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US 2015O164945A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0164945 A1 KILIAAN et al. (43) Pub. Date: Jun. 18, 2015

(54) PREPARATION FOR IMPROVING THE Publication Classification ACTION OF RECEPTORS (51) Int. Cl. (71) Applicant: N.V. Nutricia, Zoetermeer (NL) A633/30 (2006.01) A633/06 (2006.01) (72) Inventors: Amanda Johanne KILIAAN, A613 L/445 (2006.01) Nijimegen (NL); Robert Johan Joseph A613 L/714 (2006.01) Hageman, Utrecht (NL) A63L/202 (2006.01) A 6LX3/59 (2006.01) (52) U.S. Cl. (73) Assignee: N.V. Nutricia, Zoetermeer (NL) CPC ...... A61 K33/30 (2013.01); A61 K3I/202 (2013.01); A61 K3I/519 (2013.01); A61 K (21) Appl. No.: 14/634,368 3 1/44.15 (2013.01); A61 K3I/714 (2013.01): A6 IK33/06 (2013.01) (22) Filed: Feb. 27, 2015 (57) ABSTRACT The present invention relates to the use of Related U.S. Application Data polyunsaturated fatty acids and one or more components which have a beneficial effect on (60) Continuation of applit N. E. filed o methionine selected from the group li 1. ty. y h 1C M. Oos consisting of B12 and precursors thereof. Vita apply 9. 888.39 1. which Gion of app i. min B6 and derivatives thereof, folic acid, and mag • L vs. sy- Yo Yos--- us nesium, Sir No, Cited "Sis 2 y in the manufacture of a preparation for improving the action • s- so I s- Y - us of receptors. NL02/00731 on Nov. 14, 2002. This preparation is advantageously applied in patients Suffer O O ing from Parkinson's disease, Huntington's chorea, epilepsy, (30) Foreign Application Priority Data Schizophrenia, paranoia, depression, sleep disorders, Nov. 14, 2001 (NL) ...... 101968 impaired memory function, psychoses, dementia and ADHD. US 2015/O164945 A1 Jun. 18, 2015

PREPARATION FOR IMPROVING THE the metabolism of the cell. Many comprise the seven trans ACTION OF RECEPTORS membrane domain receptors, which usually function via G 0001. This application is a divisional application of Ser. . These types of receptors play a role, interalia, in the No. 12/045,112, filed Mar. 10, 2008, currently pending, case of neurotransmitters which belong to the adrenergic which is a divisional application of Ser. No. 10/495.341 filed agents (for example noradrenaline and adrenaline), in the May 13, 2004, which claims priority to PCT/NL2002/00731, case of dopamine, serotonin and in the case of neurotransmit filed Nov. 14, 2002. The teachings of the above applications ters which belong to the cholinergic agents (such as acetyl are hereby incorporated by reference. Any disclaimer that or ). Other examples of seven transmem may have occurred during prosecution of the above refer brane domain receptors are receptors which are activated by enced applications is hereby expressly disclaimed. neuropeptides, such as by Substance P. Neuropeptide Y. 0002 The present invention relates to a preparation for Bombesine, Neurotensine, CCK and galanine. improving the action of receptors, in particular for improving 0009. Others include single transmembrane domain the sensitivity of receptors to neurotransmitters. receptors such as the tyrosine kinase receptor family (growth 0003 Receptors can be present in the membranes of cells. factors, insulin), the cytokine receptor family (growth hor The receptor is activated under the influence of components mone, erythropoietin, leptin, prolactin), the serine-threonine present outside the cell (for example, neurotransmitters, neu kinase receptor family (TGF-beta), the guanylyl cyclase romodulators or hormones) which bind to the receptor. The receptor family (atrial natriuretic peptides) and the phospho receptor is then capable of transmitting signals, which can tyrosine phosphatase family. start a cascade of events. Receptors can be present, interalia, 0010 Many medical disorders are associated with dis in or on nerve cells, muscle cells, endocrine cells, epithelial turbed signal transmission. This can be due to a reduced cells or other types of cells. Examples of substances which concentration of hormones and/or neurotransmitters and/or have an effect on receptors are neurotransmitters (see below), neuromodulators, but also to a reduced sensitivity of the neuromodulators, neuropeptides and hormones such as insu receptor towards the specific Substance. lin and steroids. 0011. A neurotransmitter functioning that is disturbed to a 0004. A specific class of receptors is, for example, consti more or less severe extent can play a role in neurological tuted by receptors in nerve cells (neurones) which are con disorders such as dementia, depression, Parkinson's disease, trolled by neurotransmitters. These neurones consist of a cell Huntington's chorea, epilepsy, schizophrenia, paranoia and body (soma) with several, frequently short fimbriae (den ADHD, but also in other emotional disorders. drites) and one long fimbria, termed an axon. An electrical 0012 Various ways for improving the functioning of the signal is transmitted from the Soma via the axon. The axon nerve processes have been conceived in the past. For example, branches into axon ends which can terminate next to the neurotransmitters such as dopamine or derivatives thereof dendrites of adjacent nerve cells, onto another axon, next to have been administered to people suffering from Parkinson's the soma of nerve cells or in tissues or parts thereof. The disease in order to increase the amount of dopamine in the so-called synaptic cleft is located between the axon of the one synapse. Substances have also been administered in order to nerve cell and the dendrite (or also soma) of the other nerve reduce the reuptake of the neurotransmitter serotonin from cell. the synaptic cleft into the dendrite. Agents which inhibit a 0005. If a nerve cell is stimulated, substances can be specific metabolic conversion of the neurotransmitter acetyl released which are termed neurotransmitters or neuromodu choline (acetylcholinesterase inhibitors), as a result of which lators and which are able to activate another nerve cell. The the concentrations of in the synaptic cleft (i.e. neuro-transmitters/neuromodulators are recognised by extracellular) remain high for a prolonged period, have also receptors in the postsynaptic membrane of the “receiving been described. Monoamine oxidase inhibitors partially pre nerve cell. vent the conversion of monoamines Such as dopamine. 0006 Examples of classic endogenous neurotransmitters 0013. In contrast with the aforementioned approaches, the are biogenic such as serotonin, dopamine, histamine, aim of the invention is to improve the action, and especially noradrenaline and adrenaline; amino acids such as GABA the sensitivity of receptors, in particular in nerve processes, (gamma-aminobutyric acid), glutamate, aspartate and gly but also in other physiological processes in which, for cine; cholinergic agents, such as acetylcholine; peptides. Such example, hormones play a role. What is meant by an as endorphins and other types of neurotransmitters such as improved action of receptors is that less , in particular nitrogen oxide and adenosine. In addition, many substances less neurotransmitter, is needed to achieve the same effect. have been found which are recognised by the neurotransmit The present invention may advantageously be applied in ter receptors, such as certain drugs (for example clenbuterol), patients who suffer from an imbalanced neurotransmitter which usually are prepared synthetically, but also substances functioning and/or neurodegenerative disorder. In addition, from natural preparations (such as muscarine antagonists or the invention may be applied in healthy individuals to ephedrine-rich plant extracts). improve the concentration and/or learning ability of these 0007 Receptors can be classified on the basis of their individuals. action. Ionotropic receptors act rapidly and determine ion 0014. The invention relates to the use of transport through the membrane. They consist of a large 0.015 polyunsaturated fatty acids and complex of multiple sub-units made up of five individual 0016 components which have a beneficial effect on proteins which combine to establish an ion channel through methionine metabolism for improving the action of the membrane. The sub-units have four transmembrane receptors. domains which form the pore. These ion channels are imper 0017. The inventors have unexpectedly found that the meable to ions in the absence of a neurotransmitter. combined application of polyunsaturated fatty acids and 0008 Metabotropic receptors constitute another class. methionine metabolism stimulating compounds improves the These act relatively slowly and have a wide range of effects on action of receptors, but not as a result of the increased pro US 2015/O164945 A1 Jun. 18, 2015

duction of neurotransmitter or a reduced reuptake of neu 0023 The total composition in the preparation must be rotransmitter from the synaptic cleft. According to the inven such that the proportion of unsaturated fatty acids is relatively tors, the Surprising effect of the active principles according to high, that is to say more than 50% of the fat. The unsaturated the invention may be explained from the improved arrange fatty acids preferably do not have a trans configuration, that is ment and more fluid nature of the cell membranes, especially to say the proportion of unsaturated fatty acids having a trans of the membranes of neurons, that results from the combined configuration is less than 0.8%, preferably less than 0.5% administration. Because of the improved arrangement and based on the total amount of fat (weight). In addition, the fluidity, in vivo membrane processes can proceed more effec preparation contains as little linoleic acid as possible. tively after receptor activation. This improvement is not only 0024. The proportion of G2-3 polyunsaturated fatty acids advantageous in individuals in whom these membrane pro relative to the proportion of G2-6 polyunsaturated fatty acids cesses are adversely affected by, for instance, a neurodegen must be relatively high. This means that the ratio between S2-6 erative disorder. The improvement is also beneficial to indi fatty acids and S2-3 fatty acids is preferably less than 3, more viduals who wish to improve their ability to learn and/or preferentially less than 2, for example 1.4. concentrate, e.g. for study or work. 0025 Cholesterol can be present in the fat composition, 0018. The treatment of a variety of disorders, including for example in an amount of 0.5 to 5% (m/m) of the total neurodegenerative disorders such as Alzheimer disease and amount of fat. Parkinson's disease with polyunsaturated fatty acids and Vita 0026. Such a fat composition ensures that the membrane min B6, B12 and/or folic acid is described in WO 01/03696. of the cells, in particular nerve cells, has good arrangement In this PCT-application a link is made between an elevated and a fluid nature, so that in vivo membrane processes can serum homocysteine concentration and the undesired oxida take place efficiently after activation of the receptor. tion of essential fatty acids, in particular of eicosapentenoic 0027. The polyunsaturated fatty acids are preferably acid and arachidonic acid. The administration of , present in the form of bound fatty acids, for example fatty folic acid and is said to decrease the serum acids bound to glycerol. Such as in the form of triglycerides, homocysteine concentration and consequently to diminish but also, and this is preferred, in the form of phospholipids. the oxidation of the aforementioned essential fatty acids, as a 0028 Components which have a beneficial effect on total result of which, in combination with the administration of methionine metabolism (TMM) are understood to be the these same essential fatty acids, an increase in the serum components as described in EP 0 891 719, which is included concentration of these essential fatty acids is achieved. herein by reference. These components are selected from According to the PCT-application an increase of the concen vitamin B12 and precursors thereof, vitamin B6 and deriva tration of essential fatty acids can be advantageous in the tives thereof, folic acid, zinc and . Preferably treatment of (a) illnesses, (b) cardiovascular or cerebrovascu these components are selected from vitamin B12 and precur lar disorders, (c) diabetes, syndrome X and macro or sors thereof, vitamin B6 and folic acid. More preferably a microvascular complications of diabetes, (d) psychiatric dis combination of folic acid, vitamin B6 and vitamin B12 is orders, (e) neurological or neurodegenerative disorders, (f) used. kidney disorders, (g) inflammatory or immunological disor 0029 Suitable forms of vitamin B12 are , ders of the gastrointestinal tract, (h) eye or hearing disorders, hydroxy-, adenosyl- or methyl-cobalamin or mixtures (i) forms of obesity and () any form of cancer. Nowhere in the thereof, which may or may not be bound to binding proteins PCT-application reference is made to an effect of the prepa in Such a way that these can be completely and easily rations described therein on receptor action. absorbed in the small intestine. These substances are suitably 0019 Suppletion with the preparation according to the incorporated in the preparation in an amount Such that it invention is beneficial in those situations where the endog contains at least 3 Jug, preferably at least 10 ug and in particu enous production of neurotransmitters is marginal but the lar 50 to 1000 ug cobalamin per daily dose of the product. receptor is still functional, as is the case for minor manifes 0030. Folic acid must be present in an amount of at least tations of neurological disorders. 250 ug, in particular 300 to 1500 g, per daily dose of the 0020. In persons suffering from serious forms of neuro product. Suitable forms are , folic acid and methyl logical disorders it is advantageous that, in addition to the derivates thereof, in the non-oxidised or oxidised form. aforementioned components, at least one substance is admin 0031. or derivatives thereof, such as pyridox istered that increases the concentration of the neurotransmit or pyridoxal, can be used in the product as Suitable ters, neuromodulators or hormone in the synapse or at the sources of vitamin B6. At least 1 mg vitamin B6, preferably 2 receptor. to 20 mg vitamin B6, per daily dose is contained in the 0021 Polyunsaturated fatty acids are fatty acids contain product. ing at least two unsaturated bonds and having a chain length 0032. In addition to S2-3 polyunsaturated fatty acids and of at least 18. The unsaturated bond is located in the 3, 6 or 9 components which have a beneficial effect on methionine position relative to the terminal methyl group. metabolism, the preparation according to the invention can 0022. The preparation of the invention preferably contains also contain phospholipids. These are preferably phosphati S2-3 polyunsaturated fatty acids. The S2-3 polyunsaturated dylserine, phosphatidylinositol, and fatty acids include O-linolenic acid, Stearidonic acid, eicosa . Preferably a mixture of two or pentaenoic acid and docosahexaenoic acid and arachidonic more of these phospholipids is used, in particular a mixture acid. The preparation preferably contains at least docosa that contains at least phosphatidyl-choline and phosphati hexaenoic acid. For cardiovascular-associated neurological dylserine. The daily dose of phospholipids is preferably at disorders such as dementia eicosapentaenoic acid is also Suit least 0.2g, more preferentially at least 1 g. ably present. The daily dose of G2-3 polyunsaturated fatty 0033. Another characteristic of the phospholipids is the acids is preferably at least 120 mg, more preferentially at least fatty acid group of the phospholipids. These preferably have 350 mg. a composition corresponding to the S2-3 polyunsaturated fatty US 2015/O164945 A1 Jun. 18, 2015

acids as described above. This can be achieved by using dopamine, noradrenaline (norepinephrine) and adrenaline known interesterification techniques using crude phospho (epinephrine) can be formed under certain conditions from mixtures and ingredients rich in the Suitable fatty acids L-phenylalanine and/or L-tyrosine. as the starting materials. 0043 Functional equivalents of these amino acids can also 0034. This can also be achieved by feeding birds with be used as precursor for neuro-transmitters, such as, for special , so that the phospholipid fraction obtained from example, N-alkylated forms or esterified forms and salts. An their eggs has a fatty acid composition that is as similar as example of a suitable derivative of tryptophan is 5-hydrox possible to the desired composition. Varieties of plants can ytryptophan. However, it is preferable to use proteins or also be genetically modified so that they contain the active hydrolysed products thereof or peptides. Preferably, the pro compounds in the correct amounts. An example of this is teins used contain a relatively high concentration of the rel genetically modified soya where the phospholipid fraction evant amino acids. Enriched proteins can also be used, for contains additional EPA and/or DHA. example obtained by dialysis and membrane filtration tech 0035. Phospholipids can be obtained from egg or niques. An example of a enriched in tryptophan is Soya and can be isolated using known techniques, for example C.-lactalbumin. by acetone extraction and Subsequent chromatographic tech 0044) The amounts of neurotransmitters or agents which niques or adsorption methods. Ifrequired, synthetic phospho increase the concentration of neuro-transmitters in the Syn lipid fractions can also be used, but this is not preferred. apse are dependent on the nutritional status of the patient and 0036. Other substances which are preferably present in the his or her diet. Per daily dose, at least 14 mg/kg body weight preparation are components selected from , pan phenylalanine--tyrosine, that is to say on average 1 g/day, tothenic acid, , , , carotenoids, must be consumed via the complete diet. The product accord coenzyme Q10 and flavinoids. ing to the invention preferably contributes at least 50% to this, 0037 Amongst these, carnitine is a preferred compound. that is to say at least 0.5 g/day and preferably 0.7-3 g/day. The This also includes functional equivalents of carnitine, Such as diet must also provide at least 3.5 mg/kg body weight tryp salts thereof or alkanoyl- and acyl-carnitines (acetyl-L-car tophan. The product according to the invention preferably nitine). Carnitine can be incorporated in an amount of 0.1 to contributes at least 50% of this, that is to say at least 130 3 g, preferably 0.2 to 1 g per daily dose. Coenzyme Q10 can mg/day. Preferably the preparation contains 200-2200 mg be incorporated in an amount of 0.8 to 200 mg, preferably 5 to tryptophan per daily dose. 70 mg per daily dose. 0045. Under certain conditions, acetylcholine can be 0038. In the preparation of the invention the components formed from choline and betaine. Choline can also originate are preferably combined with existing agents which increase from phosphatidylcholine. It is advantageous that the product the amount of neurotransmitter in the synapse. These can be contains at least 0.4 g choline equivalents per daily dose, the neurotransmitters themselves, but also derivates thereof, preferably in the form of 0.4 to 2 g betaine or in the form of 3.5 precursors of the neuro-transmitters and drugs that are used to 18 g phosphatidylcholine, in particular obtained from leci for this purpose. Such as drugs that inhibit the reuptake of the thins with rapeseed, egg or Soya as possible source. neurotransmitters released in the synapse, such as the so called serotonin-reuptake inhibitors, or Substances that 0046 Nucleotides play an important role in the formation inhibit the metabolic conversion of the neurotransmitters, of acetylcholine. It is preferable to incorporate nucleotides in Such as the cholinesterase inhibitors, monoamine oxidase the preparation, in particular in the form of ribonucleic acids inhibitors and inhibitors. Certain nucle Such as, for example, are present in yeast or extracts thereof. otides or precursors thereof also stimulate the formation of Preferably the product contains at least 50 mg nucleobases, neurotransmitters. including uridine or cytidine, per daily dose. This corre 0039 Examples of the neurotransmitters themselves are, sponds to, for example, at least 2.5 g crude brewer's yeast. for example, dopamine and the known analogues thereof Instead of the bases it is also possible to use the phosphates which are already widely used in combating the symptoms of thereof. Such as the mono-, di- or tri-phosphate (for example Parkinson's disease. These substances are obtainable in syn uridine monophosphate (UMP)). thetic form. When the preparation of the invention is used, the 0047. A pentose, such as D-ribose, xylitol, L-arabinose or dosage of these substances can be reduced by as much as an oligosaccharide or polysaccharide that contains these Sug 50%. ars can also be incorporated in the product instead of or in 0040 Known drugs that increase the levels of neurotrans addition to nucleotides. Oligosaccharides that contain D-ri mitters, for example serotonin or serotonin reuptake bose and arabans are most preferred. At least 0.5 g of the inhibitors, which can be combined with the preparation of the pentose, preferably 1 to 20 g, is administered per daily dose. invention are Prozac, Zoloft, Luvox, Redux, Pondimin, Max 0048. The preparations according to the invention can be alt, Imitrex, Almogram, Zelapar, Selegiline, Mirapex, Per used for improving the action of receptors in cells of the max, Exelon, Remilnyl, Aricept, Cognex, Tasaclidine, central nervous system, in particular for improving the sen Ergoset and many other similar drugs. Insulin is also used to sitivity of receptors to neurotransmitters. Specific receptors stimulate the insulin receptor. that can be influenced by the preparation of the invention are 0041. Other examples of neurotransmitters are serotonin, metabotropic receptors, preferably G protein coupled recep adrenaline, noradrenaline, glutamate, acetylcholine and tOrS. gamma-aminobutyric acid. These can also be incorporated in 0049. Examples of metabotropic receptors are the seven the preparation. transmembrane domain receptors which usually function via 0042 Examples of precursors of neurotransmitters are the G proteins, but also single transmembrane domain receptors amino acids L-tryptophan, L-phenyl-alanine and L-tyrosine. Such as the tyrosine kinase receptor family (growth factors, Under certain conditions, serotonin can be formed from insulin), the cytokine receptor family (growth hormone, L-tryptophan in the body of the animal. Also, for example, erythropoietin, leptin, prolactin), the serine-threonine kinase US 2015/O164945 A1 Jun. 18, 2015 receptor family (TGF-beta), the guanylyl cyclase receptor receptor . The NMDA receptor differs from the here family (atrial natriuretic peptides) and the phosphotyrosine investigated M and 5-HT1A receptors in that the NMDA phosphatase family. receptor is an ion channel receptor versus the other two G 0050 Disorders of which the severity can be reduced by protein-coupled, metabotropic receptors. NMDA receptors increasing the action of the receptor are, in particular, disor are ionotropic receptors which need no major conformational ders associated with disturbed neurotransmitter functioning, changes like the metabotropic receptors during binding. Specific examples of these are Parkinson's disease, Hunting Metabotropic receptors like the muscarinic1 acetylcholine ton's chorea, epilepsy, schizophrenia, paranoia, depression, receptor and the serotonergic 5-HT1 receptor bind transmitter sleep disorders, impaired memory function, psychoses, and through a series of conformational changes bind to G dementia and ADHD and motor disorders such as can arise proteins and activate them. These conformations are facili after, for example, a trauma, stroke and ALS and chronic tated when membranes are fluid. fatigue syndrome. 0051. In view of the general nature of the improvement in TABLE 1 receptor function, in a number of cases it is desirable to add an antagonist. This is, for example, the case when aiming for Placebo S1 S2 weight loss. A more rapid effect is obtained if an antagonist Component g/100 g g/110 g g110 g for the C-2 receptor is given. EPA O.S O.S DHA 0.37 0.37 0052. The preparation of the invention can be used both ALA 0.155 0.137 O.184 for humans and animals, preferably for humans. LA O.640 1.321 1661 0053. The preparation can be brought into a suitable form AA O.2 O.2 and administered either as a pharmaceutical preparation or as 3-caroteine O.O2 O.O2 a nutritional preparation. Suitable additives and excipients for Flavonoids O.2 O.2 O.OOO784 O.OO1 O.OO1 Such preparations are known to those skilled in the art. O.OOOO19 OOOOO4 OOOOO4 Vitamin B6 O.OO153 O.OO172 O.OO172 EXPERIMENTAL Vitamin B12 O.OOOOS O.OOO12 O.OOO12 Vitamin C O.2 O.2 0054 The chronic dietary intake of essential polyunsatu Vitamin E O.OO63 O.3 O.3 rated fatty acids can modulate learning and memory pro Acetylcarnitine O6 Choline 0.4 cesses by being incorporated into neuronal and glial plasma Phosphatidylcholine O.2 membranes. Phosphatidylserine O.2 0055 Representatives of the two important polyunsatu Q10 O.O3 rated fatty acid families, the n-3 and n-6 types become inte Thiamine O.OO2 O.2 grated into membrane phospholipids, where the actual (n-6)/ Tyrosine O.944 1 (n-3) ratio can determine membrane fluidity. In the present Tryptophan O.232 1 experiment we studied hippocampal neurotransmitter recep tor after chronic administration of diets enriched in docosahexaenoic/eicosapentaenoic acid and methionine TABLE 2 metabolism stimulating components in a brain hypoperfusion model which mimics decreased cerebral perfusion as it nCi/ng tissue occurs in ageing and dementia. Serotonin receptor 0056 Sixty 30-day-old Wistar rats were randomly divided into 3 groups of 20. Each group was given a specific diet, the Stratum Stratum first ordinary chow (placebo), the second group chow of a stratum oriens radiatum Stratum oriens radiatum specific composition S1 and the third group the same feed as Placebo 2.8 3.1 7.3 9.6 Group 2 with additional components (S2); see Table 1. The S1 3.2 3.6 7.8 10.8 diets contained identical quantities of proteins, carbohy S2 3.3 3.7 8.5 11.6 drates, minerals and energy. At the age of 4 months, two of the four carotid arteries of half of each group of animals were We claim: occluded (2VO animals). The other half was subjected to a 1. A method for reducing the severity of Parkinson's dis similar operation without occlusion of the arteries. At the age ease, comprising administering to a person in need thereofan of 7 months the animals were sacrificed for further investiga tion. Inter alia, the receptor density in specific parts of the effective amount of a composition comprising: brain was determined with the aid of labelling using a radio (a) ()-3 polyunsaturated fatty acids comprising docosa active marker Substance. hexaenoic acid; 0057 Three receptor types, the muscarinic 1, serotonergic (b) at least one of folic acid, vitamin B6 and vitamin B12: 1A and the glutaminergic NMDA receptors were labelled in (c) a source of tyrosine and/or phenylalanine. hippocampal slices by autoradiographic methods. The 2. The method according to claim 1, in which said w-3 increased ratio of n-3 fatty acids in combination with addi polyunsaturated fatty acids further comprise eicosapen tional dietary supplements (table 1) enhanced the density of taenoic acid. the serotonergic 1A and muscarinic 1 receptors (Table 2), but 3. The method according to claim 1, in which said ()-3 no major effects were found on the NMDA receptors. Since polyunsaturated fatty acids are administered in a daily dose the examined receptor types reacted differently to the dietary amount of at least 120 mg. Supplementation, it can be concluded that besides changes in 4. The method according to claim 3, in which said ()-3 membrane fluidity, the biochemical regulation of receptor polyunsaturated fatty acids are administered in a daily dose sensitivity may also play a role in increasing hippocampal amount of at least 350 mg. US 2015/O164945 A1 Jun. 18, 2015

5. The method according to claim 1, in which said compo 18. The method according to claim 1, in which said com sition comprises folic acid which is administered in a daily position comprises folic acid, vitamin B6 and vitamin B12. dose amount of at least 250 ug. 19. The method according to claim 1, in which said com 6. The method according to claim 1, in which said compo position comprises at least 0.5g of tyrosine and/or phenyla sition comprises vitamin B6 which is administered in a daily lanine. dose amount of at least 1 mg of one or more of Vitamin B6, 20. A preparation comprising: pyridoxine, and pyridoxal. (a) ()-3 polyunsaturated fatty acids comprising docosa hexaenoic acid; 7. The method according to claim 1, in which said compo (b) at least one of folic acid, vitamin B6 and vitamin B12: sition comprises vitamin B12 which is administered in a daily (c) a source of tyrosine and/or phenylalanine. dose amount of at least 3 Lig cobalamin equivalents. 21. The preparation according to claim 20, containing a 8. The method according to claim 1, in which said compo daily dose amount of the sum of tyrosine and phenylalanine of sition comprises a daily dose amount of at least 0.5g of the 0.7-3.5g. Sum of tyrosine and phenylalanine. 22. The preparation according to claim 20, in which said 9. The method according to claim 8, in which said compo Source of tyrosine comprises a protein or a hydrolysed pro sition comprises a daily dose amount of 0.7-3.5g of the sum tein. of tyrosine and phenylalanine. 23. The preparation according to claim 20, which com 10. The method according to claim 1, in which said com prises folic acid in a daily dose amount of at least 250 g. position further comprises tryptophan in a daily dose amount 24. The preparation according to claim 20, which com of at least 130 mg. prises folic acid, vitamin B6, vitamin B12, vitamin C and 11. The method according to claim 1, in which said com vitamin E. position further comprises at least one of Zinc and magne 25. The preparation according to claim 20, which further sium. comprises at least one component selected from thiamine, 12. The method according to claim 1, in which said com pantothenic acid and carnitine. position further comprises phospholipids in a daily dose 26. The preparation according to claim 20, further com amount of at least 0.2g. prising a daily dose amount of at least 0.4 g choline equiva 13. The method according to claim 10, in which said com lents. position further comprises a daily dose amount of 0.4-2 g of 27. The preparation according to claim 20, further com betaine or 5 to 18 g of phosphatidylcholine. prising tryptophan. 14. The method according to claim 1, in which said com 28. The preparation according to claim 20, further com position further comprises at least one component selected prising alpha-linolenic acid, Stearidonic acid, eicosapen from thiamine, pantothenic acid and carnitine. taenoic acid and arachidonic acid. 15. The method according to claim 1, in which said com 29. The preparation according to claim 20, further com position further comprises a component selected from Vita prising nucleotides comprising uridine and/or cytidine, and/ min C and vitamin E. or phosphates thereof. 16. The method according to claim 1, in which said source 30. The preparation according to claim 20, comprising of tyrosine comprises a protein or a hydrolysed protein. folic acid, vitamin B6 and vitamin B12. 17. The method according to claim 1, in which said com 31. The preparation according to claim 20, comprising at position further comprises nucleotides comprising uridine least 0.5g of tyrosine and/or phenylalanine. and/or cytidine, and/or phosphates thereof. k k k k k