Nowadays, polyphenols are one of the main topics of interest for many scientists. Polyphenols are one of the strongest natural antioxidants and micronutrients that are biologically active compounds in plant-based foods. They are the reason behind the fruit’s specific colours and taste (Gharras, 2009). Polyphenols also protect plants from ultraviolet radiation, pathogens and extreme weather conditions, and thanks to these specific characteristics, they are very useful for humans’ health (Pandey and Rizvi, 2009).

Some of the best-known polyphenol sources are berries, dark chocolate, red wine, green and black tea but there are many others (see Table 1 and Figure 1). As an illustration, fruits including berries, cherries, apples, grapes, and pears provide up to 200–300 mg of polyphenols per 100 grams of fresh weight. Polyphenols are present in substantial concentrations in the products made from these fruits as well. The average amount of polyphenols in a glass of red wine, a cup of tea, or coffee is 100 mg (Pandey and Rizvi, 2009).

Table 1: Food rich with polyphenols
Table 1: Food rich with polyphenols

Table reference:

Table with food
Figure 1: Food rich with polyphenols

The main classes in the polyphenols are phenolic acids (hydroxybenzoic acids and hydroxycinnamic acids), flavonoids (flavonols, flavones, flavanols, flavanones, isoflavones, proanthocyanidins), stilbenes, phenolic alcohols and lignans (Manach et al., 2005). See Figure 2 for classification diagram of polyphenols.

It’s important to emphasize that the distribution of polyphenols in plants is not uniform and that its content depends on many factors such as environmental factors, storage, processing and cooking. While flavanones and isoflavones are unique to certain foods, some polyphenols, such as quercetin, are present in all plant products. Plants’ outer layers have larger concentrations of phenolics than their inner layers do. After 15 minutes of cooking, tomatoes and onions lose between 75% and 80% of their original quercetin content (Pandey and Rizvi, 2009). On the other hand, the bioavailability of polyphenols in the human body is not maximal. The metabolites of polyphenols in the blood and tissues differ from those present in food. That is why the polyphenols that are most common in our diets may not always have the largest levels of active metabolites in the target tissues (Pandey and Rizvi, 2009).

Although polyphenols are best known for their function as natural antioxidants, numerous studies have discovered compelling evidence that long-term consumption of nutrients high in plant polyphenols can protect against cancer, diabetes, osteoporosis, cardiovascular, neurodegenerative diseases and neurodevelopmental disorders (Pandey and Rizvi, 2009).

Neurodevelopmental disorders can be defined as a heterogeneous group of conditions characterized by developmental deficits in the social, cognition, motor and language domain. The group of disorders includes autism spectrum disorder (ASD), intellectual disability, global developmental delay, attention deficit/hyperactivity disorder (ADHD) and social communication disorder (Tsukada et al., 2019). Autism Spectrum Disorders (ASD) are most commonly caused by Fragile X syndrome (FXS) and are found in approximately 60% of patients with FXS (Rajaratnam et al., 2020). There have been certain studies showing the benefits of polyphenols in the treatment of neurodevelopmental disorders and particularly ASD patients. In contrast to conventional therapeutic strategies for ASD treatment which use the brain as the target organ, polyphenols have a heterogenous action mechanism. After oral administration, polyphenols reach the highest quantities in the intestinal compartment, reduce intestinal inflammation and regulate gut flora, but they also have neuroprotective effects on the brain (Serra et al., 2019). Some polyphenols, such as resveratrol, regulate mitochondrial activity and prevent mitochondrial dysfunction, which is typically present in patients with ASD (Jardim et al., 2018). Not all polyphenols can cross the blood-brain barrier, but they all reach high concentrations in the intestinal lumen (Pangrazzi et al., 2020). It is shown that polyphenols can change the microbiota, which is the part of the microbiota–gut–brain axis (Duda-Chodak et al., 2015) that connects the intestinal system to the cognitive and emotional centers of the brain. Gut-brain axis is the reason why polyphenols, modulating gut microbiota and showing their antiinflammatory activity can have a positive effect on brain disorders (Serra et al., 2019).

Dietary polyphenols have also been reported to interrupt cell signaling pathways, contributing to the protection against oxidative stress, inflammation, and abnormal cell proliferation which is proven in many preclinical studies using animal models. Na et al. (2016) have shown that rutin (flavonoid easily found in citrus fruit) activates SIRT1, inhibiting oxidative stress and inflammation in rats. On the other side, in a mouse model of Down syndrome, the major flavonoid in green tea, epigallocatechin-3-gallate (EGCG), and the stilbene resveratrol stimulate neurogenesis due to activation of SIRT1/AMPK/PGC1 axis (Valenti et al., 2016) and there are more examples (Serra et al., 2019).

So far, there are only a few clinical studies showing the potential effects of dietary polyphenols as a new therapeutic strategy for ASD. Taliou et al. performed a pilot study including 50 children with ASD, of which 42 boys and 8 girls, all 4-10 years old (Taliou et al., 2013). Children were exposed to an oral formulation constituted of the flavonoids quercetin, luteolin, and quercetin glycoside rutin administered every day for 26 weeks. Children that completed the established protocol revealed a significant improvement in communication, concentration and cooperation, with a decrease in abnormal behaviors. Serum levels of TNF-α and IL-6 of these patients significantly decreased as compared to the beginning of the study (Taliou et al., 2013).

Tsilioni et al. (2015) suggest that the decrease in the proinflammatory cytokine levels can be related to the reduction of the neuroinflammatory process after flavonoid administration.
Bertolino et al. reported a single case study of a 10-year-old ASD boy who received microgranules with palmitoylethanolamide and luteolin twice a day for one year and has shown an improvement in ASD-like behaviors (Bertolino et al., 2017).

Despite limitations, the results of these studies are encouraging and show the potential effects of polyphenols in the treatment of ASD (Serra et al., 2019).

During this project, in our laboratory, we are planning to investigate the behavior and molecular aspects of Fragile X syndrome Drosophila model treated with polyphenols.

Figure 2: Classification of polyphenols. Our laboratory plans to investigate application of the polyphenols that are highlighted in yellow.
Figure 2: Classification of polyphenols. Our laboratory plans to investigate application of the polyphenols that are highlighted in yellow.

Although there are many studies showing benefits of the polyphenols for the treatment of ASD and other neurodevelopmental diseases, there are not too many of them examining the role of polyphenols in the therapy of Fragile X syndrome. Almost all studies use chemically induced autism rats and mice as the animal model. That is why we are looking forward to seeing the results of our studies on the Fragile X Drosophila model treated with polyphenols and we are hoping to be able to give our modest contribution to this topic.


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