Pterostilbene for Neuromodulation – worth a look?

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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.

The Okinawan Diet and Anthocyanin

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: -  

Effects of pterostilbene and resveratrol on brain and behavior

           

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. 

A Review of Pterostilbene Antioxidant Activity and Disease Modification

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, pterostilbene, and dementia

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

Reversing autism by targeting downstream mTOR signalling

and was the subject of this blog post from 2015

https://epiphanyasd.blogspot.com/2015/06/mtor-indirect-inhibition-holy-grail-for.html

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.

Conclusion

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.