenth of a small capsule, so the dosing was probably a bit uneven. After 2 weeks use we noticed that she was doing "speech sounds" like "mmm" and "mmmaa". At 3 weeks her daycarers surprisingly announced that she had said both "ma-ma" and "pa". This was the same day I decided to change dosing to around 1 mg/kg/day (= 16 mg and easier to dose). After this, she was still using her new sounds occasionally, but we also saw side effects creeping up. Staring spells became more frequent and toe-walking suddenly appeared. After 6 weeks we pulled off and all effects and were lost (speech sounds, toe-walking, staring spells).
      I'm not sure what conclusions to draw from this, but dosing seems to be important.

      18 June 2018 at 22:29

      Time for some reporting!

      My daughter, 3 years and 15 kg, has been on a second round of pterostilbene for 5+ weeks. The dose has been low: 7.5 mg per day and divided into two doses. (According to some sources, 6.5 mg is the lowest dose where pterostilbene has any cognitive effect.)

      The aim was to target PKA via PDE-inhibition with the hope of inducing SATB2 and L-LTP/memory as one important downstream effect.

      Disclaimer: Three weeks before starting pterostilbene we also started vegEPA (fish oil), so this could potentially
      affect the result.

      First three weeks:
      We saw nothing special, only a "good baseline". At the time we were trying to make her learn colours, and for the first time it seemed like she understood what we meant.

      Around day 21:
      There was a sudden cognitive lift, with more presence, happening at the same time as in round 1.

      After 4 weeks:
      She made my jaw fall to the ground one day by throwing a frisbee 4 meters.
      At a couple of occasions she was overhearing and reacting to simple things in our "parental" discussions. Totally unheard of.
      At one evening we were lying in the dark and she pointed and signed what the colours on her blanket where out of memory.
      She discovered her own shadow and has had a lot of fun with it.
      She is opening drawers and doors to check what's behind them.
      At this point I noticed that she had much dryer skin than before (vegEPA effect?).

      Summary after 5 weeks:
      Language comprehension is much better
      Memory is slightly better (very hard to measure but she knows her colours now and maybe even a letter or two)
      More presence - but far from enough
      More exploratory behaviour
      More play and interaction with her sister
      No expressive language gains
      No obvious ongoing cognitive lift after day 21, plateauing?

      All in all - a similar experience to Ponstan/mefenamic acid (but maybe stronger). I guess that I have hit a path where the SATB2 protein is induced, close to CREB.
      Unfortunately this is either not enough or not targeting the place where SATB2 works as a transcription factor, because then I would also see expressive language changes.
      A big question for me is if I should try to work even harder on this pathway (adding Ponstan to pterostilbene) or try another synergistic path like PKC or CamKII.

    2. Interesting stuff Ling. I have tried Fisetin personally for a month with a lot of skepticism due to it along with Resveratrol supposedly being poorly absorbed in oral form and oddly noticed some skin elasticity improvements. Of course it could be other things, but it kinda makes me go humm...

      My interest in Fisetin piqued after recently reading about its properties as a superior senolytic to quercetin and dasatinib and then reading some papers to see its other useful properties including its hypothetical use in neuroprotection. Unfortunately, it's price also peaked at the time so I only ordered one bottle. The price has come down a lot in the last couple of months so I may trial this with my son on your recommendation.

    3. It's interesting to read the concerns of Fisetin's bioavailability on the longevity forums given the obvious effect I see in my daughter. Maybe these people already have the affected functions upregulated by other substances, and so doesn't note any change.

      I think one common denominator is the unfolded protein response, which seems to upregulate protection from oxidative stress, mitochondrial function and heat shock proteins. One effect from Fisetin mimics Sulforaphane (both act on NRF2), and if I remember it right this was implicated for people with the fever effect (doesn't apply to my daughter though). But then Fisetin has other properties too, promoting bone for example and suppressing mast cells. Maybe I should try it for allergy this season?
      As I reported previously, Fisetin had an effect on energy levels (mitochondria), irritability and trichotillomania (oxidative stress) and language (in combination with Bacopa).

      I think a weeks trial is what you need to see any effect. I use 33 mg once daily for a 16 kg-ish kid, which probably is a little low. Have tried 50 mg daily without any problems for 3 consecutive days, one researcher recommended 2-4 mg/kg and day for adults.

      I do hope it helps your son too!

    4. The concerns over the bioavailability were from the actual research group that looked into Fisetin's use recently as a potent senolytic. I think I even posted the study here not long ago.

    5. Fisetin is next in my list of trials. My daughter (14yo) started to eat strawberries couple years ago. I noticed some cognitive effect, but never explored further.
      Thought that is my imagination, but, in spite of that, I used to give her them before every important test in school. And it worked, even it was less than 37 pieces.
      Ling, would you please tell me can I mix fisetin with some fish oil (CLO)? Do you give it every day? Thanks in advance,

    6. Maja, I mix fisetin with VegEPA, pterostilbene, bacopa, buttermilk powder and K2 vitamin every morning, since about 3 months back.

    7. Since pollen season is here, I'd like to mention that yes, Fisetin has a small ameliorating effect on allergy too.

      I think the Fisetin molecule has some resemblance to quercetin, but I don't know if these substances work on the same pathways. Anyway, I can feel a difference with one 100 mg Fisetin capsule, but adding 200 mg on top of that doesn't make any big difference.
      Quercetin is often sold as 400 or 500 mg capsules.

      Unfortunately none of these substances help completely, and so does not any allergy drug I've used so far. Just wanted to mention this self-trialled mode of action of Fisetin.


  4. Hey everyone, its been a while.

    I was wondering if anyone has had success with resveratrol.
    Like last year around early januari till end januari I felt very off/sick yet again this year. Im seeing a specialist next week hope they can shed some light on whats wrong with me regarding my immune function.

    Either way has anyone had success with resveratrol? From the reading that Ive done is that it looks impressive, ERbeta activation, socialibity increase and all that.

  5. Would like to point that resveratrol (not sure about Pterostilbene, but i would assume it shares this) is a GPR estrogen agonist on top of that it is DNMT inhibitor (what does this mean? it means that Estrogen receptor beta activity will stay around longer so to speak). And we all know about the importance of ERbeta in ASD.

    Some impressive recent studies on resveratrol with regards to autism and asd:

    Resveratrol enhances 5-hydroxytryptamine type 3A receptor-mediated ion currents: the role of arginine 222 residue in pre-transmembrane domain I. (no 5ht3a is not always the devil, patients with shizo disorders improved on risperdal ONLY when 5ht3a activity increased!)

    Evaluation of brain SERT occupancy by resveratrol against MDMA-induced neurobiological and behavioral changes in rats: A 4-[¹⁸F]-ADAM/small-animal PET study.
    Looks like resveratrol can actually be anti-serotoninergic in high serotonin settings such as reduced SERT expression during MDMA withdrawal.

    Resveratrol prevents social deficits in animal model of autism induced by valproic acid

    Adenosine receptors as a new target for resveratrol-mediated glioprotection

    Resveratrol exerts anti-inflammatory and neuroprotective effects to
    prevent memory deficits in rats exposed to chronic unpredictable
    mild stress
    "The 20 mg/kg resveratrol + CUMS group
    showed improved performance compared to the CUMS group. In addition, the CUMS procedure induced lower
    expression of brain-derived neurotrophic factor and c-Fos in hippocampal CA1 and CA3 and in the amygdala of
    stressed rats. These effects were reversed by chronic administration of resveratrol (20 mg/kg). In addition, plasma
    levels of tumor necrosis factor-alpha and interleukin-1 beta were increased by CUMS, but were restored to normal
    by resveratrol. These results indicate that resveratrol significantly attenuates the deficits in emotional learning and
    spatial memory seen in chronically stressed rats. These effects may be related to resveratrol-mediated changes in
    neurotrophin factor expression in hippocampus and in levels of proinflammatory cytokines in circulation."

    Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERβ activation

    Lack of synergistic effect of resveratrol and sigma-1 receptor agonist (PRE-084) in SOD1G93A ALS mice: overlapping effects or limited therapeutic opportunity?

  6. Neuroprotective effects of resveratrol and epigallocatechin gallate polyphenols are mediated by the activation of protein kinase C gamma

    Oxidative stress mediated by NMDA, AMPA/KA channels in acute hippocampal slices: Neuroprotective effect of resveratrol

    Resveratrol Prevents Cellular and Behavioral Sensory Alterations in the Animal Model of Autism Induced by Valproic Acid.
    "Male pups were analyzed in Nest Seeking (NS) behavior and in whisker nuisance task (WNT). At P30, the tissues were removed and analyzed by immunofluorescence and western blotting. Our data showed for the first time an altered localization of PV+-neurons in primary sensory cortex and amygdala. We also showed a reduced level of gephyrin in the primary somatosensory area (PSSA) of VPA animals. The treatment with RSV prevented all the aforementioned alterations triggered by VPA. Our data shed light on the relevance of sensory component in ASD and highlights the interplay between RSV and VPA animal model as an important tool to investigate the pathophysiology of ASD."

    PM345. Resveratrol Suppresses Neuroinflammation in the Experimental Paradigm of Autism Spectrum Disorders

    Resveratrol stimulates cortisol biosynthesis by activating SIRT-dependent deacetylation of P450scc. (remember cortisol is critical for learning, it is not the devil, only in excess it is bad)

    Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network

    Some more:

    Resveratrol ameliorates dysregulation of Th1, Th2, Th17, and T regulatory cell-related transcription factor signaling in a BTBR T + tf/J mouse model of autism. Mol Neurobiol 2017; 54: 5201–5212.
    Bakheet SA, Alzahrani MZ, Nadeem A, Ansari MA, Zoheir KMA, Attia SM, et al: Resveratrol treatment attenuates chemokine receptor expression in the BTBR T + tf/J mouse model of autism. Mol Cell Neurosci 2016; 77: 1–10.
    Bhandari R, Kuhad A: Resveratrol suppresses neuroinflammation in the experimental paradigm of autism spectrum disorders. Neurochem Int 2017; 103: 8–23.

  7. To keep it all realistic and sincere:

    Pterostilbene raises low density lipoprotein cholesterol in people

    Pterostilbene on metabolic parameters: a randomized, double-blind, and placebo-controlled trial.

    Thought id put that out there, considering some recommendations are made on this blog for statins, yet adding pterostilbene for example could possibly undo that effect and potentially be harmfull in that context.

  8. Thank you Aspie, for those last studies - I knew there had to be some less flattering regarding pterostilbene on cholesterol. It's good to know the possible side effects - in my case the positives outweigh this anyway.

    Since you are mentioning ERbeta:

    "Here we report that resveratrol binds ERbeta and ERalpha with comparable affinity, but with 7,000-fold lower affinity than estradiol (E2). Thus, resveratrol differs from other phytoestrogens that bind ERbeta with higher affinity than ERalpha. [..]. This indicates that those tissues that uniquely express ERbeta or that express higher levels of ERbeta than ERalpha may be more sensitive to resveratrol's estrogen agonist activity. For the natural, imperfect EREs from the human c-fos, pS2, and progesterone receptor (PR) genes, resveratrol shows activity comparable to that induced by E2. We report that resveratrol exhibits E2 antagonist activity for ERalpha with select EREs. In contrast, resveratrol shows no E2 antagonist activity with ERbeta. These data indicate that resveratrol differentially affects the transcriptional activity of ERalpha and ERbeta in an ERE sequence-dependent manner."


    1. Yep Ling, in one of the studies (not sure if it was in humans but I think it was) Ptero also raises triglycerids :/

      With regards to ERa and ERb in the brain: if you look at a lot of herbals that actually have an effect and do something and are not just your average snake oil pill you will find out that they are often phyto estrogens/progestins. Some examples being panax ginseng, icariin and obviously resveratrol.
      They exert a minimal effect on E2 and often even displace (most from ERa binding in tissues such as breast, hence them being investigated for possible prevention for things such as breastcancer).
      It seems to me that in the brain these phytoestrogens actually potentiate signalling there in mental disorders where there is improper estrogen binding in the brain.

      Relationships among estrogen receptor, oxytocin and vasopressin gene expression and social interaction in male mice.

      "OTR and V1aR mRNAs were highly correlated with estrogen receptor α (ERα) mRNA in the medial amygdala, and OT and AVP mRNAs with estrogen receptor β (ERβ) mRNA in the PVN, indicating that OT and AVP systems are tightly regulated by estrogen receptors. A significant difference in the level of ERα mRNA in the medial amygdala between high and low social interaction mice was also observed. These results support the hypothesis that variations of estrogen receptor levels are associated with differences in social interaction through the OT and AVP systems, by upregulating gene expression for those peptides and their receptors."

      Oxytocin and Estrogen Receptor β in the Brain: An Overview
      "OT binds to the widely expressed OT receptor (OTR), and, in doing so, it regulates homeostatic processes, social recognition, and fear conditioning. In addition to these functions, OT decreases neuroendocrine stress signaling and anxiety-related and depression-like behaviors. Steroid hormones differentially modulate stress responses and alter OTR expression. In particular, estrogen receptor β activation has been found to both reduce anxiety-related behaviors and increase OT peptide transcription, suggesting a role for OT in this estrogen receptor β-mediated anxiolytic effect."

      Estrogen Receptor β and Oxytocin Interact to Modulate Anxiety-like Behavior and Neuroendocrine Stress Reactivity in Adult Male and Female Rats
      Study showing blocking oxytocin (with an OT antagonist) blocked the anxiolytic effect of a ERbeta agonist.

      One more thing which Peter has discussed before about sonic hedgehog, resveratrol seems to have an effect on it aswell:

      Resveratrol Enhances Neurite Outgrowth and Synaptogenesis Via Sonic Hedgehog Signaling Following Oxygen-Glucose Deprivation/Reoxygenation Injury

  9. Decreased levels of G protein-coupled estrogen receptor in children with autism spectrum disorder

    Lab values actually showed identical estrogen levels between asd and normal controls, but the different between GPR30 (aka GPER) was quite huge.

    GPER, ng/ml, mean±sd
    ASD= 0,14±0,06*
    CONTROL = 0,20±0,09 P=0,002


    Evidence that the G-Protein Coupled Membrane Receptor GPR30 Contributes to the Cardiovascular Actions of Estrogen

    One of the reasons why there are a lot of vascular problems in ASD?


    Resveratrol inhibits Kv2.2 currents through the estrogen receptor GPR30-mediated PKC pathway


    Same seems to apply to quercetin, which is also classed a GPR30 agonist.
    GPR30/GEPR is worth looking into.


  10. Estrogen receptor GPR30 exerts anxiolytic effects by
    maintaining the balance between GABAergic and
    glutamatergic transmission in the basolateral
    amygdala of ovariectomized mice after stress


Post a comment