CN113181366A - Nutritional composition containing GABA and CB1 receptor agonists, and preparation and application thereof - Google Patents
Nutritional composition containing GABA and CB1 receptor agonists, and preparation and application thereof Download PDFInfo
- Publication number
- CN113181366A CN113181366A CN202110514225.9A CN202110514225A CN113181366A CN 113181366 A CN113181366 A CN 113181366A CN 202110514225 A CN202110514225 A CN 202110514225A CN 113181366 A CN113181366 A CN 113181366A
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- Prior art keywords
- gaba
- nutritional composition
- receptor
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Classifications
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- A—HUMAN NECESSITIES
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Abstract
The invention discloses a nutritional composition containing GABA and CB1 receptor agonists and a preparation method thereof. The nutritional composition comprises GABA and CB1 receptor agonists in a mass ratio of 100: 3-40, and the sum of the mass of the GABA and the mass of the CB1 receptor agonists is not less than 47% of the total mass of the nutritional composition. The preparation method comprises the following steps: mixing the above materials at a certain proportion, and filling or tabletting or packaging. The invention also provides application of the nutritional composition in preparing medicines and health products for relieving anxiety, relieving difficulty in falling asleep, improving sleep quality and/or treating insomnia, mental stress-induced fatigue, anxiety, memory impairment, reaction retardation and reduced motility, and application in oral preparations.
Description
Technical Field
The invention relates to the technical field of dietary supplements and biomedicines, in particular to a nutritional composition containing GABA and CB1 receptor agonists, and preparation and application thereof.
Background
Gamma-aminobutyric acid (GABA), a naturally occurring nonprotein amino acid, is an important inhibitory neurotransmitter in the mammalian central nervous system, and GABA is the mediator in about 30-50% of central synapses.
GABA produces a powerful calming (inhibiting) effect on the brain, when GABA acts on excitatory nerves and binds with receptors on synapses of the excitatory nerves, the neuron ends cannot release neurotransmitters to the next neurons, and signal conduction between the nerves is interrupted, so that the effects of inhibiting excessive excitation of central nerves, relieving anxiety, smoothing mood and promoting better sleep are achieved. GABA also has protective effect on brain wave form in sleep state, and can inhibit alpha wave, promote beta wave, and promote deep sleep time.
At the molecular level, the major GABA receptor in the brain is GABAAAnd GABABWherein GABAAThe influence on sleep is larger. When GABA or other GABAAAgonists of and GABAABind and activate GABAAThis configuration increases the frequency of chloride channel opening and thereby hyperpolarizes the cell membrane, thereby inhibiting the transmission of neural signals.
GABA levels in brain tissue decrease with age and increased mental stress, leading to restlessness, anxiety and difficulty falling asleep, which also decrease GABA levels in the brain. Many nutritional supplements elevate GABA levels in sleep disorders and anxiety patients by oral GABA intake, but exogenous GABA is difficult to penetrate the brain in large amounts due to the presence of the blood brain barrier. Meanwhile, under the action of mental stress, the brain has low content of GABA and GABAAThe binding efficiency of the receptor is further reduced, and the exogenous GABA administered orally is further wasted.
Currently GABA is added to nutrient combinationsAThe receptor activator can help the generation of GABA to form a synergistic effect through the theanine in the blood brain barrier, or ingest the precursor of GABA to generate GABA in the brain, or assist the exogenous effective component to pass through the blood brain barrier to increase the absorption rate through a microencapsulation technology.
Cannabinoid receptors are a class of specialized proteins found in cells or intracellularly that regulate the release of chemical transmitters, with CB1 receptors being found primarily in the brain, spinal cord, and peripheral nervous system.
The present study found that the binding efficiency of GABA to its receptors is enhanced by the preferred amount of a natural and safe non-addictive plant derived CB1 receptor agonist, and that the synergistic effect of the CB1 receptor agonist and the nutrient combination formed by GABA enhances the hypnotic and anxiolytic effects.
Disclosure of Invention
Aiming at the defects in the field, the invention provides a nutritional composition containing GABA and CB1 receptor agonists, which can be directly orally taken, and solves the problems that the existing sleep-aiding and nerve-soothing product mainly comprising GABA in the field of health care products has limited GABA content and can not penetrate blood brain barrier to be combined with receptors in brain because exogenous GABA is orally taken to penetrate through the blood brain barrierThe efficacy of the product is well developed. In the prior art, for example, the penetration rate of the effective components through the blood brain barrier is improved by utilizing the microencapsulation technology and GABA is addedAOn the basis that the activation component of the receptor improves the binding efficiency of GABA and the receptor thereof, the invention further forms a composition by utilizing the CB1 receptor agonist and the GABA according to a certain proportion, and assists GABA to play a role more effectively in improving the binding capacity of GABA and the receptor thereof in the brain by relieving anxiety through activating the CB1 receptor.
A nutritional composition containing GABA and CB1 receptor agonists comprises GABA and CB1 receptor agonists in a mass ratio of 100: 3-40, and the sum of the masses of the GABA and the CB1 receptor agonists is not less than 47% of the total mass of the nutritional composition.
The present inventors have found that anxiety relief may allow GABA to bind better to receptors. The nutritional composition of the present invention helps lower anxiety values by activating in vivo cannabinoid receptors (CB1 receptors), thereby helping GABA and GABA, which are originally present in the brain in low amountsAThe combination of the receptor is recovered to a normal state, GABA is better combined with the receptor, the central nerve overheating is more fully inhibited, and the effect of the unit component of the combined nutrient is improved.
In a preferred embodiment, the nutritional composition further comprises 5-23% of other effective components by mass fraction;
the other effective components include, but are not limited to, at least one of melatonin, theanine, 5-hydroxytryptophan (5-HTP), alpha-lactalbumin, 5-aminolevulinic acid (5-ALA), vitamin B, glutamine, arginine, cinnamic acid, and lipoic acid.
In a preferred embodiment, the nutritional composition further comprises 15-30% of auxiliary materials by mass;
the excipients include, but are not limited to, at least one of microcrystalline cellulose, gelatin, lecithin, maltodextrin, magnesium stearate, silicon dioxide, chitosan, povidone.
In the nutritional composition, the CB1 receptor agonist is taken from a CB1 receptor natural ligand library and meets the following conditions: when molecular docking and molecular dynamics calculation are carried out by using molecular docking software, the binding energy value of the CB1 receptor agonist to the active form CB1 receptor is negative and is larger than the binding energy value of the agonist to the inactive form CB1 receptor.
Specifically, the CB1 receptor agonist is preferably a natural non-psychoactive ingredient, including but not limited to at least one of non-psychoactive Cannabidiol (CBD) and its derivatives, tea leaf extract, flavonols, lignans.
The derivative of the non-psychoactive CBD includes, but is not limited to, at least one of cannabichromene (CBC), Cannabigerol (CBG), Cannabinol (CBN).
When the CB1 receptor agonist in the composition is a non-psychoactive CBD, the mass ratio of the GABA to the CBD is preferably 100: 12-20.
When the CB1 receptor agonist in the composition is a certain derivative of the CBD (such as the CBC, CBG or CBN), the mass ratio of the GABA to the CBD derivative is preferably 100: 18-30.
The tea extract includes, but is not limited to, at least one of EGCG (epigallocatechin gallate), EGC (epigallocatechin), ECG (epicatechin gallate), EC (epicatechin).
When the CB1 receptor agonist in the composition is tea extract EGCG, the mass ratio of GABA to EGCG is preferably 100: 16-28;
when the CB1 receptor agonist in the composition is a certain tea extract (such as the EGC, the ECG or the EC) which is not EGCG, the mass ratio of the GABA to the tea extract is preferably 100: 18-30.
The flavonol compound comprises at least one of rutin and flavonol extracts in desmodium adsurae (Chinese herbal medicine).
When the CB1 receptor agonist in the composition is rutin, the mass ratio of the GABA to the rutin is preferably 100: 6-16.
When the CB1 receptor agonist in the composition is one of flavonol extracts in the desmodium adscendens leaves, the mass ratio of the GABA to the desmodium adscendens leaves extract is preferably 100: 22-38.
The lignan compound includes, but is not limited to, at least one of magnolol and honokiol.
When the CB1 receptor agonist in the composition is magnolol, the mass ratio of GABA to magnolol is preferably 100: 5-12.
When the CB1 receptor agonist in the composition is honokiol, the mass ratio of GABA to honokiol is preferably 100: 4-6.
The nutritional composition may be a powder, tablet or capsule.
The invention also provides a preparation method of the nutritional composition, which comprises the following steps: mixing the above materials at a certain proportion, and filling or tabletting or packaging to obtain powder, tablet or capsule.
The invention also provides application of the nutritional composition in preparing medicines and health-care products for relieving anxiety, relieving difficulty in falling asleep, improving sleep quality and/or treating insomnia, mental stress-induced fatigue, anxiety, memory impairment, reaction retardation and reduced motility.
GABA plays a role in alleviating anxiety, calming mood, and promoting better sleep by inhibiting the release of neurotransmitters from the over-excited central neuron terminals to the next neuron, blocking signal conduction between nerves. In the present invention, CB1 receptors activated by CB1 receptor agonists may further promote more efficient binding of GABA to its receptors in the brain. Compared with the prior art, the GABA and the CB1 receptor agonist are mixed to prepare the nutrient composition, the multi-channel effect and the synergistic effect are utilized to improve the unit sleep-aiding and nerve-soothing effects of the formula, and a user can obtain effective body feeling under the same dosage.
The invention also provides application of the nutritional composition in oral preparations.
The inventor designs SLEEMOD series components containing the nutritional composition, applies the SLEEMOD series components to health-care food, can be directly orally taken, and solves the problems that the existing sleep-aiding and nerve-soothing product mainly comprising GABA in the field of health-care products has limited GABA content combined with receptors in the brain because exogenous GABA is orally taken, penetrates through the blood brain barrier and cannot well exert the efficacy of the product.
Compared with the prior art, the invention has the main advantages that:
1) GABA is taken in with CB1 receptor agonists, acting synergistically. The CB1 receptor agonist can intervene and regulate the release of chemotransmitter by activating CB1 receptor so as to relieve anxiety and lead the content of GABA and GABA in the brain to be lowerAThe binding effect of the receptor is restored to normal values and even improved, so that a lower GABA content under the influence of the blood brain barrier can achieve the effect of high dosage.
2) The preferred weight ratio of GABA to CB1 receptor agonist maximizes the effectiveness of improving sleep, anti-stress and soothing nerves without causing adverse side effects to the user.
3) The screening of the CB1 receptor agonist is carried out by utilizing molecular docking and molecular dynamics, a large amount of screening can be carried out in a natural ligand library of CB1, the screening range is wider than that of an experimental method which relies on less manpower, and the efficiency of component research and development is improved.
4) GABA and a selected range of natural non-psychoactive CB1 receptor agonists are both safe and low side effects and are suitable as functional nutritional supplements.
5) The product of the patent has controllable quality, clear efficacy principle, easy operation and controllability of the preparation process, and is suitable for manufacturers to produce.
Drawings
FIG. 1 is a graph of the docking results of several CB1 receptor agonists with the CB1 receptor, where (a) is the binding of CBD to CB1 receptor, (b) is the binding of rutin to CB1 receptor, and (c) is the binding of EGCG to CB1 receptor;
FIG. 2 is a graph showing the binding site and binding energy of rutin binding to active CB1 receptor in example 1;
FIG. 3 is a graph showing the binding site and binding energy of EGCG to active CB1 receptor in example 2;
FIG. 4 is a graph comparing the effect of the combination of GABA and rutin on sleep in example 3 with that of the control group, wherein (a) is the effect of different weight ratios of GABA to rutin in the composition on the sleep-aiding effect, (b) is 100mg/kg (100/12) of the GABA/rutin composition on the sleep texture, and (c) is 100mg/kg (100/12) of GABA/rutin compositionComposition for GABAAEffect of receptor mRNA expression levels;
FIG. 5 is a graph comparing the effect of the combination of GABA and EGCG on sleep in example 4 with that of the control group, wherein (a) is the effect of different weight ratios of GABA to EGCG in the composition on sleep aiding effect, (b) is 100mg/kg (100/20) of the composition of GABA/EGCG on sleep texture, and (c) is 100/20mg/kg (100/20) of the composition of GABA/EGCG on GABAAEffect of receptor mRNA expression levels.
Detailed Description
The invention is further described with reference to the following drawings and specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The following examples are conducted under conditions not specified, usually according to conventional conditions, or according to conditions recommended by the manufacturer.
As shown in fig. 1-3, natural CB1 receptor agonists from plant extracts were screened from natural small molecule component libraries by molecular docking and molecular dynamics simulation calculations with the following criteria:
1) the candidate ingredients can be extracted from plants, are natural, safe, nontoxic and non-psychotropic;
2) candidate agents may act as ligands for the CB1 receptor;
3) screening out components with good overall stability of the ligand receptor and good stability of the binding site after docking through molecular docking and molecular dynamics simulation;
4) the fraction obtained by preliminary screening in 3) above was further analyzed for binding energy, and if the binding energy of the ligand to the active form of the CB1 receptor is greater than the binding energy to the inactive form of the CB1 receptor and is negative (in the present invention, the binding energy is preferably negative), the fraction can be used as an agonist of the CB1 receptor.
The compositions used in the examples are all solid powders. And uniformly mixing GABA powder with the purity of more than 90% and the CB1 receptor agonist powder according to the mass ratio of the formula, and using the mixture for a mouse sleep experiment.
As shown in FIGS. 4-5, the effect of the nutrient combinations comprising GABA and CB1 receptor agonists was tested by sleep on adult miceVerification is obtained. The selected mice were adult healthy mice, all of which were bred in the same environment and randomly divided into experimental and control groups before the start of the experiment to ensure consistency of results. The effect of the nutrient combination on sleep duration and quality is known from electroencephalography (EEG) monitoring of sleep duration, rapid eye movement sleep (REM) and non-rapid eye movement sleep (NREM) duration. Determination of GABA by RT-PCR detectionAmRNA expression level of receptor, and the nutrient combination is known to play GABAAInfluence of receptor expression profile.
Example 1
According to the method flow, rutin is screened out to be used as an agonist of a CB1 receptor to form a nutrient combination with GABA through molecular docking and molecular dynamics simulation calculation, and the specific steps are as follows:
CB1 receptor structure files in the form of active and inactive, respectively, were obtained from PDB library as 5xra. PDB and 5tgz. pbd, respectively. The rutin structure obtained by the primary screening of the stability test is CID 5280805. The binding energy of rutin and active CB1 receptor after docking is-48.6002 kcal/mol, the binding energy of rutin and inactive CB1 receptor after docking is-31.6176 kcal/mol, the binding energy of rutin and two forms of CB1 receptors after docking is negative, and the comparison of the values of the two forms shows that the rutin is more easily bound with the active CB1 receptor. It is thus concluded that rutin acts synergistically with GABA as an agonist at the CB1 receptor.
Example 2
According to the method flow, EGCG which can be used as an agonist of a CB1 receptor and GABA forms a nutrient combination is screened out through molecular docking and molecular dynamics simulation calculation, and the specific steps are as follows:
CB1 receptor structure files in the form of active and inactive, respectively, were obtained from PDB library as 5xra. PDB and 5tgz. pbd, respectively. The EGCG structure obtained by the primary screening of the stability test is CID 65064. The binding energy of the EGCG after being docked is calculated by CDOCKER, the binding energy of the EGCG after being docked with the active CB1 receptor is-54.4430 kcal/mol, the binding energy of the EGCG after being docked with the inactive CB1 receptor is-43.5688 kcal/mol, the binding energy of the EGCG after being docked with the two forms of CB1 receptors is negative, and the EGCG is more easily bound with the active CB1 receptor by comparing the values of the EGCG and the inactive CB1 receptor. It is therefore concluded that EGCG acts synergistically as an agonist at the CB1 receptor in combination with GABA.
Example 3
Based on the results of example 1, GABA powder was mixed with rutin powder and orally fed to mice in the experimental group. For the effect of GABA/rutin weight ratio on sleep duration and quality, the experimental groups were further divided into five groups, one group orally administered 100mg/kg GABA, one group orally administered 100mg/kg (m/m-100/5, same below) GABA/rutin combination, one group orally administered 100mg/kg (100/12) GABA/rutin combination, one group orally administered 100mg/kg (100/50) GABA/rutin combination, and one group orally administered 100mg/kg rutin, and a total of six groups of mice were monitored by EEG after 45 minutes of mouse administration. As can be seen from FIG. 4(a), compared with the control group (no formulation), the 100mg/kg GABA group had more sleep time than the control group, the 100mg/kg (100/5) GABA/rutin group had slightly more sleep time than the 100mg/kg GABA group, the 100mg/kg (100/12) GABA/rutin group was significantly more than the control group (. about.1.7 times) and than the other experimental groups, the 100mg/kg (100/50) GABA/rutin group was comparable to the 100mg/kg GABA group, and the 100mg/kg rutin was slightly more than the control group. As can be seen from fig. 4(b), the light sleep (REM) and deep sleep (NREM) durations were both greater in the 100mg/kg GABA group than in the control group, the REM duration was greater in the 100mg/kg (100/5) GABA/rutin group than in the 100mg/kg GABA group and the NREM duration was slightly greater than in the 100mg/kg GABA group, the REM duration was greater in the 100mg/kg (100/12) GABA/rutin group than in the control group and other experimental groups and the NREM duration was significantly greater than in the control group (-1.5 times) and other groups, the REM duration was slightly greater in the 100mg/kg (100/50) GABA/rutin group than in the 100mg/kg GABA group and the NREM duration was not much different from that in the 100mg/kg GABA group, and the REM duration was slightly greater in the 100mg/kg rutin group than in the control group and the NREM duration was slightly greater than in. It is known that 100mg/kg (100/12) of the GABA/rutin group performs best. Comparison of mRNA transcript levels was performed for the control group, 100mg/kg GABA group, 100mg/kg (100/12) GABA/rutin group and 100mg/kg rutin group. As can be seen from FIG. 4(c), GABA of 100mg/kg GABA groupAThe expression level of receptor mRNA is higher than that of a control group, the GABA/rutin group of 100mg/kg (100/12) is obviously higher than that of the control group (about 1.5 times), and the rutin group of 100mg/kg is slightly higher than that of the control group. It is known to pass throughActivating CB1 receptor, rutin helps relieve stress and promotes GABA and GABAAReceptor binding of GABAAThe receptor has the effect of helping sleep, the optimal weight ratio of GABA to rutin is 100:12, and the nutrient combination prepared according to the ratio can obviously improve the effects of helping sleep and soothing the nerves.
Example 4
Based on the results of example 2, GABA powder was mixed with EGCG powder and orally fed to mice of the experimental group. For the effect of GABA/EGCG weight ratio on sleep duration and quality, the experimental groups were further divided into five groups, one group orally administered 100mg/kg GABA, one group orally administered 100mg/kg (100/15) GABA/EGCG combination, one group orally administered 100mg/kg (100/20) GABA/EGCG combination, one group orally administered 100mg/kg (100/50) GABA/EGCG combination, and one group orally administered 100mg/kg EGCG, and a total of six groups of mice were monitored by EEG after 45 minutes of mouse administration. As can be seen from FIG. 5(a), compared to the control group (no formulation), the 100mg/kg GABA group had more sleep than the control group, the 100mg/kg (100/15) GABA/EGCG group had more sleep than the 100mg/kg GABA group, the 100mg/kg (100/20) GABA/EGCG group was significantly more than the control group (. about.1.8 times) and more than the other experimental groups, the 100mg/kg (100/50) GABA/EGCG group was slightly more than the 100mg/kg GABA group, and the 100mg/kg EGCG group was more than the control group and slightly less than the 100mg/kg GABA group. As can be seen from FIG. 5(b), the light sleep (REM) and deep sleep (NREM) durations were both longer in the 100mg/kg GABA group than in the control group, the REM duration was more than 100mg/kg GABA and the NREM duration was slightly more than 100mg/kg GABA in the 100mg/kg (100/15) GABA/EGCG group, the REM duration was more than in the control group and other experimental groups and the NREM duration was significantly more than in the control group (. about.1.6 times) and other groups, the REM duration was slightly more than 100mg/kg GABA and the NREM duration was slightly more than 100mg/kg GABA in the 100mg/kg (100/50) GABA/EGCG group than in the control group (about.1.6 times) and other groups, the REM duration was slightly longer in the 100mg/kg EGCG group than in the control group than in the 100mg/kg GABA group and the NREM duration was slightly longer in the control group than in the 100mg/kg GABA group. It is seen that the 100mg/kg (100/20) GABA/EGCG group performed best. Comparison of mRNA transcription levels was performed for the control group, 100mg/kg GABA group, 100mg/kg (100/20) GABA/EGCG group and 100mg/kg EGCG group. As can be seen from FIG. 5(c), GABA of 100mg/kg GABA groupAThe expression level of receptor mRNA is higher than that of the control group, 100mg/kg (100/20) GABA/EGThe CG group was significantly higher (1.6 times) than the control group, and the 100mg/kg EGCG group was slightly higher than the control group. It is known that EGCG promotes GABA and GABA by activating CB1 receptor to help stress relaxationAReceptor binding of GABAAThe receptor exerts the effect of helping sleep, the mass ratio of 100:20 is the optimal weight ratio of GABA and EGCG, and the nutrient combination prepared according to the ratio can obviously improve the effects of helping sleep and soothing the nerves.
Application example
Based on the results of examples 1-4, the present invention further designs a novel sleep aid series of combination formulas, such as: in one formula, the main effective components are GABA and rutin with the weight ratio of 100: 8-16; in another formula, the main effective components are GABA and EGCG with the weight ratio of 100: 16-28. Agonists of the CB1 receptor include, but are not limited to, rutin and EGCG in examples 1-4. The CB1 receptor agonist in the combined formula can exert a synergistic effect with GABA, promote the combination efficiency of GABA and receptors thereof in brain, and obviously improve the effects of the formula on helping sleep, improving sleep quality, resisting anxiety and calming nerves.
Furthermore, it should be understood that various changes and modifications can be made by one skilled in the art after reading the above description of the present invention, and equivalents also fall within the scope of the invention as defined by the appended claims.
Claims (9)
1. A nutritional composition containing GABA and CB1 receptor agonists is characterized by comprising GABA and CB1 receptor agonists in a mass ratio of 100: 3-40, wherein the sum of the masses of the GABA and the CB1 receptor agonists is not less than 47% of the total mass of the nutritional composition.
2. The nutritional composition according to claim 1, wherein the nutritional composition further comprises 5 to 23 mass% of other active ingredients;
the other effective components include at least one of melatonin, theanine, 5-hydroxytryptophan, alpha-lactalbumin, 5-aminolevulinic acid, vitamin B, glutamine, arginine, cinnamic acid and lipoic acid.
3. The nutritional composition according to claim 1 or 2, wherein the nutritional composition further comprises 15 to 30 mass percent of an auxiliary material;
the auxiliary materials comprise at least one of microcrystalline cellulose, gelatin, lecithin, maltodextrin, magnesium stearate, silicon dioxide, chitosan and povidone.
4. The nutritional composition according to claim 1, wherein the CB1 receptor agonist is taken from the CB1 receptor natural ligand library and satisfies the following condition: when molecular docking and molecular dynamics calculation are carried out by using molecular docking software, the binding energy value of the CB1 receptor agonist to the active form CB1 receptor is negative and is larger than the binding energy value of the agonist to the inactive form CB1 receptor.
5. The nutritional composition according to claim 1 or 4, wherein the CB1 receptor agonist is a natural non-psychoactive ingredient comprising at least one of a non-psychoactive CBD and its derivatives, tea leaf extract, flavonols, lignans;
the derivative of the non-psychoactive CBD comprises at least one of CBC, CBG, CBN;
the tea extract comprises at least one of EGCG, EGC, ECG, and EC;
the flavonol compound comprises at least one of rutin and flavonol extracts in desmodium adsurae leaves;
the lignan compound comprises at least one of magnolol and honokiol.
6. The nutritional composition according to claim 1, wherein the nutritional composition is a powder, tablet or capsule.
7. A method of preparing a nutritional composition according to any one of claims 1 to 6, comprising: mixing the above materials at a certain proportion, and filling or tabletting or packaging.
8. Use of the nutritional composition according to any one of claims 1 to 6 for the preparation of a medicament or health product for relieving anxiety, relieving difficulty falling asleep, improving sleep quality and/or treating insomnia, mental stress-induced fatigue, anxiety, memory impairment, unresponsiveness, reduced motility.
9. Use of the nutritional composition according to any one of claims 1 to 6 in an oral formulation.
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