Resveratrol’s neglected siblings

 

We have previously discussed the powerful antioxidant Resveratrol, and reviewed the research suggesting that it could be beneficial in the context of Parkinson’s disease (Click here to read that post).

I have subsequently been asked by several readers to provide a critique of the Parkinson’s-associated research focused on Resveratrol’s twin sister, Pterostilbene (pronounced ‘Terra-still-bean’).

But quite frankly, I can’t.

Why? Because there is NO peer-reviewed scientific research on Pterostilbene in models of Parkinson’s disease.

In today’s post we will look at what Pterostilbene is, what is known about it, and why we should seriously consider doing some research on this compound (and its cousin Piceatannol) in the context of Parkinson’s disease.


Blue berries are the best natural source of Pterostilbene. Source: Pennington

So this is likely to be the shortest post in SoPD history.

Why?

Because there is nothing to talk about.

There is simply no Parkinson’s-related research on the topic of today’s post: Pterostilbene. And that is actually a crying shame, because it is a very interesting compound.

What is Pterostilbene?

Like Resveratrol, Pterostilbene is a stilbenoid.

Stilbenoids are a large class of compounds that share the basic chemical structure of C6-C2-C6:

Resveratrol is a good example of a stilbenoid. Source: Wikipedia

Stilbenoids are phytoalexins (think: plant antibiotics) produced naturally by numerous plants. They are small compounds that become active when the plant is under attack by pathogens, such as bacteria or fungi. Thus, their function is generally considered to part of an anti-microbial/anti-bacterial plant defence system for plants.

The most well-known stilbenoid is resveratrol which grabbed the attention of the research community in a 1997 study when it was found to inhibit tumour growth in particular animal models of cancer:

Title: Cancer chemopreventive activity of resveratrol, a natural product derived from grapes
Authors: Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC, Pezzuto JM.
Journal: Science. 1997 Jan 10;275(5297):218-20.
PMID: 8985016

In this study, the investigators found the resveratrol – which usually acts like an antioxidant – has anti-mutagenic properties (meaning it reduces the chances of a genetic mutation occurring). It also mediated anti-inflammatory effects and inhibited the development of cancerous growths in mammary glands and skin cancer models. The researcher concluded that resveratrol warrants further investigation “as a potential cancer chemopreventive agent in humans”.

And these results were quickly replicated by other research groups (Click here, here and here to read more about this).

Then in 2006, a research article was published in the prestigious journal Nature suggesting that resveratrol improved the health and survival of mice on a high-calorie diet:

Wine2Title: Resveratrol improves health and survival of mice on a high-calorie diet.
Authors: 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.
Journal: Nature. 2006 Nov 16;444(7117):337-42.
PMID: 17086191          (This article is OPEN ACCESS if you would like to read it)

In this study, the investigators placed middle-aged (one-year-old) mice on either a standard diet or a high-calorie diet (with 60% of calories coming from fat). The mice were maintained on this diet for the remainder of their lives. Some of the high-calorie diet mice were also placed on resveratrol (20mg/kg per day). After 6 months of this treatment, the researchers found that resveratrol increased survival of the mice and insulin sensitivity. Resveratrol treatment also improved mitochondria activity and motor performance in the mice.

Now, as you can imagine that this report caused a quite a bit of excitement – suddenly there was the possibility that we could eat whatever we wanted and this amazing little chemical would save us from any negative consequences.

And then the news got even better!

Fruit are a particularly good source of resveratrol, especially the skins of grapes, blueberries, raspberries, mulberries and lingonberries. One issue with fruit as a source of resveratrol, however, is that tests in rodents have shown that less than 5% of the fruit-based dose of resveratrol was found to be passed through to the blood (Source).

This has lead to the extremely popular idea of taking resveratrol in the form of wine, in the hope that it would have higher absorption (the difference between taking your medication in liquid (wine) versus pill (grape) form).

Red wines have the highest levels of Resveratrol in their skins (particularly Mabec, Petite Sirah, St. Laurent, and pinot noir), and folks fell in love with the idea that ageing and disease could potentially be cured by drinking lots of big Bordeaux wines (which contain approximately 3-6 mg of resveratrol per 750ml bottle).

Grape

Everyone thought it was party time. Source: Nature

Unfortunately (and it truly pains me to rain on this parade) a study out of the University of Illinois suggested that resveratrol needs to be used at levels of at least 8mg/kg of body weight in mice. If translated to humans, this equates to a 150-pound (70kg) individual needing to consume about 550mg of resveratrol per day.

For those of you that struggled with Maths class, that’s approximately 266 bottles of red wine…per day!

Obviously consuming red wine is NOT the most efficient way of absorbing resveratrol. Grape juice is a much better (less exciting) option. It has much higher levels of resveratrol than wine (Click here to read more on this).

EDITOR’S NOTE HERE: The recommended daily dose of resveratrol should not exceed 250 mg per day over the long term (Source). Resveratrol might increase the risk of bleeding in people with bleeding disorders and should be used with caution if you are being treated with blood thinning medication (such as warfarin). PLEASE discuss any change in treatment regimes with your doctor before starting.

Given the hype that surrounded this particular research, it is very safe to say that of all the stilbenoids, resveratrol has received most of the attention thus far.

So what research has been done on pterostilbene?

Well, with regards to Parkinson’s disease, please see my statement above. There has been no research involving this compound in any models of Parkinson’s disease that I am aware of. And I’d be very pleased to be corrected on this.

In other disease models, however, pterostilbene has demonstrated some very impressive properties:

Title: Low-dose pterostilbene, but not resveratrol, is a potent neuromodulator in aging and Alzheimer’s disease.
Authors: Chang J, Rimando A, Pallas M, Camins A, Porquet D, Reeves J, Shukitt-Hale B, Smith MA, Joseph JA, Casadesus G.
Journal: Neurobiol Aging. 2012 Sep;33(9):2062-71.
PMID: 21982274

The Senescence Accelerated Mouse-Prone 8 (or SAMP8) is a naturally occurring strain of mouse that displays accelerated ageing (Click here to read an interesting review about this mouse). In this study, SAMP8 mice were fed a diet either rich in pterostilbene or rich in resveratrol and then they were assessed in various tests of ability. After two months on the pterostilbene diet, the SAMP8 mice performed significantly better in the tests of ability than both the resveratrol-diet mice and the control-fed SAMP8 animals. Pterostilbene treatment also modulated markers of cellular stress, decreased inflammation, and reduced Alzheimer’s-like damage in the brain. By comparison, resveratrol compared little better than control on these measures.

Curiously, the researchers found that neither resveratrol nor pterostilbene increased levels of sirtuin 1 (or SIRT1). This is the ‘wonder protein’ associated with resveratrol (Click here to read a previous post on resveratrol and sirtuin 1).

The researchers concluded that ‘pound-for-pound’ pterostilbene provides more neuroprotective punch than resveratrol. And more recently this neuroprotective property of pterostilbene has been demonstrated in other models of brain injury:

Title: Orally administrated pterostilbene attenuates acute cerebral ischemia-reperfusion injury in a dose- and time-dependent manner in mice.
Authors: Zhou Y, Zhang XM, Ma A, Zhang YL, Chen YY, Zhou H, Li WJ, Jin X.
Journal: Pharmacol Biochem Behav. 2015 Aug;135:199-209.
PMID: 26086685

In this model of stroke, different doses of pterostilbene was administered to mice for three days before stroke was induced (by blocking the middle cerebral artery, resulting in a lack of oxygen to parts of the brain). This oxygen deprivation resulted in damage and loss of cells in mice that were treated with a control solution, but pterostilbene treatment demonstrated neuroprotection in a dose-dependent manner.

Other groups have observed similar neuroprotective properties in pterostilbene (Click here and here to read more on this), some of which may be associated with NRF2-pathway involvement:

Title: Neuroprotective effects of pterostilbene against oxidative stress injury: Involvement of nuclear factor erythroid 2-related factor 2 pathway.
Authors: Wang B, Liu H, Yue L, Li X, Zhao L, Yang X, Wang X, Yang Y, Qu Y.
Journal: Brain Res. 2016 Jul 15;1643:70-9.
PMID: 27107941

The researchers conducting this study were interested in the effect that pterostilbene has on oxidative stress in cells (Click here to read more about what oxidative stress is). What they found was pterostilbene activated Nuclear Factor Erythroid 2-Related Factor 2 (or NRF2).

What is NRF2?

NRF2 is a transcription factor with some interesting properties.

What is a transcription factor?

A transcription factor is a protein that is involved in the process of converting (or transcribing) DNA into RNA.

In the case of NRF2, a transcription factor can be an ‘activator’ of transcription – that is initiating or helping the process of generating RNA from DNA.

6567f50d30ad3ac65aff1e815caf202b3abd7111

An example of a transcriptional activator. Source: Khan Academy

Nrf2 is an activator of transcription. When it binds to DNA to aids in the production of RNA, which then results in specific proteins being produced. And this is where NRF2 gets interesting.

You see, NRF2 binds to antioxidant response elements (ARE).

What are ARE?

Antioxidant response elements (ARE) are regions of DNA is commonly found in the regulatory region of genes encoding various anti-oxidant and protective proteins. The regulatory region of genes is the section of DNA where transcription is initiated for each gene. They are pieces of DNA that a transcription factor like NRF2 binds to and activates the production (or transcription) of RNA.

ARE are particularly interesting because these regions reside in the regulatory regions of genes that encode naturally occurring antioxidant and protective proteins. Given that antioxidants and protective proteins are generally considered a good thing for sick/dying cells, you can see why NRF2 is an interesting protein to investigate (Click here to read a previous post on this topic).

And you can see why the researchers were excited by the idea of pterostilbene activating NRF2.

And there is no research on Parkinson’s disease?

Nope.

The closest study I could find that had anything to do with Parkinson’s was this study:

Title: Cellular and behavioral effects of stilbene resveratrol analogues: implications for reducing the deleterious effects of aging.
Authors: Joseph JA, Fisher DR, Cheng V, Rimando AM, Shukitt-Hale B.
Journal: J Agric Food Chem. 2008 Nov 26;56(22):10544-51.
PMID: 18954071

In this study, the researchers assessed the ability of different stilbenes “in reversing the deleterious effects of ageing in 19 month old rats”. And guess which stilbene was the pick of the bunch?

That’s right: pterostilbene!

The weakly Parkinson’s related aspect of the study relates to dopamine release.

Dopamine is the chemical that is severely reduced in the brains of people with Parkinson’s, and the researchers found that both low- and high-pterostilbene diets rescued the decrease in dopamine release following a toxin (H2O2). They concluded that “pterostilbene protected against the decrease in dopamine release following an oxidative stressor”. 

But that is it!

That is all the research I can find on pterostilbene and Parkinson’s.

Ok, so what does it all mean?

Before we sum up and finish the post, there is another stilbenoids I would like to bring to your attention: Piceatannol.

Stilbenoids: Spot the difference. Source: Royal Society 

Piceatannol is actually a metabolite of resveratrol, meaning that as resveratrol is processed, piceatannol is produced. And based on the research that has already done conducted, this particular stibene also deserves more attention.

The thing that is interesting about Piceatannol is that it has already been shown to have an impact on Parkinson’s related proteins. Last year, this research report was published:

Title: Piceatannol and Other Wine Stilbenes: A Pool of Inhibitors against α-Synuclein Aggregation and Cytotoxicity
Authors: Temsamani H, Krisa S, Decossas-Mendoza M, Lambert O, Mérillon JM, Richard T.
Journal: Nutrients. 2016 Jun 15;8(6). E367.
PMID: 27314384                (This article is OPEN ACCESS if you would like to read it)

In this study, the researchers investigated the ability of stilbenes to inhibit the clustering (or aggregation) of Parkinson’s associated protein alpha synuclein. The aggregation of this protein is believed to be toxic in Parkinson’s. The researchers looked at three stilbenes – piceatannol, ampelopsin A, and isohopeaphenol – and tested them on cells that produce a lot of alpha synuclein. Piceatannol, in particular, was found to inhibit the formation of the toxic form of alpha synuclein and also destabilise pre-formed versions of this toxic protein. Piceatannol was also able to protect the cells from alpha synuclein-induced cell death.

And alpha synuclein is not the only Parkinson’s-associated protein that piceatannol can influence:

Title: Antioxidants inhibit neuronal toxicity in Parkinson’s disease-linked LRRK2.
Authors: Angeles DC, Ho P, Dymock BW, Lim KL, Zhou ZD, Tan EK.
Journal: Ann Clin Transl Neurol. 2016 Mar 2;3(4):288-94.
PMID: 27081659                 (This article is OPEN ACCESS if you would like to read it)

In this study, the investigators were interested in finding compounds that inhibit the Parkinson’s-associated protein called Leucine-rich repeat kinase 2 (or LRRK2).

What is LRRK2?

Also known as ‘Dardarin (from the Basque word “dardara” which means “trembling”), LRRK2 is an enzyme that has many functions within a cell – from supporting efforts to move things around inside the cell to helping to keep the power on (involved with mitochondrial function).

Fig-2-LRRK2-involvement-in-cellular-mechanisms-Several-data-posit-that-LRRK2-through

The many jobs of LRRK2. Source: Researchgate

The gene that provides the instruction for making the LRRK2 enzyme resides on the 12th chromosome, in an area of DNA referred to as ‘PARK8’ (one of the Parkinson’s disease-associated genetic regions). It is made up of many different regions, each of which is involved with the different functions of the eventual protein.

image5

The regions and associated functions of the LRRK2 gene. Source: Intechopen

Genetic mutations within the LRRK2 gene are recognised as being some of the most common with regards to increasing ones risk of developing Parkinson’s disease.

image1

The structure of Lrrk2 and where various mutations lie. Source: Intech

As the image above suggests, mutations in the PARK8 gene are also associated with Crohn’s disease (Click here and here for more on this) – though that mutation is in a different location to those associated with Parkinson’s disease. And one particularly common Parkinson’s-associated LRRK2 mutation – called G2019S – is also associated with increased risk of certain types of cancer, especially for hormone-related cancer and breast cancer in women – Click here to read more about this. If you have a G2019S mutation, it is good to be aware of this association and have regular check ups.

The G2019S mutation (the name designates its location on the gene) is the most common LRRK2 mutation. In some populations of people it can be found in 40% of people with Parkinson’s disease (Click here to read more about this). But what is interesting about this mutation is that it gives rise to a LRRK2 enzyme that is hyperactive.

Protein_LRRK2_PDB_2ZEJ

The structure of LRRK2. Source: Wikipedia

As a protein, LRRK2 interacts with many different types of other proteins, and you can imagine that in a finely balanced environment like the cells, a hyperactive form of LRRK2 is going to cause problems. And it is believed that this hyperactivity is the cause of the problems associated with Lrrk2-associated Parkinson’s disease.

For this reason, researchers have been looking for inhibitors of Lrrk2, for the purpose of therapeutically reducing the levels of hyperactive Lrrk2 in the cells (we have recently discussed research relating to this – click here to read that post).

In the current piceatannol-related research report, the investigators screened a large batch of anti-oxidant compounds (84 all together) for their ability to inhibited Lrrk2 activity. They identified three compounds that exhibited strong Lrrk2 inhibitory activity:

  • piceatannol
  • thymoquinone
  • esculetin

When they tested these three compound on a Lrrk2-G2019S fly model of Parkinson’s, the researchers found that all of them reduced the loss of dopamine neurons, reduced oxidative stress, and improved overall locomotive ability in the flies (when compared to weaker inhibitors).

The researchers concluded their study by indicating the more research is needed on piceatannol, particularly to determine if it can cross the blood-brain-brain (a protective membrane surrounding the brain that stops some chemicals from entering the brain).

And in addition to these protein influencing activities, it seems that piceatannol also has the anti-oxidant properties of the other stilbenes:

Title: Effects of piceatannol and pterostilbene against β-amyloid-induced apoptosis on the PI3K/Akt/Bad signaling pathway in PC12 cells.
Authors: Fu Z, Yang J, Wei Y, Li J.
Journal: Food Funct. 2016 Feb;7(2):1014-23.
PMID: 26757883

The researchers conducting this study wanted to assess the effects of two stilbenes (piceatannol and pterostilbene) against the toxic effects of the Alzheimer’s related protein Beta-Amyloid. Not only did piceatannol inhibit many biological pathways related to cell death (apoptosis), but it also exhibited larger anti-oxidant effects than pterostilbene:

These results further support the idea that this particular stilbene warrants further investigation, particularly in the realm of Parkinson’s disease.

So what does it all mean?

Summing up: I was asked some time ago to look into pterostilbene and the other stilbenes. But this post was hard to write because there is so little research on these interesting little compounds. They appear to have some very interesting properties, but until further research is conducted, it is difficult to make any real conclusions about the potential utility.

I don’t want to start channelling Lenin here, but our market-based system sometimes can be a bit frustrating. Interesting compounds that can not be patented are often left to languish in favour of novel treatments that arrive with a health fat margin attached. Pterostilbene and piceatannol are just such languishing compounds. The fact that there is nothing known about this stilbenoid in the context of Parkinson’s disease is rather disturbing.

So rather than really answering a readers question about these compounds, this post has become a rallying call for fellow researchers to investigate these compounds to determine if there is potentially something useful here.


EDITOR’S NOTE: The information provided by the SoPD website is for information and educational purposes only. Under no circumstances should it ever be considered medical or actionable advice. It is provided by research scientists, not medical practitioners. Any actions taken – based on what has been read on the website – are the sole responsibility of the reader. Any actions being contemplated by readers should firstly be discussed with a qualified healthcare professional who is aware of your medical history. While some of the information discussed in this post may cause concern, please speak with your medical physician before attempting any change in an existing treatment regime.


The banner for today’s post was sourced from the Royal Society

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