Activate your mind! The wild green oat herb extract, Neuravena, is scientifically proven to enhance stress resistance, learning ability and alertness.

Although green oat herb preparations have traditionally been used to support mental fitness and cognitive function since medieval times, the ability to utilize these properties in modern-day nutraceuticals, food supplements and functional foods is contingent on solid scientific evidence. (1-2) Efficacy, safety and quality take centre stage in the herbal extracts market and formulators are increasingly demanding ingredients with product-specific data to substantiate health-related claims. Common bibliographic data are often not sufficient, as the pharmacological profile of different herbal extracts can vary dramatically.

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Using modern scientific methods, Frutarom has been able to substantiate the beneficial effects of the wild green oat herb extract, Neuravena EFLA 955, derived from a specific oat variety. Initially, Neuravena was selected from a large range of different oat varieties, because of its superior bioactivity, using a bioassay-guided development approach. Its selective effects on brain enzymes were then backed up by convincing evidence from animal studies and, most recently, from a human clinical trial. The results indicated a promising avenue for using Neuravena as a safe and natural ingredient for food supplements, nutraceuticals and functional foods targeted at improving mental fitness, stress resistance and learning abilities.

Bioassay-Guided Approach: Screening for Evidence

The clinical effect of a herbal extract cannot be attributed to one single substance; it is the result of the synergistic interplay of all of the extract's constituents. The genetic and phenotypic variability of a plant, as well as the extraction and refining technologies used when developing a multicomponent herbal extract, are critical when it comes to maximizing the health benefits and minimizing the side-effects of the final product. (3) Bioassay-guided development is a state-of-the-art research method for the rational development of efficacious and safe herbal extracts. The impact of different plant varieties and extract preparation methods on the efficacy of the extract can be assessed by screening its bioactivity profile from the raw material up to the final product in vitro (Figure 1). Similarly, safety and tolerance aspects of possible concern, such as liver toxicity and the presence of unwanted enzyme activities (such as cytochrome P450 oxygenases) can be monitored. These are important for determining the extract's drug interaction potential and safety profile. Hence, bioassay-guided development is not just used to substantiate traditional or novel areas of indication, it also provides a scientific basis for the rational selection of raw materials and process technologies that are best suited to design safe and efficient herbal extracts.

Activity Profile

In line with Frutarom's drive for safety and quality, dozens of different varieties of green oats were screened for their activity in various Central Nervous System (CNS) test systems that examined various targets associated with the traditional uses of green oats. The activity screening focused on 36 old and wild type varieties with high secondary or 'traditional' plant metabolite profiles. The bioassay screenings of these oat varieties revealed a clinically significant inhibitory effect on two enzymes that are closely connected to mental health and cognitive function: monoamine oxidase B (MAO-B) and phosphodiesterase 4 (PDE 4).5-7 Depending on which variety was used to source the raw material, the inhibitory activity of the extract on the two enzymes varied dramatically (Figure 2). Using the best performing green oat variety, Neuravena, the bioassay-oriented process was further developed: extraction procedures and key manufacturing parameters were evaluated to identify critical steps. In the meantime, the contract growing of Neuravena ensured consistent raw material quality. The dual activity profile of bioactivity-tested green oat extracts on MAO-B and PDE 4 provided a reliable, pharmacological basis on which to confirm the traditional indication profile of green oat extracts.

Animal Trial Results

To assess the activity profile of Neuravena in further detail, the impact of an oral application of the extract on the brain's electrical activity was investigated in freely moving rats using a continuous in vivo analysis of brain field potentials (Tele-Stereo-EEG). (8,9) The extract was found to attenuate brain activity in nearly all frequency ranges, indicating activated behaviour. Neuravena seems to stimulate the dopaminergic (DA) transmitter system, which is implicated in cognitive functioning and motivation and is related to depression. The main changes were observed within the hippocampus, a brain area closely connected to memory (Figure 3). In the model used in this study, the extract approached the results obtained from drugs used to treat dementia. (10) Additionally, the results of placebo-controlled trials in rats investigating the effects of Neuravena on behaviour concluded that the extract improves general learning performance and speed of learning, ameliorates stress-coping abilities and increases alertness. Moreover, test animals clearly displayed increased social interest and improved reactions to social signals, indicating Neuravena's positive effect on 'soft' skills such as social intelligence. (11) The findings of both in vivo trials revealed a strong correlation with the pharmacological activity profile of Neuravena on MAO-B and PDE 4 found in the bioassay-guided development process, reinforcing its mode of action as well as its indications.

Human Study: Significant Changes in Brain Activity

Following the successful in vitro and animal trials, the impact of Neuravena on mental fitness and cognitive performance under stressful situations was assessed in humans using quantitative measurements of electrical brain activity. This study was conducted in Germany by Prof. Dr Dimpfel, Neurocode AG (see sidebar), according to GCP (Good Clinical Practice). The randomized, double-blind, placebo-controlled, crossover clinical study comprised 20 healthy men and women, aged 46.5 [+ or -] 8.2 years, who ingested one single dose of 2500 mg Neuravena or a placebo. During a period of 4 hours, their baseline brain activity signals were recorded and analysed. Brain activity was also measured while the participants were subjected to mental pressure during standardized concentration stress and performance tests.

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By convention, brain activity signals are expressed in six different frequency ranges: delta, theta, alpha 1 and 2, and beta 1 and 2. As each frequency range characterizes the activity of specific signalling substances in the brain, and different brain regions are related to certain tasks, the overall pattern of how brain activity is influenced by Neuravena can be related to changes in human behaviour. Whereas delta wave brain activity seems to be modulated by the cholinergic transmitter system, theta brain activity is related to the neurotransmitter, noradrenaline. (9) In humans, delta and theta waves have been linked to cognitive and memory performance. (12,13) Neuravena was found to significantly change the brain activity of the study participants. A considerable decrease in delta and theta baseline wave activity was observed, particularly in brain regions closely connected to cognitive performance. In addition, alpha 2 wave activity increased. (10)

These changes are related to improved concentration, learning and memory, as well as stimulatory properties. It can therefore be concluded that Neuravena improves overall mental fitness in everyday life and can help to avoid dips in cognitive performance during the course of the day. (10) Both theta and delta wave activity was significantly increased during the concentration stress and performance tests in the Neuravena group (Figure 4). As activity levels at resting conditions are low, greater increases in delta and theta wave activity can be achieved during mental work, corresponding to better performance. (14) This finding confirms that Neuravena positively influences brain activity under pressure and thus helps to improve concentration, learning and alertness during stressful situations.

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A different way to look at the brain's communication structure is to transform the results of the frequency analysis into spectral colours. With this special kind of "brain mapping" (see sidebar), the impact of Neuravena on brain activity during the performance of different mental tasks can be visualized in an "Electropsychogram." The changes occurring during the performance of the concentration stress and performance tests confirm that Neuravena specifically affects the left temple/forefront area of the brain, which is implicated in cognitive function (Figure 5).

Tailored Product Concepts for a Growing Market

Looking at the evidence presented in this article, it can be concluded that bioactivity-tested green oat extracts, such as Neuravena, are safe and natural new candidates for the emerging market of products that support mental fitness and cognitive function. Because of its strengthening and balancing effects on the brain, Neuravena offers potentially lucrative positioning possibilities for nutraceuticals, food supplements and functional foods that target cognitive support and stress coping abilities. Depending on the specific indication, there are several opportunities to combine Neuravena with other functional ingredients. For example, products targeting "Learning and Concentration" may profit from Neuravena in combination with magnesium, L-glutamine or phosphatidylserine. "Memory" could be enhanced with a Neuravena product enriched with vitamin E, omega-3 or selenium, to mention just a few possibilities. Manufacturers who want to offer an end-product targeting stress coping abilities might choose EFLA Green Tea or EFLA Ginseng extracts, as well as B vitamins or minerals such as magnesium and zinc. A product combining Neuravena with dextrose, guarana or caffeine is, by contrast, suitable for "Alertness and Energy." Neuravena can be used in a wide range of applications, including tablets, instant products, soft drinks, dairy products, liquids, bars and even toffees.

Products targeting improved concentration, stress resistance and mental alertness are attractive to various groups; in today's stressful world, consumers of all ages are looking for mental support during their daily lives. Stressed working professionals, teenagers preparing for exams and ageing baby boomers all want to stay active, efficient, sharp-minded and full of vitality. Because of its positive effects on mental fitness, Neuravena offers a great way to benefit from a promising new market. Using this bioactivity-tested and patented extract, manufacturers of food supplements, nutraceuticals and functional foods now have a new tool that can add a mental and cognitive health dimension to their products.

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References

1. I. Muller, Die pflanzlichen Heilmittel bei Hildegard von Bingen (Otto Muller Verlag, Salzburg, Austria, 1928).

2. M. Wichtl, Herbal Drugs and Phytopharmaceuticals, 3rd Edition (Medpharm Scientific Publishers, Stuttgart, Germany, 2002).

3. P.H. Canter, et al., Trends Biotechnol. 23(4), 180-185 (2005).

4. T. Moccetti, et al., Zeitschrift fur Phytotherapie 27, 24 (2006).

5. P. Riederer, et al., Curr. Med. Chem. 11, 2033-2043 (2004).

6. J.M. O'Donell, et al., Trends Pharmacol. Sci. 25(3), 158-163 (2004).

7. M.D. Houslay, et al., Drug Discov. Today 10(22), 1503-1519 (2006).

8. W. Dimpfel, et al., Neuropsychobiology 16, 163-168 (1986).

9. W. Dimpfel, Eur. Neuropsychopharmacol. 15, 673-682 (2005).

10. Frutarom Switzerland, Unpublished Data.

11. T. Perrinjaquet-Moccetti, et al., Planta Med. 73, 980 (2007).

12. M. Kikuchi, et al., Neuropsychobiology 39, 219-226 (1999).

13. W. Klimesch, Brain Red. Rev. 29, 169-195 (1999).

14. F. Schober, et al., Neuropsychobiology 31, 98-112 (1995).

For more information

Carla Wullschleger, Pharmacist, MBA

Product Manager, EFLA-Line

Frutarom Switzerland Ltd

Rutiwisstrasse 7

CH-8820 Wadenswil, Switzerland.

Tel. [phone]

[e-mail]

www.frutarom.com

RELATED ARTICLE: The language of the brain: substantiating mental health claims by Electropsychogram.

With new EU Health Claim regulations now in force, it is becoming more and more important to be able to offer scientifically sound means of substantiating the efficacy of functional ingredients. Quite often, a substance will have been used traditionally for decades, but to make a health claim today, scientific evidence has to be delivered. In the "brain health" sector, providing clinical proof for the beneficial effects of extracts and other substances is particularly challenging for ingredients suppliers. However, pharmacologist Prof. Dr Wilfried Dimpfel (Justus Liebig University of Giessen) has established a method of reading and understanding the "language of the brain" that uses EEG measurements to make thought processes visible and measurable. In the following interview, Prof. Dr. Dimpfel explains how this method works and how it can help to back up a product's health claims.

NBT: Can you describe your method in a nutshell?

Prof. Dimpfel: Basically, our method translates the electric "language" of the brain into visible conclusions regarding human behaviour. In fact, the brain speaks a clear language that consists of electrochemical activities and we have developed a method of interpreting it, using a multistage process. After our volunteers have ingested a particular substance, we measure the brain's electrical activity via EEG (electroencephalogram) in a relaxed state and under different stimuli. This gives us a reading of electric brain signals that we are able to quantify and classify. With Neuravena, we generated an EEG and, from this, we derived what we call an "Electropsychogram." Owing to the fact that ingested substances chemically intervene with the brain's electrical activity, we were able to observe certain changes in the brain's electrochemical communication system. To quantitatively evaluate these changes, we use Discriminant Analysis, which allows us to classify the changes we have observed.

NBT: How do you then translate these changes in brain activity into conclusions about human behaviour?

Prof. Dimpfel: Before we can begin to draw any conclusions, the electric brain activity first has to be mathematically transformed ... and we do this using several specialized methods of analysis. We are able to collate quantified spectral frequency results using CATEEM (Computer Aided Topographical ElectroEncephaloMetry), which allows us to transform the spectral information into spectral colours. This method of transforming information into colours is totally unique and allows us to create a very visual kind of brain mapping with High Time Resolution.

During the last 20 years, we have been able to record a huge amount of reference data, which currently serves as a "dictionary" for the interpretation of "brain language." We're particularly proud of the fact that we have succeeded in setting up a quantitative description of mental fitness and emotions. We can therefore provide clinical proof of brain health claims and classify substances in comparison with other preparations or standard drugs.

NBT: What were the main results of the Neuravena study?

Prof. Dimpfel: We observed various changes in brain activity and the results we achieved are quite significant. In particular, during a concentration test, there were changes that could be interpreted with regard to enhanced cognitive processes. This hints at the fact that Neuravena contributes significantly to mental fitness.

NBT: How does your method help to substantiate a health claim?

Prof. Dimpfel: First of all, it is a generally accepted method, even by health authorities. This means that--having obtained positive results--it can serve as one pillar upon which to substantiate a health claim. Depending on the specific demands, this can mean a major step forward in achieving a certain claim. Furthermore, we are an independent scientific body and we guarantee high quality standards according to Good Clinical Practice. Maybe it's because of this that we are seeing increasing activity and demand for EEG studies, especially in the field of phytonutrients and other ingredients for functional food and nutraceutical products (www.neurocode-ag.com).