AMINOACIDS FOR TREATMENT OF NEUROLOGICAL DISORDERS

Abstract

There is provided a composition for use in a therapeutic method of treatment of a subject suffering from a neurological disorder, said composition comprising: A) serine, glycine, betaine, N-acetylglycine, N-acetylserine, dimethylglycine, sarcosine and/or phosphoserine; B)N-acetyl cysteine, cysteine and/or cystine; C) carnitine, deoxycarnitine, gamma-butyrobetaine, 4-trimethylammoniobutanal, 3-hydroxy-N 6,N6,N 6-trimethyl-L-lysine, N6,N6,N6-trimethyl-L-lysine and/or lysine; and D) nicotinamide.

Claims

1. A composition for use in a therapeutic method of treatment of a subject suffering from a neurological disorder, said composition comprising: A) serine, glycine, betaine, N-acetylglycine, N-acetylserine, dimethylglycine, sarcosine and/or phosphoserine; B)N-acetyl cysteine, cysteine and/or cystine; C) carnitine, deoxycarnitine, gamma-butyrobetaine, 4-trimethylammoniobutanal, 3-hydroxy-N6,N6,N6-trimethyl-L-lysine, N6,N6,N6-trimethyl-L-lysine and/or lysine; and D) nicotinamide.

2. The composition for use according to claim 1, wherein the molar ratio of A) to B) is between 16:1 and 1:4, such as between 12:1 and 1.5:1, preferably between 10:1 and 3:1.

3. The composition for use according to claim 1 or 2, wherein the molar ratio of A) to C) is between 150:1 and 1:1, such as between 100:1 and 2:1, preferably between 30:1 and 3:1, more preferably between 15:1 and 4:1.

4. The composition for use according to any one of the preceding claims, wherein the molar ratio of A) to D) is between 250:1 and 1.5:1, such as 150:1 and 3:1.

5. The composition for use according to any one of the preceding claims, wherein A) is serine, preferably L-serine.

6. The composition for use according to any one of the preceding claims, wherein B) is N-acetyl cysteine.

7. The composition for use according to any one of the preceding claims, wherein C) is carnitine.

8. The composition for use according to any one of the preceding claims, which is powderous mixture.

9. The composition for use according to any one of the preceding claims, wherein the neurological disorder is a neurodegenerative disease.

10. The composition for use according to claim 9, wherein the neurodegenerative disease is selected from the group consisting of dementia, Parkinson's′ disease, multiple sclerosis, epilepsy, brain injuries and neuroinfectious diseases.

11. The composition for use according to claim 9, wherein the neurodegenerative disease is Alzheimer's disease.

12. The composition for use according to any one of the preceding claims 1-1, wherein the subject is a human subject.

13. The composition for use according to any one of the preceding claims, wherein said therapeutic method comprises oral administration of composition.

14. The composition for use according to any one of the preceding claims, wherein said method comprises administration of: A) in a dose of 0.48-24 mmol/kg/day, such as 0.48-4.8 mmol/kg/day, such as 1.8-4.8 mmol/kg/day, such as 2.9-4.7 mmol/kg/day; B) in a dose of 0.31-3.05 mmol/kg/day, such as 0.31-1.84 mmol/kg/day, such as 0.40-1.23 mmol/kg/day; C) in a dose of 0.100-2.50 mmol/kg/day, such as 0.200-2.00 mmol/kg/day, such as 0.230-1.00 mmol/kg/day, such as 0.300-0.800 mmol/kg/day; and D) in a dose of 0.020-1.96 mmol/kg/day, such as 0.020-0.39 mmol/kg/day, such as 0.039-0.31 mmol/kg/day, such as 0.059-0.24 mmol/kg/day.

15. A method of treatment of a subject suffering from a neurological disorder, said method comprising administration to a subject in need thereof: A) serine, glycine, betaine, N-acetylglycine, N-acetylserine, dimethylglycine, sarcosine and/or phosphoserine; B) N-acetyl cysteine, cysteine and/or cystine; C) carnitine, deoxycarnitine, gamma-butyrobetaine, 4-trimethylammoniobutanal, 3-hydroxy-N6,N6,N6-trimethyl-L-lysine, N6,N6,N6-trimethyl-L-lysine and/or lysine; and D) nicotinamide.

16. A method of treatment of a subject suffering from a neurological disorder, comprising administration to a subject in need thereof: A) serine, glycine, betaine, N-acetylglycine, N-acetylserine, dimethylglycine, sarcosine and/or phosphoserine in a dose of 0.48-24 mmol/kg/day, such as 0.48-4.8 mmol/kg/day, such as 1.8-4.8 mmol/kg/day, such as 2.9-4.7 mmol/kg/day; B)N-acetyl cysteine, cysteine and/or cystine in a dose of 0.31-3.05 mmol/kg/day, such as 0.31-1.84 mmol/kg/day, such as 0.40-1.23 mmol/kg/day; C) carnitine, deoxycarnitine, gamma-butyrobetaine, 4-trimethylammoniobutanal, 3-hydroxy-N6,N6,N6-trimethyl-L-lysine, N6,N6,N6-trimethyl-L-lysine and/or lysine in a dose of 0.100-2.50 mmol/kg/day, such as 0.200-2.00 mmol/kg/day, such as 0.230-1.00 mmol/kg/day, such as 0.300-0.800 mmol/kg/day; and D) nicotinamide in a dose of 0.020-1.96 mmol/kg/day, such as 0.020-0.39 mmol/kg/day, such as 0.039-0.31 mmol/kg/day, such as 0.059-0.24 mmol/kg/day.

17. A method of treatment of a subject suffering from a neurological disorder, comprising administration to a subject in need thereof: A) serine, glycine, betaine, N-acetylglycine, N-acetylserine, dimethylglycine, sarcosine and/or phosphoserine in a dose of 100-600 mmol/day, such as 150-450 mmol/day, such as 170-350 mmol/day; B)N-acetyl cysteine, cysteine and/or cystine in a dose of 12-100 mmol/kg/day, such as 16-75 mmol/day, such as 20-50 mmol/day; C) carnitine, deoxycarnitine, gamma-butyrobetaine, 4-trimethylammoniobutanal, 3-hydroxy-N6,N6,N6-trimethyl-L-lysine, N6,N6,N6-trimethyl-L-lysine and/or lysine in a dose of 12-100 mmol/kg/day, such as 16-75 mmol/day, such as 20-50 mmol/day; and D) nicotinamide in a dose of 3-20 mmol/day, such as 4-15 mmol/day, such as 5-12 mmol/day.

18. The method of any one of claims 15-17, wherein the administration is oral administration.

19. Substances comprising A) serine, glycine, betaine, N-acetylglycine, N-acetylserine, dimethylglycine, sarcosine and/or phosphoserine, B)N-acetyl cysteine, cysteine and/or cystine, C) carnitine, deoxycarnitine, gamma-butyrobetaine, 4-trimethylammoniobutanal, 3-hydroxy-N6,N6,N6-trimethyl-L-lysine, N6,N6,N6-trimethyl-L-lysine and/or lysine and D) nicotinamide for simultaneous, separate or sequential use in a method of treatment of a subject suffering from a neurological disorder.

20. Substances according to claim 19, wherein the neurological disorder is a neurodegenerative disease.

21. Substances according to claim 19 or 20, wherein said therapeutic method comprises oral administration of said substances.

22. Substances according to any one of claims 19-21, wherein said therapeutic method comprises oral administration of: A) in a dose of 0.48-24 mmol/kg/day, such as 0.48-4.8 mmol/kg/day, such as 1.8-4.8 mmol/kg/day, such as 2.9-4.7 mmol/kg/day; optionally B) in a dose of 0.31-3.05 mmol/kg/day, such as 0.31-1.84 mmol/kg/day, such as 0.40-1.23 mmol/kg/day; optionally C) in a dose of 0.100-2.50 mmol/kg/day, such as 0.200-2.00 mmol/kg/day, such as 0.230-1.00 mmol/kg/day, such as 0.300-0.800 mmol/kg/day; and D) in a dose of 0.020-1.96 mmol/kg/day, such as 0.020-0.39 mmol/kg/day, such as 0.039-0.31 mmol/kg/day, such as 0.059-0.24 mmol/kg/day.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0036] FIG. 1 shows the density of tyrosine hydroxylase-positive fibers in the striatum. The first bar from the left represents Group 1 (“Saline”). The second bar from the left represent Group 2 (“Saline+supplements”). The third bar from the left represents Group 3 (“MPTP”), i.e. the untreated group of mice having MPTP-induced PD. The fourth bar from the left represents Group 4 (“MPTP+supplements”), i.e. the mice having MPTP-induced PD that were given the supplements.

[0037] FIG. 2 shows the number of tyrosine hydroxylase-positive cells in substantia nigra (SN). The first bar from the left represents Group 1 (“Saline”). The second bar from the left represent Group 2 (“Saline+supplements”). The third bar from the left represents Group 3 (“MPTP”), i.e. the untreated group of mice having MPTP-induced PD. The fourth bar from the left represents Group 4 (“MPTP+supplements”), i.e. the mice having MPTP-induced PD that were given the supplements.

[0038] FIG. 3 shows the results of a vertical grid test. In each chart of FIG. 3: the first bar from the left represents a wild type mouse; the second bar from the left represent wild type mice given the supplements; the third bar from the left represents untreated virus-induced PD mice; and the fourth bar from the left represents virus-induced PD mice given the supplements.

DETAILED DESCRIPTION

[0039] As a first aspect of the present disclosure, there is provided a composition for use in a method of treating a subject suffering from a neurological disorder. The subject of the present disclosure is preferably a human subject.

[0040] The composition comprises: [0041] A) serine, glycine, betaine, N-acetylglycine, N-acetylserine, dimethylglycine, sarcosine and/or phosphoserine; [0042] B) optionally N-acetyl cysteine, cysteine and/or cystine; [0043] C) optionally carnitine, deoxycarnitine, gamma-butyrobetaine, 4-trimethylammoniobutanal, 3-hydroxy-N6,N6,N6-trimethyl-L-lysine, N6,N6,N6-trimethyl-L-lysine and/or lysine; and [0044] D) nicotinamide riboside, quinolinate, deamino-NAD+, nicotinate D-ribonucleotide, nicotinamide D-ribonucleotide, nicotinate D-ribonucleoside, nicotinamide and/or nicotinate.

[0045] In a variant of the first aspect, the composition comprises A), B), C) and optionally D).

[0046] In group A), serine and glycine are preferred. The most preferred substance in group A) is serine, which is usually provided as L-serine.

[0047] In group B), N-acetyl cysteine (NAC) and cysteine are preferred. The most preferred substance in group B) is NAC.

[0048] The substance of group C) is preferably carnitine, optionally in the form of a carnitine salt, such as carnitine tartrate. Most preferably, the substance of group C) is L-carnitine, optionally in the form of a L-carnitine salt, such as L-carnitine tartrate.

[0049] The substance of group D) is preferably nicotinamide riboside (NR) or nicotinamide, most preferably nicotinamide.

[0050] The substance(s) of group A) is preferably included in a higher molar amount than the substance(s) of group D). When efficacy and toxicity is also considered (see the discussion about doses below), the molar ratio of A) to D) is normally between 250:1 and 1.5:1 and typically between 150:1 and 3:1. Preferably, the molar ration is between 90:1 and 10:1, more preferably between 50:1 and 20:1.

[0051] In embodiments including the substance(s) of group B), the molar ratio of A) to B), considering efficacy and toxicity, is typically between 16:1 and 1:4, preferably between 12:1 and 1.5:1 and more preferably between 10:1 and 3:1.

[0052] In embodiments including the substance(s) of group C), the molar ratio of A) to C), considering efficacy and toxicity, is normally between 150:1 and 1:1, typically between 100:1 and 2:1, preferably between 30:1 and 3:1, more preferably between 15:1 and 4:1.

[0053] The above ratios entail that a patient consuming the composition can obtain appropriate doses of the respective substances.

[0054] In one embodiment, the composition of the first aspect is a solid, such as a solid powder. Such a powder can be mixed with water, e.g. by the patient/consumer, a nurse or a physician. In another embodiment, the composition of the first aspect is an aqueous solution or suspension (“cocktail”), which facilitates convenient oral administration. Such an aqueous solution or suspension is preferably ready to drink.

[0055] As a particularly preferred embodiment of the first aspect, the composition is a powder comprising: [0056] A) serine; [0057] B) N-acetyl cysteine; [0058] C) carnitine; and [0059] D) nicotinamide riboside or nicotinamide, wherein the molar ratio of A) to B) is between 12:1 and 1:1.5, preferably between 10:1 and 3:1,

[0060] the molar ratio of A) to C) is between 100:1 and 2:1, preferably between 30:1 and 3:1, more preferably between 15:1 and 4:1; and

[0061] the molar ratio of A) to D) is between 150:1 and 3:1.

[0062] As another particularly preferred embodiment of the first aspect, the composition is a powder comprising: [0063] A) serine; [0064] B) N-acetyl cysteine and/or cysteine; [0065] C) carnitine; and [0066] D) nicotinamide riboside or nicotinamide, wherein

[0067] the molar ratio of A) to D) is between 150:1 and 3:1.

[0068] In embodiments of the solution or suspension according to the first aspect: [0069] the concentration of A) is typically 0.20-2.4 mmol/ml, preferably 0.40-2.4 mmol/ml and more preferably 0.60-2.4 mmol/ml; and/or [0070] the concentration of D) is typically 0.006-0.12 mmol/ml, preferably 0.012-0.08 mmol/ml and more preferably 0.018-0.07 mmol/ml.

[0071] When included in the solution or suspension according to the first aspect: [0072] the concentration of B) is normally 0.09-0.90 mmol/ml, typically 0.09-0.54 mmol/ml, preferably 0.11-0.40 mmol/ml and more preferably 0.013-0.30 mmol/ml; and/or [0073] the concentration of C) is normally 0.009-0.38 mmol/ml, typically 0.009-0.19 mmol/ml, preferably 0.016-0.16 mmol/ml and more preferably 0.028-0.12 mmol/ml.

[0074] The solution or suspension of the first aspect may be provided in a package for convenient handling and distribution. Further, the volume of such a package may be such that drinking the whole contents of the package at once or during a single day results in oral administration of appropriate doses of the substances in the solution or suspension. In one embodiment, the volume of the package is 25-1000 ml. The volume is preferably 50-500 ml. When it is intended that the consumer/patient shall drink more than one package per day, the volume is typically relatively low, such as 25-500 ml, preferably 25-400 ml.

[0075] In one embodiment, the packaged solution or suspension comprises 48-478 mmol of A). Thereby, the dose of A) is effective, but not toxic. In a preferred embodiment, A) is serine in an amount of 5-50 g, more preferably 10-50 g.

[0076] In an alternative of complimentary embodiment, the packaged solution or suspension comprises 2.0-39.2 mmol of D) when D) is NR and 2.0-196 mmol of D) when D) is not NR. Thereby, the dose of D) is effective, but not toxic. In a preferred embodiment, D) is NR in an amount of 0.5-10 g, more preferably 1.5-6 g.

[0077] When the composition of the first aspect is a powder, it may also be packaged. As an example, the powder may be provided in unit dose packs. It follows from the discussion above that such a unit dose may comprise 48-478 mmol of A) and/or 2.0-39.2 mmol of D) when D) is NR and 2.0-196 mmol of D) when D) is not NR. Further, such as packed powder preferably comprises serine in an amount of 5-50 g and/or NR in an amount of 0.5-10 g. More preferably, such a packed powder comprises serine in an amount of 10-50 g and/or NR in an amount of 1.5-6.0 g.

[0078] The substances of the present disclosure are preferably a significant part of the composition of the first aspect. For example, the substances included in groups A)-D) may amount to at least 10%, such as at least 25%, such as at least 50% of the dry weight of the composition of the first aspect. In one embodiment, the weight of serine is at least 10%, such as at least 25%, such as at least 40% of the dry weight of the composition of the first aspect.

[0079] The composition of the first aspect may comprise one or more tasting agent(s), such as one or more sweetener(s) (e.g. sucralose) and/or one or more flavor agent(s). It may also comprise a lubricant, such as a polyethylene glycol lubricant (e.g. Polyglykol 8000 PF (Clariant)).

[0080] The neurological disorder treated according to the first aspect may be a neurodegenerative disease. Examples of neurodegenerative diseases are dementia (e.g. Alzheimer's disease), Parkinson's disease, multiple sclerosis, epilepsy, brain injuries and neuroinfectious diseases.

[0081] In one embodiment, the neurological disorder is Alzheimer's disease or Parkinson's disease.

[0082] In another embodiment, the neurological disorder is selected from the group consisting of cerebrovascular diseases including stroke, migraine and other headache disorders, multiple sclerosis, brain tumors and neurological disorders as a result of malnutrition.

[0083] In an embodiment, the method of treatment comprises oral administration of the composition.

[0084] The method of treatment may for example comprise administration, such as oral administration, of: [0085] A) in a dose of 0.48-24 mmol/kg/day, such as 0.48-4.8 mmol/kg/day, such as 1.8-4.8 mmol/kg/day, such as 2.9-4.7 mmol/kg/day; [0086] optionally B) in a dose of 0.31-3.05 mmol/kg/day, such as 0.31-1.84 mmol/kg/day, such as 0.40-1.23 mmol/kg/day; [0087] optionally C) in a dose of 0.100-2.50 mmol/kg/day, such as 0.200-2.00 mmol/kg/day, such as 0.230-1.00 mmol/kg/day, such as 0.300-0.800 mmol/kg/day; and/or [0088] D) in a dose of 0.020-1.96 mmol/kg/day, such as 0.020-0.39 mmol/kg/day, such as 0.039-0.31 mmol/kg/day, such as 0.059-0.24 mmol/kg/day, provided that the dose is not higher than 0.39 mmol/kg/day when D) is NR.

[0089] If the doses are not adjusted to the weight of the patient, the method of treatment may for example comprise administration, such as oral administration, of: [0090] A) in a dose of 100-600 mmol/day, such as 150-450 mmol/day, such as 170-350 mmol/day; [0091] optionally B) in a dose of 12-100 mmol/kg/day, such as 16-75 mmol/day, such as 20-50 mmol/day; [0092] optionally C) in a dose of 12-100 mmol/kg/day, such as 16-75 mmol/day, such as 20-50 mmol/day; [0093] D) in a dose of 3-20 mmol/day, such as 4-15 mmol/day, such as 5-12 mmol/day.

[0094] The daily dose may be reached by administrating one or more doses per day to the patient. In one embodiment, the number of daily doses is one, two or three. For example, the patient may consume a drink formed from the composition in powderous form one, two or three times per day. Each dose or drink preferably comprises no more than 4.78 mmol/kg of A).

[0095] The method of treatment may be carried out for a period of 1 week to 1.5 years, e.g. 1-52 weeks, such as 3-46 weeks, such as 6-30 weeks.

[0096] As a second aspect of the present disclosure, there is provided a method of treatment of a subject suffering from a neurological disorder, comprising administration, such as oral administration, of: [0097] A) serine, glycine, betaine, N-acetylglycine, N-acetylserine, dimethylglycine, sarcosine and/or phosphoserine, for example in a dose of 0.48-24 mmol/kg/day, such as 0.48-4.8 mmol/kg/day, such as 1.8-4.8 mmol/kg/day, such as 2.9-4.7 mmol/kg/day; [0098] B) optionally N-acetyl cysteine, cysteine and/or cystine, for example in a dose of 0.31-3.05 mmol/kg/day, such as 0.31-1.84 mmol/kg/day, such as 0.40-1.23 mmol/kg/day; [0099] C) optionally carnitine, deoxycarnitine, gamma-butyrobetaine, 4-trimethylammoniobutanal, 3-hydroxy-N6,N6,N6-trimethyl-L-lysine, N6,N6,N6-trimethyl-L-lysine and/or lysine, for example in a dose of 0.100-2.50 mmol/kg/day, such as 0.200-2.00 mmol/kg/day, such as 0.230-1.00 mmol/kg/day, such as 0.300-0.800 mmol/kg/day; and [0100] D) nicotinamide riboside (NR), quinolinate, deamino-NAD+, nicotinate D-ribonucleotide, nicotinamide D-ribonucleotide, nicotinate D-ribonucleoside, nicotinamide and/or nicotinate, for example in in a dose of 0.020-1.96 mmol/kg/day, such as 0.020-0.39 mmol/kg/day, such as 0.039-0.31 mmol/kg/day, such as 0.059-0.24 mmol/kg/day, provided that the dose is not higher than 0.39 mmol/kg/day when D) is NR.

[0101] The embodiments and examples of the first aspect apply to the second aspect mutatis mutandis.

[0102] For the patient/consumer, it is not necessary to take the substances of the present disclosure simultaneously. A therapeutic effect can also be achieved if the substances are taken separately or sequentially, preferably within a day and more preferably within an hour.

[0103] As a third aspect of the present disclosure, there is thus provided substances comprising: [0104] A) serine, glycine, betaine, N-acetylglycine, N-acetylserine, dimethylglycine, sarcosine and/or phosphoserine; [0105] B) optionally N-acetyl cysteine, cysteine and/or cysteine; [0106] C) optionally carnitine, deoxycarnitine, gamma-butyrobetaine, 4-trimethylammoniobutanal, 3-hydroxy-N6,N6,N6-trimethyl-L-lysine, N6,N6,N6-trimethyl-L-lysine and/or lysine; and [0107] D) nicotinamide riboside, quinolinate, deamino-NAD+, nicotinate D-ribonucleotide, nicotinamide D-ribonucleotide, nicotinate D-ribonucleoside, nicotinamide and/or nicotinate

[0108] for simultaneous, separate or sequential use in a therapeutic method of treatment of a subject.

[0109] The third aspect may for example be a combined preparation of two or more units, such as a first unit comprising A), a second unit comprising D), optionally a third unit comprising B) and optionally a fourth unit comprising C).

[0110] The embodiments and examples of the first and second aspect apply to the third mutatis mutandis.

Animal Experiments

[0111] The Effect of Supplements in a MPTP-Based Experiment

[0112] Administration of MPTP and Supplements

[0113] This experiment was based on the Protocol for the MPTP Mouse Model of Parkinson's Disease (PD) (Nat Protoc. 2007; 2(1):141-51; https://pubmed.ncbi.nlm.nih.gov/17401348/).

[0114] Male C57Bl/6 mice (21-25 g; age 8 weeks) were divided into four groups of three animals each (N=3): [0115] Group 1 (“Saline”); [0116] Group 2 (“Saline+supplements”); [0117] Group 3 (“MPTP”); and [0118] Group 4 (“MPTP+supplements”).

[0119] The mice of groups 3 and 4 received intraperitoneal injections of MPTP. The mice of groups 1 and 2 received intraperitoneal injections of sterile saline. MPTP was administered as 4 times injections of 20 mg/kg at 2 hr intervals. Control animals were injected an equal volume of 0.9% sterile saline.

[0120] The supplements were: [0121] serine (400 mg/kg/day la gavage); [0122] carnitine tartrate (400 mg/kg/day la gavage); [0123] NR (400 mg/kg/day la gavage); and [0124] NAC (1 g/l in the drinking water to a total of 400 mg/kg/day).

[0125] The supplements were given once a day starting day 4 after the final MPTP injection. The control mice received water on day 3 after the final MPTP injection. The mice were sacrificed seven days after the final MPTP injection.

[0126] Immunohistochemistry and Results

[0127] Since PD is generally considered to a tyrosine hydroxylase-deficiency syndrome, the tyrosine hydroxylase level in two parts of the brains of the mice was measured.

[0128] The sacrificed mice were perfused with a perfusion solution and post-fixated with 4% paraformaldehyde for one day at 4° C. The perfusion solution contained NaCl, NaNO.sub.3, (Sigma-Aldrich) and heparin dissolved in distilled water. The perfused mice were stored in a 30% sucrose solution for 24-48 h at 4° C. until they sank. Then, the brains of the mice were cut coronally to slices of 30 μm thickness. Brain slices were fixed with tissue stock solution and rinsed three times in Phosphate-buffered saline (PBS pH 7.4). 0.3% TritonX-100, 2% donkey serum (Gene Tex, Irvine, Calif., USA) in PBS was used for blocking for 90 min, then brain slices were contacted with anti-tyrosine hydroxylase at 4° C. for overnight. After that, brain slices were incubated with rabbit secondary antibodies (Dako EnVision.sup.+ system-HRP, USA) for 90 min, and then reacted with DAB+ substrate buffer. After mounting by fluorescent mounting medium (Dako North America Inc, USA) on cover slides, immunofluorescent images were acquired using Olympus™ confocal microscope (Olympus).

[0129] The density of tyrosine hydroxylase-positive fibers in the striatum was quantified. Group 4 showed a significantly higher density than Group 3 (see FIG. 1). In other words, the supplements significantly increased the tyrosine hydroxylase level in mice having MPTP-induced PD. No corresponding effect was observed in mice without MPTP-induced PD (compare Group 2 to Group 1). Notably, the tyrosine hydroxylase level in the supplemented mice having an MPTP-induced PD (i.e. Group 4) was almost as high as in the control group (i.e. Group 1).

[0130] Further, the number of tyrosine hydroxylase-positive cells in substantia nigra (SN) was quantified. Group 4 showed a significantly higher number than Group 3 (see FIG. 2). In other words, the supplements significantly increased the tyrosine hydroxylase level in mice having MPTP-induced PD also in the SN. No corresponding effect was observed when Group 2 was compared to Group 1. Notably, the tyrosine hydroxylase level in the supplemented mice having an MPTP-induced PD (i.e. Group 4) was as high as in the control group (i.e. Group 1).

[0131] In conclusion, the experiment supports that the supplements are effective in treating neurological disorders, such as PD.

[0132] The Effect of Supplements in a Virus Injection Mouse Model

[0133] C57BL/6J male mice were used for the experiment. When the experiment started, the mice were 8 weeks old. The mice, which were given a high fat diet throughout the experiment, were divided into four groups. [0134] Group 1(N=1): wild type mouse [0135] Group 2 (N=3): wild type mice, administration of supplements starting on day 15 [0136] Group 3 (N=3): virus-induced PD mice [0137] Group 4 (N=3): virus-induced PD mice, administration of supplements [0138] starting on day 15

[0139] Virus-induced PD was achieved by stereotaxic injections of alpha-synuclein (AAV-A53T virus) in the substantia nigra of the 8 weeks old mice of groups 3 and 4.

[0140] The supplements were: [0141] serine (400 mg/kg/day la gavage); [0142] carnitine tartrate (400 mg/kg/day la gavage); [0143] NR (400 mg/kg/day la gavage); and [0144] NAC (1 g/l in the drinking water to a total of 400 mg/kg/day).

[0145] The supplements were dosed daily. After the 15th dose, the mice were fasted for 4 hours and then, the vertical grid test was performed.

[0146] The apparatus for the vertical grid test was an open box (8 cm×55 cm×5 cm) with a black wall made of 0.8 cm×0.8 cm wire mesh. All groups were adapted to the vertical grid test by placing inside the apparatus for 5 days and allowing them to turn and climb down. Experiments were performed by recording and analysing total time, time to turn, time to climb down and missteps/total steps.

[0147] The vertical grid test showed that the supplements significantly reduced the total time, the time to turn and the proportion of missteps of group 4 compared to group 3 (FIG. 3). This supports that the supplements are effective in treating neurological disorders, such as PD.

[0148] Clinical Trial (Humans)

[0149] Trial Design

[0150] Preparation of the Investigational Drug and Placebo

[0151] This trial is a double-blind, randomized, placebo-controlled, investigator-initiated, multi-centre trial, which aims to establish metabolic improvements in AD and PD subjects by dietary supplementation with N-acetylcysteine, L-carnitine tartrate, nicotinamide riboside and serine. In the trial, supplements or matching placebo are taken by the subjects as powder dissolved in water by mouth.

[0152] The drug product, i.e. the mixture of the four supplements, and the placebo was produced in Turkey according to GMP regulations by Pharmactive Company (www.pharmactive.com.tr/en/anasayfa.html) according to EU standards and packed according to GMP rules with the appropriate dosage.

[0153] The drug product and the placebo were not identifiable from its packaging. Both were dissolved by patients in 200 mL preferably cold water before use.

[0154] The drug product and the placebo were administered in white plastic bottles (containing dry powder) with a desiccant cap.

[0155] Stability tests performed by ChromaDex in USA has shown that the mixture of supplements is stable at 25° C. for at least three months in the plastic bottles.

[0156] Strawberry aroma had been added to the drug product. As placebo, sorbitol (5 g) flavoured with strawberry aroma and colouring agent were given.

[0157] Study Population

[0158] The study population was 69 Alzheimer's disease and 48 Parkinson's disease patients on Day 0 and Day 28; 60 Alzheimer's disease and 43 Parkinson's disease patients on Day 84. Eligible subjects had signed an informed consent, met all inclusion criteria and had none of the exclusion criteria listed below.

[0159] Inclusion Criteria

[0160] I-1. Men and women diagnosed with Parkinson's Disease (Hoehn Yahr 2-4, age >40 years) or men and women diagnosed with Alzheimer's Disease.

[0161] Include patients older than 50 years with mild to moderate Alzheimer's disease according to ADAS-cog (Alzheimer's Disease Assessment Scale-cognitive subscale; ADAS≥12) and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB; CDR≤2).

[0162] 1-2. Patients with stable treatments and clinical course

[0163] Exclusion Criteria [0164] E-1. Inability or unwillingness to give written informed consent [0165] E-2. History of stroke, severe brain trauma, toxic drug exposure [0166] E-3. Neurological examination which indicate to Parkinson-Plus syndrome (i.e., pyramidal, cerebellar and autonomic dysfunction findings and gaze paralysis) for PD [0167] E-4. Uncontrolled Type 1 or type 2 diabetes [0168] E-5. Diarrhea (defined as more than 2 stool per day) within 7 days before enrolment [0169] E-6. Chronic kidney disease with an estimated glomerular filtration rate <60 ml/min/1.73 m2 [0170] E-7. Significant cardiovascular co-morbidity (i.e. heart failure) [0171] E-8. Patients with active bronchial asthma [0172] E-9. Patients with phenylketonuria (contraindicated for NAC) [0173] E-10. Patients with histamine intolerance [0174] E-11. Clinically significant TSH level outside the normal range (0.04-6 mU/L) [0175] E-12. Known allergy for substances used in the study [0176] E-13. Concomitant medication use: [0177] Self-administration of dietary supplements such as any vitamins, omega-3 products, or plant stanol/sterol products within 1 week [0178] Use of an antimicrobial agent in the 4 weeks preceding randomization [0179] E-14. Active smokers consuming >10 cigarettes/day [0180] E-15. Alcohol consumption over 192 grams for men and 128 grams for women per week [0181] E-16. Patients considered as inappropriate for this study for any reason (patients unable to undergo MRI study, noncompliance etc.) [0182] E-17. Active participation in another clinical study [0183] E-18. Women with potential to give birth. Post-menopausal women, women who had hysterectomy or women with acceptable medical proof shoving that she can't get pregnant according to the investigator's decision may be enrolled to the study.

[0184] Randomization and Blinding

[0185] The study subjects were randomized on a 2:1 basis to the supplements mixture or placebo. A web-based randomization system was used to assign a randomization code for each patient. An investigator or other responsible person at the investigational site was able to enter the web-based randomization system specific to the study through assigned username and password. After entering patient-related information (patient number, date of birth, patient initials), the system provided randomization code for the future use by investigators. This randomization code was entered into the electronic case report form (e-CRF).

[0186] Dosage and Administration

[0187] Subjects in active treatment received dietary supplementation with N-acetylcysteine, L-carnitine tartrate, nicotinamide riboside, and serine, administered as a mixture. Half dosage of the supplements was given for four weeks (one dose taken just after dinner), and full dosage for 8 weeks (two equal doses taken just after breakfast and dinner).

[0188] The dosage of the supplements will be as follows:

TABLE-US-00002 Weeks 1-4 (28 days) Weeks 5-12 (56 days) L-Carnitine tartrate 3.73 g/day 7.46 g/day N-Acetylcysteine 2.55/day 5.1 g/day Nicotinamide riboside 1 g/day 2 g/day Serine 12.35 g/day 24.7 g/day

[0189] Study Plan

[0190] The study comprises four clinical visits.

[0191] Visit 1

[0192] Screening visit (Weeks −1; Days −3 to −1). The subjects got the informed consent form and oral information on the study protocol, including genetic studies, number of visits and procedures to be performed in each visit. After the subject had given written informed consent to participate in the study, the data obtained in the screening visit included the following: [0193] Demographic data [0194] Medical history including associated conditions, previous operations, smoking and alcohol consumption and concomitant drug usage [0195] Physical examination including body weight, height, waist circumference, hip circumference, blood pressure and pulse rate [0196] Neurological examination to stage PD and AD patients [0197] Functional Medicine Assessment [0198] Review of inclusion/exclusion criteria [0199] Laboratory safety parameters including complete blood count (blood cells, haemoglobin), alkaline phosphatase (ALP), alanine aminotransferase (ALT), Aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), bilirubin, albumin, creatinine kinase (CK), total cholesterol, high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglycerides, creatinine, urea, urate, glucose, sodium (Na), potassium (K), insulin, HbAic and thyroid-stimulating hormone (TSH) [0200] The motor and cognitive functions of PD patients evaluated via UPDRS and MoCa, respectively. [0201] The cognitive functions of AD patients evaluated via MMSE and ADAS-cog. [0202] The daily life activity of AD patients evaluated via ADCS-ADL. [0203] Clinical Dementia Rating Scale Sum of Boxes (CDR) for clinical evaluation of AD. [0204] The behavioral functions of PD and AD patients will be evaluated via NPI. [0205] CNS atrophy and functional network activity of PD and AD patients evaluated via volumetric Magnetic resonance Imaging (MRI) and resting state functional magnetic resonance imaging (rest-fMRI), respectively. [0206] Information on prior and concomitant medications will be collected

[0207] Visit 2

[0208] Randomization visit (Week 1; Day 1). Eligible study subjects were randomized to active therapy or placebo groups and study agents were dispensed.

[0209] At the randomization visit the subjects were asked to take the first dose at the hospital and observed for development of adverse events. The changes in concomitant medications were evaluated. Patients who tolerated the study agents started to take half dose of supplements mixture (i.e., one administration daily just after dinner) for four weeks. Treatment compliance and adverse event questioning were performed by the study nurse by weekly telephone contacts.

[0210] Visit 3

[0211] On-treatment first visit (Week 4; Day 28). The subjects came to the study center for complete evaluation including and adverse events recording. Clinical and physical examination, determination of the motor, cognitive and behavioral functions using clinical scales, laboratory safety parameters, lipidomic, metabolomic and oral/gut microbiota analysis were repeated as in Visit 1.

[0212] Clinical scales included MMSE, ADAS-cog, ADCS-ADL and CDR for AD patients and UPDRS and MoCA for PD patients. NPI was applied to both group of patients in order to evaluate behavioral symptoms.

[0213] After Visit 3, subjects started to take full dose of final concentrations (i.e., two dosages daily taken just after breakfast and after dinner). Treatment compliance and adverse event questioning were performed by the study nurse by weekly telephone contacts.

[0214] Visit 4

[0215] End of study, on-treatment second visit (Week 12; Day 84). The subjects returned to the study center after eight weeks to evaluate efficacy, tolerability and safety.

[0216] At the end of the treatment, all procedures including clinical and physical examination, adverse events recording, MRI volumetric and rest-state fMRI, determination of the motor, cognitive and behavioral functions using clinical scales, biochemical, lipidomic, metabolomic and oral/gut microbiota analysis were repeated as in Visit 1. Treatment compliance and development of any adverse events were questioned during this visit.

[0217] After Visit 4, participants stopped taking study agents.

[0218] Results

[0219] The present disclosure can present the MoCA results at Day 28 for 32 PD subjects given the drug product and 16 PD subjects given placebo (i.e. results from Visit 3). In treated group, there was a significant positive effect (p-value: 0.0013; log 2foldchange: 0.173). There was also a significant effect in the group given placebo (p-value: 0.001; log 2foldchange: 0.159).

[0220] Further, the present disclosure can present the MoCA results at Day 84 for 28 PD subjects given the drug product and 15 PD subjects given placebo (i.e. results from Visit 4). In treated group, there was a significant positive effect (p-value: 0.0001; log 2foldchange: 0.27). There was also a significant effect in the group given placebo (p-value: 0.039; log 2foldchange: 0.15). However, the effect was limited in the placebo group compared to the treated group.

[0221] Also, the present disclosure can present the ADAS-cog results at Day 28 for 47 AD subjects given the drug product and 22 AD subjects given placebo (i.e. results from Visit 3). In treated group, there was a significant positive effect (p-value: 0.000000322; log 2foldchange: −0.32). There was also a (less) significant effect in the group given placebo (p-value: 0.009; log 2foldchange: −0.15).

[0222] Further, the present disclosure can present the ADAS-cog results at Day 84 for 40 AD subjects given the drug product and 20 AD subjects given placebo (i.e. results from Visit 4). In treated group, there was a significant effect (p-value: 0.000013107; log 2foldchange: −0.37). There was also a significant effect in the group given placebo (p-value: 0.001; log 2foldchange: −0.19). However, the effect was limited in the placebo group compared to the treated group.

[0223] The differences between clinical parameters are analyzed by stratifying the patients into high- and low-scored ADAS-Cog groups (>20ADAS-Cog score is high, ≤20 is low). More interestingly, the present disclosure can present a significant difference of ADAS-Cog scores at day 28 in the high scored CMA group (p-value: 0.001; log 2foldchange: −0.30) and no difference in the high scored placebo group (p-value: 0.08; log 2foldchange: −0.1). Similarly, the present disclosure can present a significant difference of ADAS-Cog scores at day 84 in the high scored CMA group (p-value: 0.003; log 2foldchange: −0.38) and no difference in the high scored placebo group (p-value: 0.3; log 2foldchange: −0.07).

[0224] Alzheimer's Disease Study (Rats)

[0225] Rat Study Design

[0226] 12 weeks old female Sprague-Dawley rats (weighing 320-380 g) were kept at a controlled temperature of 22±2° C. and a controlled humidity of 50±5% on a 12-hour light/dark cycle. Food and water were available ad libitum. The animal experiments are performed at Medical Experimental Research Center, Ataturk University, Erzurum, Turkey. All experiments for the treatment of the animals were approved by the Ethics Committee of Atatürk University, and were conducted following the National Institutes of Health Guide for Care and Use of Laboratory Animals.

[0227] After acclimation to laboratory conditions for one (1) week, rats were randomly divided into two dietary regimens receiving either a Chow diet (CD) or a high-fat diet (HFD. The animals of Group 1 (n=4) were fed with only regular CD for five (5) weeks. The animals of Group 2 (n=4) were fed with CD and treated with STZ. The remaining animals (n=4) were fed with HFD for 3 weeks and sacrificed to verify the model development (Group 3). Groups 4-13 were fed with HFD for 5 weeks. After 3 weeks, the animals in Groups 5-13 were treated with STZ and administered with individual or combined substances. The animals in Group 4 were injected (icy) with a control substance (saline) after 3 weeks.

[0228] Intracerebroventricular-Streptozotocin (STZ) Injection

[0229] Before surgical procedures, the rats were anesthetized by intraperitoneal administration of ketamine-xylazine (50 mg/kg ketamine and 5 mg/kg xylazine) and placed individually in the stereotaxic instrument (Stoelting, Ill., USA). Stereotaxic coordinates for injection were 0.8 mm posterior to the bregma, 1.5 mm lateral to the sagittal suture and 3.6 mm below the brain surface (Pellegrino et al. 1979). Then, 10 microliters of STZ (3 mg/kg, Sigma-Aldrich, Darmstadt, Germany) were injected over 3 min with a Hamilton micro-syringe into the bilateral ventricle. The injection needles were left in place for an additional 2 min to allow diffusion.

[0230] Administration of Substances

[0231] For carrying out the treatment experiments, the HFD rats were randomly separated into nine (9) subgroups of four (4) animals (Groups 5-13). As explained above, all animals of these groups had been treated with 3 mg/kg STZ (10 μL, icv).

[0232] The Groups Received the Following Treatments: [0233] Group 5, control (no administration); [0234] Group 6, serine (1000 mg/kg once daily by oral gavage); [0235] Group 7, NAC (300 mg/kg once daily by oral gavage); [0236] Group 8, L-carnitine tartrate (LCAT) (100 mg/kg once daily by oral gavage); [0237] Group 9, nicotinamide riboside chloride (NRCl) (120 mg/kg once daily by oral gavage); [0238] Group 10, nicotinamide (120 mg/kg once daily by oral gavage); [0239] Group 11, serine (1000 mg/kg once daily by oral gavage), NAC (300 mg/kg once daily by oral gavage) and LCAT (100 mg/kg once daily by oral gavage); [0240] Group 12, serine (1000 mg/kg once daily by oral gavage), NAC (300 mg/kg once daily by oral gavage), LCAT (100 mg/kg/day) and NRCl (120 mg/kg once daily by oral gavage); [0241] Group 13, serine (1000 mg/kg once daily by oral gavage), NAC (300 mg/kg once daily by oral gavage), LCAT (100 mg/kg once daily by oral gavage) and nicotinamide (120 mg/kg once daily by oral gavage).

[0242] The body weight of the rats was recorded each week. After 5 weeks, all animals were anesthetized with isoflurane and sacrificed. Blood samples were collected from the abdominal aorta and centrifuged at 8000 rpm for 15 min at 4° C. The plasma was separated and stored at −80° C. until further analysis. Other internal organs, including the heart, adipose tissues, liver, kidney, brain, muscle, intestine (duodenum, ileum, jejunum), pancreas, colon and stomach were immediately removed and then snap-frozen in liquid nitrogen and stored at −80° C.

[0243] Tissue Samples

[0244] Tissue samples obtained as a result of the experimental procedure were fixed in 10% buffered formalin solution for 48 hours. Following the routine tissue procedure, the tissues were embedded in paraffin blocks and 4 μm thick sections were taken from each block. Preparations prepared for histopathological examination were stained with hematoxylin-eosin (HE) and examined with a light microscope (Olympus BX51, Germany). According to histopathological findings, sections were evaluated as absent (−), very mild (+), mild (++), moderate (+++) and severe (++++).

[0245] Immunohistochemical Examination

[0246] Tissue sections taken on adhesive (poly-L-Lysin) slides for immunoperoxidase examination were deparaffinized and dehydrated. After washing the tissues with suppressed endogenous peroxidase activity in 3% H.sub.2O.sub.2 were boiled in antigen retrieval solution. In order to prevent nonspecific background staining in the sections, protein block compatible with all primary and secondary antibodies was dropped and incubated for 5 minutes. 8-OHdG (Cat no: sc-66036 dilution ratio: 1/100 US) was used as the primary antibody for brain tissues. 3-3′ Diaminobenzidine (DAB) chromogen was used as chromogen, and according to their immunopositivity, sections were evaluated by independent pathologist and scored as absent (−), very mild (+), mild (++), moderate (+++) and severe (++++).

[0247] Immunofluorescence Examination

[0248] Tissue sections taken on adhesive (poly-L-Lysin) slides for immunoperoxidase examination were deparaffinized and dehydrated. After washing the tissues with suppressed endogenous peroxidase activity in 3% H.sub.2O.sub.2 were boiled in antigen retrieval solution. In order to prevent nonspecific background staining in the sections, protein block compatible with all primary and secondary antibodies was dropped and incubated for 5 minutes. For brain tissues, primary antibody Caspase 3 (Cat No:sc-56053 Dilution Ratio:1/100 US) was dropped and incubated for 1 hour at 37° C. After washing, secondary FITC (Cat No: ab6717 Dilution Ratio:1/500 UK) was dropped and incubated at 37° C. for 30 minutes. The other primary antibody H2A.X (Cat No:I 0856-1 Dilution Ratio:1/100 US) was dropped and incubated at 37° C. for 1 hour. After washing, secondary Texas Red (Cat No: se-3917 Dilution Ratio:1/100 US) was dropped and incubated at 37° C. for 30 minutes. DAPI (Cat No:D-1306 Dilution Ratio:1/200 US) was dripped onto the washed tissues and incubated in the dark for 5 minutes, then glycerin was sealed. Sections were examined under a fluorescence microscope (ZEISS Germany) by an independent pathologist and, according to their immunopositivity evaluated as absent (−), very mild (+), mild (++), moderate (+++) and severe (++++).

[0249] Histopathological Findings (Summarized in Table 1 Below)

[0250] Group 1 (chow group): Brain tissues were found to be in normal histological structure. Brain tissues were evaluated as 8 OHdG negative in immunohistochemical staining, and Caspase-3 and H2A.X negative in immunofluorescence staining.

[0251] Group 3 (HFD 3w group): Moderate hyperemia in meningeal and parenchymal vessels, moderate degeneration and necrosis in neurons were observed in brain tissue. Immunohistochemical staining showed that moderate cytoplasmic 8 OHdG expression in brain tissues, while immunofluorescence staining showed moderate Caspase-3 and H2A.X expression in the brain.

[0252] Group 4 (HFD 5w group): Severe hyperemia in vessels, degeneration and necrosis in neurons were observed in brain tissues. Immunohistochemical staining of brain tissues showed severe cytoplasmic 8 OHdG expression and immunofluorescence staining of brain tissues showed severe cytoplasmic Caspase-3 and H2A.X expression.

[0253] Group 2 (STZ group): Moderate hyperemia in vessels, moderate degeneration and neurosis in neurons were detected in brain tissues. Moderate expression of 8 OHdG in immunohistochemical staining and moderate expression of Caspase-3 and H2A.X in immunfluorescence staining were determined in brain tissues.

[0254] Group 5 (HFD+STZ group): Severe hyperemia in brain tissues, severe degeneration and necrosis in neurons were detected. In brain tissues, severe cytoplasmic 8 OHdG expression in immunohistochemical staining was determined, and Caspase-3 and H2A.X expression in immunofluorescence staining were determined at a severe level.

[0255] Group 6 (HFD+STZ+Serine group): Moderate hyperemia, moderate degeneration and mild necrosis in neurons were detected in brain tissues. In brain tissues, 8 OHdG expression in immunohistochemical staining, Caspase-3 and H2A.X expression in immunofluorescence staining were found to be moderate.

[0256] Group 7 (HFD+STZ+NAC group): Severe hyperemia, severe degeneration of neurons and moderate necrosis were observed in brain tissues. In brain tissues, it was determined that 8 OHdG expression in immunohistochemical staining, Caspase-3 and H2A.X expression in immunofluorescence staining at moderate level.

[0257] Group 8 (HFD+STZ+LCAT group): Moderate hyperemia, moderate degeneration and mild necrosis in neurons were detected in brain tissues. In brain tissues, a moderate level of 8 OHdG expression was detected in immunohistochemical staining, a moderate level of Caspase-3 and H2A.X expressions were detected in immunofluorescence staining.

[0258] Group 9 (HFD+STZ+NRCl group): Moderate hyperemia, moderate degeneration and mild necrosis in neurons were detected in brain tissues. Immunohistochemical and immunofluorescence staining showed moderate expression of 8 OHdG, Caspase-3 and H2A.X in brain tissue.

[0259] Group 10 (HFD+STZ+nicotinamide group): Hyperemia, mild degeneration and very mild necrosis of neurons were detected in brain tissues. In brain tissues, were determined that moderate level of 8 OHdG expression in immunohistochemical staining, and mild Caspase-3 and H2A.X expression in immunofluorescence staining.

[0260] Group 11 (HFD+STZ+serine+NAC+LCAT group): Hyperemia in vessels, mild degeneration and very mild necrosis in neurons were detected in brain tissues. In brain tissues, were determined that mild 8 OHdG expression in immunohistochemical staining and mild Caspase-3 and H2A.X expression in immunofluorescence staining.

[0261] Group 12 (HFD+STZ+serine+NAC+LCAT+NRCl group): Hyperemia in vessels, mild degeneration and necrosis in neurons were detected in brain tissues. In brain tissues, immunohistochemical staining showed mild 8 OHdG expression, immunofluorescence staining showed mild Caspase-3 and H2A.X expressions.

[0262] Group 13 (HFD+STZ+serine+NAC+LCAT+nicotinamide group): Hyperemia in vessels, very mild degeneration of neurons was detected in brain tissues. In brain tissues, very mild 8 OHdG expression was detected in immunohistochemical staining, and very mild Caspase-3 and H2A.X expressions were detected in immunofluorescence staining.

TABLE-US-00003 TABLE 1 Scoring histopathological, immunohistochemical and immunofluorescence findings in brain tissues Caspase H.sub.2A.X Degen- Necrosis 8- 3 (IFA eration in in OHdG (IFA Texas Group Hyperemia Neurons Neurons (IHC) FITC) Red) 1 − − − − − − 3 +++ +++ +++ +++ +++ +++ 4 ++++ ++++ ++++ ++++ ++++ ++++ 2 +++ +++ +++ +++ +++ +++ 5 ++++ ++++ ++++ ++++ ++++ ++++ 6 +++ +++ ++ +++ +++ +++ 7 ++++ ++++ +++ +++ +++ +++ 8 +++ +++ ++ +++ +++ +++ 9 +++ +++ ++ +++ +++ +++ 10 ++ ++ + +++ ++ ++ 11 ++ ++ ++ ++ ++ ++ 12 ++ ++ + ++ ++ ++ 13 ++ + − + + +

[0263] As shown in the table above, all substances had an effect when administrated alone (compare each of groups 6-10 to group 5). Nicotinamide was the most effective individual substance (compare group 10 to groups 6-9). Still, the effectiveness of nicotinamide alone is insufficient. However, when nicotinamide was given together with serine, NAC and LCAT, excellent results were obtained (see group 13). Notably, serine+NAC+LCAT+nicotinamide gave much better results than serine+NAC+LCAT+NRCl (compare group 13 to group 12).

ITEMIZED LISTING OF EMBODIMENTS

[0264] 1. A composition for use in a therapeutic method of treatment of a subject suffering from a neurological disorder, said composition comprising: [0265] A) serine, glycine, betaine, N-acetylglycine, N-acetylserine, dimethylglycine, sarcosine and/or phosphoserine; [0266] B) optionally N-acetyl cysteine, cysteine and/or cystine; [0267] C) optionally carnitine, deoxycarnitine, gamma-butyrobetaine, 4-trimethylammoniobutanal, 3-hydroxy-N6,N6,N6-trimethyl-L-lysine, N6,N6,N6-trimethyl-L-lysine and/or lysine; and [0268] D) nicotinamide riboside, quinolinate, deamino-NAD+, nicotinate D-ribonucleotide, nicotinamide D-ribonucleotide, nicotinate D-ribonucleoside, nicotinamide and/or nicotinate. [0269] 2. The composition for use according to item 1, wherein the molar ratio of A) to B) is between 16:1 and 1:4, such as between 12:1 and 1.5:1, preferably between 10:1 and 3:1. [0270] 3. The composition for use according to item 1 or 2, wherein the molar ratio of A) to C) is between 150:1 and 1:1, such as between 100:1 and 2:1, preferably between 30:1 and 3:1, more preferably between 15:1 and 4:1. [0271] 4. The composition for use according to any one of the preceding items, wherein the molar ratio of A) to D) is between 250:1 and 1.5:1, such as 150:1 and 3:1, preferably between 90:1 and 10:1, more preferably between 50:1 and 20:1. [0272] 5. The composition for use according to any one of the preceding items, wherein A) is serine, preferably L-serine. [0273] 6. The composition for use according to any one of the preceding items, wherein B) is N-acetyl cysteine. [0274] 7. The composition for use according to any one of the preceding items, wherein C) is carnitine. [0275] 8. The composition for use according to any one of the preceding items, wherein D) is nicotinamide riboside. [0276] 9. The composition for use according to any one of the preceding items, which is powderous mixture. [0277] 10. The composition for use according to any one of the preceding items, wherein the neurological disorder is a neurodegenerative disease. [0278] 11. The composition for use according to item 10, wherein the neurodegenerative disease is selected from the group consisting of dementia, Parkinson's disease, multiple sclerosis, epilepsy, brain injuries and neuroinfectious diseases. [0279] 12. The composition for use according to item 10, wherein the neurodegenerative disease is Alzheimer's disease. [0280] 13. The composition for use according to any one of the preceding items 1-9, wherein the subject is a human subject. [0281] 14. The composition for use according to any one of the preceding items, wherein said therapeutic method comprises oral administration of composition. [0282] 15. The composition for use according to any one of the preceding items, wherein said method comprises administration of: [0283] A) in a dose of 0.48-24 mmol/kg/day, such as 0.48-4.8 mmol/kg/day, such as 1.8-4.8 mmol/kg/day, such as 2.9-4.7 mmol/kg/day; [0284] optionally B) in a dose of 0.31-3.05 mmol/kg/day, such as 0.31-1.84 mmol/kg/day, such as 0.40-1.23 mmol/kg/day; [0285] optionally C) in a dose of 0.100-2.50 mmol/kg/day, such as 0.200-2.00 mmol/kg/day, such as 0.230-1.00 mmol/kg/day, such as 0.300-0.800 mmol/kg/day; and [0286] D) in a dose of 0.020-0.39 mmol/kg/day, such as 0.039-0.31 mmol/kg/day, such as 0.059-0.24 mmol/kg/day. [0287] 16. A method of treatment of a subject suffering from a neurological disorder, said method comprising administration to a subject in need thereof: [0288] A) serine, glycine, betaine, N-acetylglycine, N-acetylserine, dimethylglycine, sarcosine and/or phosphoserine; [0289] B) optionally N-acetyl cysteine, cysteine and/or cystine; [0290] C) optionally carnitine, deoxycarnitine, gamma-butyrobetaine, 4-trimethylammoniobutanal, 3-hydroxy-N6,N6,N6-trimethyl-L-lysine, N6,N6,N6-trimethyl-L-lysine and/or lysine; and [0291] D) nicotinamide riboside, quinolinate, deamino-NAD+, nicotinate D-ribonucleotide, nicotinamide D-ribonucleotide, nicotinate D-ribonucleoside, nicotinamide and/or nicotinate. [0292] 17. A method of treatment of a subject suffering from a neurological disorder, comprising administration to a subject in need thereof: [0293] A) serine, glycine, betaine, N-acetylglycine, N-acetylserine, dimethylglycine, sarcosine and/or phosphoserine in a dose of 0.48-24 mmol/kg/day, such as 0.48-4.8 mmol/kg/day, such as 1.8-4.8 mmol/kg/day, such as 2.9-4.7 mmol/kg/day; [0294] B) optionally N-acetyl cysteine, cysteine and/or cystine in a dose of 0.31-3.05 mmol/kg/day, such as 0.31-1.84 mmol/kg/day, such as 0.40-1.23 mmol/kg/day; [0295] C) optionally carnitine, deoxycarnitine, gamma-butyrobetaine, 4-trimethylammoniobutanal, 3-hydroxy-N6,N6,N6-trimethyl-L-lysine, N6,N6,N6-trimethyl-L-lysine and/or lysine in a dose of 0.100-2.50 mmol/kg/day, such as 0.200-2.00 mmol/kg/day, such as 0.230-1.00 mmol/kg/day, such as 0.300-0.800 mmol/kg/day; and [0296] D) nicotinamide riboside, quinolinate, deamino-NAD+, nicotinate D-ribonucleotide, nicotinamide D-ribonucleotide, nicotinate D-ribonucleoside, nicotinamide and/or nicotinate in a dose of 0.020-0.39 mmol/kg/day, such as 0.039-0.31 mmol/kg/day, such as 0.059-0.24 mmol/kg/day. [0297] 18. A method of treatment of a subject suffering from a neurological disorder, comprising administration to a subject in need thereof: [0298] A) serine, glycine, betaine, N-acetylglycine, N-acetylserine, dimethylglycine, sarcosine and/or phosphoserine in a dose of 100-600 mmol/day, such as 150-450 mmol/day, such as 170-350 mmol/day; [0299] B) optionally N-acetyl cysteine, cysteine and/or cystine in a dose of 12-100 mmol/kg/day, such as 16-75 mmol/day, such as 20-50 mmol/day; [0300] C) optionally carnitine, deoxycarnitine, gamma-butyrobetaine, 4-trimethylammoniobutanal, 3-hydroxy-N6,N6,N6-trimethyl-L-lysine, N6,N6,N6-trimethyl-L-lysine and/or lysine in a dose of 12-100 mmol/kg/day, such as 16-75 mmol/day, such as 20-50 mmol/day; and [0301] D) nicotinamide riboside, quinolinate, deamino-NAD+, nicotinate D-ribonucleotide, nicotinamide D-ribonucleotide, nicotinate D-ribonucleoside, nicotinamide and/or nicotinate in a dose of 3-20 mmol/day, such as 4-15 mmol/day, such as 5-12 mmol/day. [0302] 19. The method of any one of items 16-18, wherein the administration is oral administration. [0303] 20. Substances comprising [0304] A) serine, glycine, betaine, N-acetylglycine, N-acetylserine, dimethylglycine, sarcosine and/or phosphoserine, [0305] B) optionally N-acetyl cysteine, cysteine and/or cystine, [0306] C) optionally carnitine, deoxycarnitine, gamma-butyrobetaine, 4-trimethylammoniobutanal, 3-hydroxy-N6,N6,N6-trimethyl-L-lysine, N6,N6,N6-trimethyl-L-lysine and/or lysine and [0307] D) nicotinamide riboside, quinolinate, deamino-NAD+, nicotinate D-ribonucleotide, nicotinamide D-ribonucleotide, nicotinate D-ribonucleoside, nicotinamide and/or nicotinate [0308] for simultaneous, separate or sequential use in a method of treatment of a subject suffering from a neurological disorder. [0309] 21. Substances according to item 20, wherein [0310] A) is serine, [0311] B) is N-acetyl cysteine, [0312] C) is carnitine, and [0313] D) is nicotinamide riboside. [0314] 22. Substances according to item 20 or 21, wherein the neurological disorder is a neurodegenerative disease. [0315] 23. Substances according to any one of items 20-22, wherein said therapeutic method comprises oral administration of said substances. [0316] 24. Substances according to any one of items 20-23, wherein said therapeutic method comprises oral administration of: [0317] A) in a dose of 0.48-24 mmol/kg/day, such as 0.48-4.8 mmol/kg/day, such as 1.8-4.8 mmol/kg/day, such as 2.9-4.7 mmol/kg/day; [0318] optionally B) in a dose of 0.31-3.05 mmol/kg/day, such as 0.31-1.84 mmol/kg/day, such as 0.40-1.23 mmol/kg/day; [0319] optionally C) in a dose of 0.100-2.50 mmol/kg/day, such as 0.200-2.00 mmol/kg/day, such as 0.230-1.00 mmol/kg/day, such as 0.300-0.800 mmol/kg/day; and [0320] D) in a dose of 0.020-0.39 mmol/kg/day, such as 0.039-0.31 mmol/kg/day, such as 0.059-0.24 mmol/kg/day.