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WO2013086327A1 - Compositions nutritionnelles comprenant de la curcumine et de l'acide phosphatidylsérine-docosahexaènoïque pour améliorer la cognition - Google Patents

Compositions nutritionnelles comprenant de la curcumine et de l'acide phosphatidylsérine-docosahexaènoïque pour améliorer la cognition Download PDF

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Publication number
WO2013086327A1
WO2013086327A1 PCT/US2012/068456 US2012068456W WO2013086327A1 WO 2013086327 A1 WO2013086327 A1 WO 2013086327A1 US 2012068456 W US2012068456 W US 2012068456W WO 2013086327 A1 WO2013086327 A1 WO 2013086327A1
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Prior art keywords
curcumin
individual
dha
composition
memory
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Inventor
Rema VAZHAPPILLY
Tapas Das
Jeffrey H. Baxter
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Abbott Laboratories
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Abbott Laboratories
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present disclosure relates to nutritional compositions comprising Curcumin and phosphatidylserine-docosahexaenoic acid (PS-DHA) and to the methods of administering the compositions for improving cognitive performance and/or memory, enhancing memory acquisition and memory retention and recall in an individual, as well as reducing brain dysfunction and cognitive decline.
  • PS-DHA phosphatidylserine-docosahexaenoic acid
  • bioavailable Curcumin is utilized in combination with the PS-DHA.
  • Manufactured nutritional liquids and powders comprising a targeted selection of nutrition ingredients are well known and widely available, some of which may provide a sole source of nutrition while others may provide a supplemental source.
  • These nutritionals include powders that can be reconstituted with water or other aqueous liquid, as well as ready to drink nutritional liquids such as milk or protein based emulsions or non-emulsified liquids. These nutritional liquids are especially useful when formulated with selected nutritional ingredients.
  • Cognitive failure which includes dysfunction or loss of cognitive function (e.g., learning, thinking and memory), commonly occurs in association with central nervous system (CNS) disorders or conditions, including neurodegenerative diseases. Cognitive dysfunction may cause significant impairment of social and/or occupational functioning, which can interfere with the ability of an individual to perform activities of daily living and greatly impact the autonomy and quality of life of the individual.
  • CNS central nervous system
  • One embodiment is directed to a method for improving memory acquisition and memory retention and recall in an individual.
  • the method comprises administering to the individual a composition comprising an effective amount of Curcumin or bioavailable Curcumin and phosphatidylserine-docosahexaenoic acid.
  • Another embodiment is directed to a method for improving cognitive performance in an individual.
  • the method comprises administering to the individual a composition comprising an effective amount of Curcumin or bioavailable Curcumin and phosphatidylserine-docosahexaenoic acid.
  • Another embodiment is directed to a method for improving memory acquisition in an individual. The method comprises administering to the individual a composition comprising an effective amount of Curcumin or bioavailable Curcumin and phosphatidylserine-docosahexaenoic acid.
  • Another embodiment is directed to a method for improving memory retention and memory recall in an individual.
  • the method comprises administering to the individual a composition comprising an effective amount of Curcumin or bioavailable Curcumin and phosphatidylserine-docosahexaenoic acid.
  • Another embodiment is directed to a method for enhancing N- Methyl-D-aspartate receptor (NMDAR) dependent hippocampal long-term
  • the method comprises administering to the individual a composition comprising an effective amount of Curcumin or bioavailable Curcumin and phosphatidylserine- docosahexaenoic acid.
  • Another embodiment is directed to a method for enhancing the NMDAR and 2-amino-3-(5-methyl-3-oxo-l,2-oxazol-4-yl)propanoic acid receptor (AMPAR) mediated hippocampal synaptic plasticity, which may be another key mechanism underlying learning and memory.
  • the method comprises administering to the individual a composition comprising an effective amount of Curcumin or bioavailable Curcumin and phosphatidylserine-docosahexaenoic acid.
  • Another embodiment is directed to a method for preventing the over- activation of NMDAR, which may result in neuronal death.
  • the method comprises administering to the individual a composition comprising an effective amount of Curcumin or bioavailable Curcumin and phosphatidylserine-docosahexaenoic acid.
  • Another embodiment is directed to a method for enhancing neuronal membrane fluidity.
  • the method comprises administering to the individual a composition comprising an effective amount of Curcumin or bioavailable Curcumin and phosphatidylserine-docosahexaenoic acid.
  • Another embodiment is directed to a nutritional composition comprising an effective amount of Curcumin or bioavailable Curcumin and phosphatidylserine-docosahexaenoic acid.
  • Nutritional compositions including Curcumin, and in particular bioavailable Curcumin, and PS-DHA in combination provide enhanced bioavailability of the individual components of Curcumin, phosphatidylserine (PS), and DHA to an individual upon administration. Therefore, this combination of components is more efficacious in providing improved cognitive functioning and/or performance to an individual, as well as reducing cognitive impairment and/or brain dysfunction in an individual.
  • the combination of Curcumin or bioavailable Curcumin and PS-DHA produces an added benefit on cognitive functioning by producing a synergistic effect in enhancing NMDAR and AMPAR dependent hippocampal synaptic plasticity, which is a molecular mechanism involved in learning and memory.
  • Curcumin or bioavailable Curcumin and PS-DHA produces a sequential action by improving memory acquisition that is essential for the process of learning, and by improving memory retention and memory recall that is necessary for the retrieval of learned processes.
  • Curcumin or bioavailable Curcumin and PS- DHA may also provide benefits to an individual by its complementary mode of action on neuroprotection. Neuronal death due to the oxidative stress resulting from
  • NMDAR over-activation i.e., NMDAR mediated excitotoxicity
  • NMDAR mediated excitotoxicity is a major problem associated with cognitive impairment, brain dysfunction, and neurodegenerative diseases (e.g., Alzheimer's Disease). It has now been found that Curcumin, and particularly bioavailable Curcumin, offers significant neuroprotection by preventing NMDAR mediated excitotoxicity and resulting neuronal death.
  • PS-DHA offers benefits such as the maintenance of neuronal membrane fluidity, which is essential for synaptic receptor function, and neurotransmitter release, which is essential for the cognitive performance of an individual. While PS-DHA may be taken up by the brain from the diet to provide the above benefits, PS-DHA is highly susceptible to oxidation and may therefore induce oxidative stress in neuronal membranes that may, in turn, negatively affect the neuronal health and function.
  • Curcumin and in particular bioavailable Curcumin, which possesses strong antioxidant properties, can prevent the oxidation of PS-DHA as well as provide neuroprotection and prevention of neuronal death due to oxidative stress, which is induced by increased calcium influx, thereby allowing the subsequent release of proteolytic enzymes, transcription factors, and reactive oxygen species. Therefore, Curcumin or bioavailable Curcumin and PS-DHA will have a complimentary mode of action to provide cognitive benefits.
  • Curcumin and in particular bioavailable Curcumin, and PS-DHA act in combination to further provide anti-inflammatory and anti-amyloidogenic properties to an individual.
  • Neuronal inflammation and amyloid ⁇ protein deposition are associated with cognitive impairment and/or brain dysfunction that results from age-related cognitive decline and/or cognitive decline associated with
  • Curcumin or bioavailable Curcumin and PS-DHA therefore, provide added benefits when used in combination, thereby reducing cognitive impairment and/or brain dysfunction.
  • the nutritional compositions and methods of the present disclosure offer an alternative therapeutic or nutritional intervention option that may contribute to the improvement of cognitive performance, as well as to the reduction of cognitive impairment and brain dysfunction, in individuals, and particularly in adults, older adults, and the elderly.
  • FIG. 1A is a chart depicting the effect of PS-DHA on memory acquisition, memory retention and memory recall as analyzed in Example 21.
  • FIG. IB is a chart depicting the effect of Curcumin on memory acquisition, memory retention and memory recall as analyzed in Example 21.
  • FIG. 2A is a chart depicting the effect of Curcumin on NMDAR dependent hippocampal LTP as analyzed in Example 22.
  • FIGS. 2B-2D are graphs depicting the effect of Curcumin on
  • FIG. 3 A is a chart depicting the effect of PS-DHA on NMDAR dependent hippocampal LTP as analyzed in Example 22.
  • FIGS. 3B-3D are graphs depicting the effect of PS-DHA on NMDAR dependent hippocampal LTP as analyzed in Example 22.
  • FIG. 4A is a chart depicting the synergistic effect of the combination of Curcumin and PS-DHA on NMDAR dependent hippocampal LTP as analyzed in Example 22.
  • FIGS. 4B-4D are graphs depicting the synergistic effect of the combination of Curcumin and PS-DHA on NMDAR dependent hippocampal LTP as analyzed in Example 22.
  • FIG. 5A is a chart depicting the neuroprotective effect of Curcumin on primary hippocampal neurons from NMDAR mediated excitotoxicity.
  • FIG. 5B is a chart depicting the neuroprotective effect of PS-DHA on primary hippocampal neurons from NMDAR mediated excitotoxicity.
  • compositions and methods herein are directed to nutritional compositions comprising Curcumin, and in particular bioavailable Curcumin, and PS- DHA that can improve general cognitive performance in an individual, including memory acquisition, memory retention and memory recall. These and other essential or optional elements or features of the various embodiments are described in detail hereafter.
  • Curcumin refers to Curcumin and derivatives and analogs thereof.
  • bioavailable refers to the ability of a compound to enter into and remain in the bloodstream of an individual such that the substance can be absorbed into cells in the body. As the degree of bioavailability of a compound increases, the compound becomes more likely to enter into and remain in the bloodstream where it can be absorbed and used by the body. As the degree of bioavailability of a compound decreases, the compound becomes more likely to go directly into the gastrointestinal area and be expelled from the body before entering the bloodstream.
  • the nutritional composition may further comprise vitamins, minerals, and other ingredients and represent a sole, primary, or supplemental source of nutrition.
  • fat lipid
  • oil oil
  • synthetic lipid materials so long as such synthetic materials are suitable for oral administration to humans.
  • the term "susceptible” as used herein, unless otherwise specified, means having little resistance to a certain condition or disease, including being genetically predisposed, having a family history of, and/or having symptoms of the condition or disease. [0038]
  • the term “synergy” or “synergistic amount” as used herein, unless otherwise specified, refers to the interaction of two or more compounds so that their combined effect is greater than the additive sum of their individual effects.
  • cognitive performance refers to the learning, thinking, and memory functions (i.e., memory acquisition, memory retention and memory recall) of the brain. Accordingly, the term “improving cognitive performance” as used herein, unless otherwise specified, refers to improving the learning, thinking, and/or memory (memory acquisition, memory retention and memory recall) functions of an individual.
  • age-related cognitive decline refers to a gradual decline in learning, thinking, and/or memory functions that are normal consequences of aging.
  • neurodegenerative disease refers to the progressive loss of structure or function of neurons, including the death of neurons and includes diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, dementia, amyotrophic lateral sclerosis, stroke, and schizophrenia.
  • compositions of the present disclosure may also be substantially free of any optional or selected essential ingredient or feature described herein, provided that the remaining composition or powder still contains all of the required ingredients or features as described herein.
  • substantially free means that the selected composition contains less than a functional amount of the optional ingredient, typically less than about 1%, including less than about 0.5%, including less than about 0.1%, and also including zero percent, by weight of such optional or selected essential ingredient.
  • the nutritional compositions may comprise, consist of, or consist essentially of the essential elements of the products as described herein, as well as any additional or optional element described herein or otherwise useful in nutritional product applications.
  • the nutritional compositions of the present disclosure may be formulated and administered in any known or otherwise suitable oral product form. Any solid, liquid, or powder form, including combinations or variations thereof, are suitable for use herein, provided that such forms allow for safe and effective oral delivery to the individual of the essential ingredients as also defined herein.
  • the nutritional compositions are most suitably formed as aqueous emulsions, including water-in-oil emulsions, oil-in-water emulsions, or complex (e.g., oil-in- water-in-oil emulsions) or other emulsion systems.
  • the nutritional emulsion embodiments are most typically oil-in- water emulsions comprising an internal or discontinuous oil phase that comprises the Curcumin or bioavailable Curcumin and PS-DHA as defined herein.
  • Curcumin is the principal Curcuminoid of turmeric. Conventionally, Curcumin has suffered lower bioavailability when taken orally, and thus when formulated at higher concentrations to counter its inherent poor bioavailability to achieve the desired systemic delivery, the products often take on an intense undesirable yellow color. In some embodiments, the present nutritional compositions use "bioavailable
  • Curcumin which has an improved bioavailability as compared to conventionally used Curcumin.
  • the bioavailable Curcumin can be utilized in lower concentrations in the nutritional compositions and methods of the present disclosure, while still maintaining its anti-inflammatory, antioxidative, and anti-amyloidogenic activity.
  • bioavailable Curcumin refers to Curcumin and derivatives and analogs thereof, including natural and synthetic derivatives of Curcumin, as well as any combination of one or more of Curcumin and a derivative and/or analog.
  • bioavailable Curcumin should be understood to encompass compounds having a 1,7-bis (4-hydroxyphenyl)-l,6-heptadiene-3,5- dione or l,7-bis(4-hydroxyphenyl) hept-4-en-3-one skeleton wherein the phenyl groups independently may bear one or more alkoxy residues, especially one methoxy residue in the 3-position.
  • additional Curcuminoids such as demethoxyCurcumin and bisdemethoxyCurcumin, may also be present in the nutritional compositions. When present, demethoxyCurcumin and
  • bisdemethoxyCurcumin may be present as part of a complex with Curcumin.
  • the "bioavailable Curcumin” used in the nutritional compositions of the present disclosure shows improved oral bioavailability as compared to Curcumins that are not substantially “bioavailable.”
  • the oral bioavailability can be determined in experiments involving oral administration of the bioavailable Curcumin composition of the present disclosure (and/or a corresponding amount of non-bioavailable
  • Curcumin to a subject and measuring the level of the Curcumin in a biological sample obtained from the subject over time
  • the biological sample may be derived from a body fluid, for example serum, plasma, whole blood, or cerebrospinal fluid, and/or a tissue, e.g. from brain, liver, kidney, or heart.
  • AUC area under the curve
  • a higher AUC relative to the AUC obtained by administration of non- bioavailable Curcumin indicates an improved bioavailability.
  • the absolute bioavailability may be calculated from the resulting AUC data as percentage based on the corresponding AUC data obtained from intravenous administration of Curcumins.
  • the bioavailable Curcumin amount in the blood determined as AUC0-6H after a single oral administration of a dose of the bioavailable Curcumin-containing nutritional composition of the present disclosure corresponding to 20 mg of total Curcumin to a human subject or an animal subject, preferably a rat, is significantly higher than after oral administration of the same amount of non-bioavailable Curcumin in the composition, preferably at least 2 times, at least 3 times, at least 4 times, at least 6 times, at least 8 times, at least 10 times, or at least 15 times, and, for example, up to 30 times higher.
  • the amount of Curcumin or bioavailable Curcumin in the blood being "significantly higher” means a statistically significant increase of this parameter in subjects after oral administration of 20 mg of bioavailable Curcumin in the nutritional composition of the present disclosure as compared to the control 20 mg of Curcumin that is not bioavailable.
  • a statistical test known in the art such as ANOVA or Student's t-test, may be used to determine the significance of this difference, wherein the p-value is at least ⁇ 0.1, ⁇ 0.5, ⁇ 0.01, ⁇ 0.005, ⁇ 0.001 or O.OOOl .
  • Bioavailable Curcumin can be prepared in a number of ways including, for example, using Meltrex® or similar melt-extrusion technology to prepare extruded solids and improve the bioavailability of the Curcumin as compared to Curcumin not produced by melt extrusion. Meltrex® or similar melt-extrusion technology methods are known in the art and can be applied to produce bioavailable Curcumin by one skilled in the art based on the disclosure herein.
  • Curcumin can be co-supplemented with piperine (generally extracted from black pepper) to increase the bioavailability and hence the absorbability of Curcumin.
  • the piperine is co- supplemented in an amount of about 20 mg to increase the bioavailability of the Curcumin.
  • the Curcumin or bioavailable Curcumin may be solubilized in an oil having an HLB of from about 0.7 to about 14 (polar oils) such that the resulting oil mixture provides increased bioavailability of Curcumin.
  • polar oils a medium chain triglyceride oil (MCT oil).
  • the bioavailable Curcumin is a mixture of Curcuminoids (i.e., Curcumin, demethoxyCurcumin and bisdemethoxyCurcumin) obtained from the rhizomes of Curcuma Longa.
  • Curcuminoids i.e., Curcumin, demethoxyCurcumin and bisdemethoxyCurcumin
  • the bioavailable Curcumin is obtained using Meltrex® technology (Abbott Nutrition, Columbus, Ohio).
  • the bioavailable Curcumin is Meriva Bioavailable Curcumin, commercially available from Idena SPA (Milan, Italy).
  • the Curcumin or bioavailable Curcumin concentration in the nutritional compositions may range from at least about 0.001%, including from about 0.002%) to about 3.4%, including from about 0.002%> to about 3.36%, including from about 0.005%) to about 1.87%, also including from about 0.03%> to about 0.935%), also including from about 0.1% to about 0.5%, also including from about 0.1 % to about 0.467%), and also including from about 0.234%> to about 0.3%>, by weight of the nutritional composition.
  • Exemplary embodiments of the present disclosure include nutritional compositions having Curcumin or bioavailable Curcumin in amounts ranging from 0.002% to about 0.234%, from about 0.005% to about 0.467%, from about 0.03% to about 0.935%, from about 0.1% to about 1.87%, and from about 0.3% to about 3.36%, by weight of the nutritional composition.
  • the nutritional compositions of the present disclosure desirably include sufficient Curcumin or bioavailable Curcumin to provide an individual with at least about 1 milligram, including at least about 3 milligrams, including from about 10 milligrams to about 10,000 milligrams, including from about 100 milligrams to about 4000 milligrams, including from about 400 milligrams to about 2000 milligrams, including from about 1200 milligrams to about 1800 milligrams, per day of Curcumin or bioavailable Curcumin.
  • the total daily amount of Curcumin or bioavailable Curcumin may be administered to an individual in a single undivided dose, or may be split into one, two, three, four or more doses per day.
  • PS-DHA Phosphatidylserine-docosahexaenoic acid
  • the nutritional compositions of the present disclosure include PS-DHA.
  • PS-DHA is a conjugated form of PS to DHA or a DHA enriched form of PS, with palmitic acid at the Sn-1 position and DHA at the Sn-2 position.
  • the inclusion of PS- DHA in the nutritional compositions provide enhanced bioavailability of both PS and DHA in the brain as conjugated DHA allows for a more efficient uptake of DHA by the brain as compared to DHA in triglyceride form.
  • PS is a phospholipid component constituting 10%> of the total phospholipids present in the human body and 15% of PS is found in the brain.
  • DHA is an omega-3 polyunsaturated fatty acid (PUFA) and is abundant in the brain and retina, accounting for 40% of the PUFAs in the brain and 60% of the PUFAs in the retina. DHA is essential for the proper functioning of adult brains, deficiencies of which have been associated with cognitive decline.
  • PUFA omega-3 polyunsaturated fatty acid
  • PS-DHA is the natural form of PS.
  • Common sources of PS-DHA include marine, plant and animal sources such as mackerel, chicken, herring, eel, pig, tuna, clams, veal, beef, pork, turkey, cod, anchovy, and trout and/or plant sources such as soybeans, cabbage, whole-grain barley, rice, and carrots.
  • the PS-DHA concentration in the nutritional compositions may range from at least about 0.001%, including from about 0.001% to about 1.2%, including from about 0.001% to about 1.121%, including from about 0.01% to about 0.6%), including from about 0.02%> to about 0.2%>, also including from about 0.02%> to about 0.1%), also including from about 0.025%) to about 0.09%>, and also including from about 0.025% to about 0.04%, by weight of the nutritional composition.
  • Exemplary embodiments of the present disclosure include nutritional compositions having PS-DHA in amounts ranging from 0.001% to about 0.037%, from about 0.002% to about 0.094%, from about 0.02% to about 0.187%, from about 0.025% to about 0.561%, and from about 0.04% to about 1.121%, by weight of the nutritional composition.
  • the nutritional compositions of the present disclosure desirably include sufficient PS-DHA to provide an individual with from about 100 milligrams to about 2000 milligrams, including from about 200 milligrams to about 2000 milligrams, including from about 200 milligrams to about 1000 milligrams, including from about 500 milligrams to about 1500 milligrams, including from about 1000 milligrams to about 1400 milligrams, per day of PS-DHA.
  • the total daily amount of PS-DHA may be administered to an individual in a single undivided dose, or may be split into one, two, three, four or more doses per day.
  • the nutritional compositions of the present disclosure may further comprise one or more optional macronutrients in addition to the Curcumin or bioavailable Curcumin and PS-DHA described herein.
  • the optional macronutrients include proteins, lipids, carbohydrates, and combinations thereof.
  • the nutritional compositions are desirably formulated as dietary products containing all three macronutrients.
  • Micronutrients suitable for use herein include any protein, lipid, or carbohydrate or source thereof that is known for or otherwise suitable for use in an oral nutritional composition, provided that the optional macronutrient is safe and effective for oral administration and is otherwise compatible with the other ingredients in the nutritional composition.
  • the concentration or amount of optional lipid, carbohydrate, and protein in the nutritional composition can vary considerably depending upon the particular product form (e.g., bars or other solid dosage forms, milk or soy-based liquids or other clear beverages, reconstitutable powders, etc.) and the various other formulations and targeted dietary needs.
  • These optional macronutrients are most typically formulated within any of the embodied ranges described in the following tables.
  • compositions may be simple, complex, or variations or combinations thereof, all of which are optionally in addition to the Curcumin or bioavailable Curcumin as described herein.
  • suitable carbohydrates include hydrolyzed or modified starch or cornstarch, maltodextrin, isomaltulose, sucromalt, glucose polymers, sucrose, corn syrup, corn syrup solids, rice-derived carbohydrate, glucose, fructose, lactose, high fructose corn syrup, honey, sugar alcohols (e.g., maltitol, erythritol, sorbitol), and combinations thereof.
  • Optional carbohydrates suitable for use herein also include soluble dietary fiber, non-limiting examples of which include gum Arabic,
  • fructooligosaccharide FOS
  • Insoluble dietary fiber is also suitable as a carbohydrate source herein, non-limiting examples of which include oat hull fiber, pea hull fiber, soy hull fiber, soy cotyledon fiber, sugar beet fiber, cellulose, corn bran, and combinations thereof.
  • Optional proteins suitable for use in the nutritional compositions include hydrolyzed, partially hydrolyzed or non-hydro lyzed proteins or protein sources, and can be derived from any known or otherwise suitable source such as milk (e.g., casein, whey), animal (e.g., meat, fish, egg albumen), cereal (e.g., rice, corn), vegetable (e.g., soy, pea, potato), or combinations thereof.
  • milk e.g., casein, whey
  • animal e.g., meat, fish, egg albumen
  • cereal e.g., rice, corn
  • vegetable e.g., soy, pea, potato
  • the proteins for use herein can also include, or be entirely or partially replaced by, free amino acids known for use in nutritional products, non-limiting examples of which include L-tryptophan, L- glutamine, L-tyrosine, L-methionine, L-cysteine, taurine, L-arginine, L-carnitine, and combinations thereof.
  • Optional lipids suitable for use in the nutritional compositions include coconut oil, fractionated coconut oil, soy oil, corn oil, olive oil, safflower oil, high oleic safflower oil, high GLA-safflower oil, MCT oil (medium chain triglycerides), sunflower oil, high oleic sunflower oil, palm and palm kernel oils, palm olein, canola oil, flaxseed oil, borage oil, cottonseed oils, evening primrose oil, blackcurrant seed oil, transgenic oil sources, fungal oils, marine oils (e.g., tuna, sardine) and so forth.
  • coconut oil fractionated coconut oil, soy oil, corn oil, olive oil, safflower oil, high oleic safflower oil, high GLA-safflower oil, MCT oil (medium chain triglycerides), sunflower oil, high oleic sunflower oil, palm and palm kernel oils, palm olein, canola oil, flaxseed oil,
  • the nutritional compositions may further comprise other optional ingredients that may modify the physical, nutritional, chemical, hedonic or processing characteristics of the products or serve as pharmaceutical or additional nutritional components when used in a targeted population.
  • optional ingredients are known or otherwise suitable for use in other nutritional products and may also be used in the nutritional compositions described herein, provided that such optional ingredients are safe and effective for oral administration and are compatible with the essential and other ingredients in the composition.
  • Non-limiting examples of such other optional ingredients include preservatives, anti-oxidants, buffers, pharmaceutical actives, sweeteners, colorants, flavors, flavor enhancers, thickening agents and stabilizers, emulsifying agents, lubricants, and combinations thereof.
  • the nutritional compositions may further include one or more minerals, non-limiting examples of which include phosphorus, sodium, chloride, magnesium, manganese, iron, copper, zinc, iodine, calcium, potassium, chromium, molybdenum, selenium, and combinations thereof.
  • minerals non-limiting examples of which include phosphorus, sodium, chloride, magnesium, manganese, iron, copper, zinc, iodine, calcium, potassium, chromium, molybdenum, selenium, and combinations thereof.
  • the nutritional compositions may also include one or more vitamins, non-limiting examples of which include carotenoids (e.g., beta-carotene, zeaxanthin, lutein, lycopene), biotin, choline, inositol, folic acid, pantothenic acid, TP AN, choline, vitamin A, thiamine (vitamin Bl), riboflavin (vitamin B2) niacin (vitamin B3), pyridoxine (vitamin B6), cyanocobalamin (vitamin B12), ascorbic acid (vitamin C), vitamin D, vitamin E, vitamin K, and various salts, esters, or other derivatives thereof, and combinations thereof.
  • carotenoids e.g., beta-carotene, zeaxanthin, lutein, lycopene
  • biotin choline
  • inositol folic acid
  • pantothenic acid TP AN
  • choline vitamin A
  • the nutritional compositions may be prepared by any known or otherwise effective manufacturing technique for preparing the selected product form. Many such techniques are known for any given product form such as nutritional liquids and nutritional powders and can easily be applied by one of ordinary skill in the nutrition and formulation arts to the nutritional products described herein.
  • Liquid, milk or soy-based nutritional liquids may be prepared by first forming an oil and fiber blend containing all formulation oils, any emulsifier, fiber and fat-soluble vitamins. Additional slurries (typically a
  • carbohydrate and two protein slurries are prepared separately by mixing the carbohydrate and minerals together and the protein in water. The slurries are then mixed together with the oil blend. The resulting mixture is homogenized, heat processed, standardized with any water-soluble vitamins, flavored and the liquid terminally sterilized or aseptically filled or dried to produce a powder.
  • compositions of the present disclosure may also be manufactured by other known or otherwise suitable techniques not specifically described herein without departing from the spirit and scope of the present disclosure.
  • the present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive and that all changes and equivalents also come within the description of the present disclosure.
  • the methods include the oral administration of the nutritional compositions that include Curcumin or bioavailable Curcumin in combination with PS-DHA, to improve cognitive performance in any individual.
  • the combination of bioavailable Curcumin and PS-DHA may improve general cognition by producing a sequential action on memory acquisition, memory retention and memory recall that contributes to the cognitive functions of learning, thinking, and memory.
  • the nutritional compositions including the combination of Curcumin or bioavailable Curcumin and PS-DHA may have a complementary mode of action in maintaining neuronal membrane fluidity, allowing for proper hormone and neurotransmitter function. This may further improve cognitive performance.
  • the nutritional compositions can be utilized to improve a cognitive impairment and/or brain dysfunction that may be associated with a neurodegenerative disease.
  • the combination of Curcumin or bioavailable Curcumin and PS-DHA shows anti-amyloido genie properties and anti-inflammation properties, thereby reducing neuronal inflammation and clearance of amyloid ⁇ protein deposit that can lead to a cognitive impairment and/or brain dysfunction associated with neurodegenerative diseases or conditions such as Alzheimer's disease, Huntington's disease, Parkinson's disease, dementia, amyotrophic lateral sclerosis, stroke, and/or schizophrenia.
  • cognitive function may be improved.
  • the nutritional compositions of the present disclosure may improve a cognitive impairment and/or brain dysfunction associated with age-related cognitive decline or cognitive decline associated with a neurodegenerative disease by enhancing synaptic plasticity, which is controlled by N- methyl-D-aspartate receptor (NMDAR).
  • NMDAR N- methyl-D-aspartate receptor
  • the composition restores the suboptimum level of NMDAR activity to optimum levels, even during weak stimulation, and, at the same time, prevents neuronal death from NMDAR over-activation. Consequently, NMDAR dependent hippocampal long term potentiation (LTP) is enhanced, which is one key underlying molecular mechanism of learning and memory.
  • NMDAR dependent hippocampal long term potentiation LTP
  • the nutritional compositions may improve learning and memory in an individual by enhancing the NMDAR and 2-amino-3-(5-methyl-3-oxo-l,2- oxazol-4-yl) propanoic acid receptor (AMPAR) mediated hippocampal synoptic plasticity.
  • AMPAR 2-amino-3-(5-methyl-3-oxo-l,2- oxazol-4-yl) propanoic acid receptor
  • the methods of the present disclosure may be directed to individuals who have a neurodegenerative disease or condition, or a disease or condition related to a neurodegenerative disease or condition
  • the methods of the present disclosure as described herein are also intended in some embodiments to include the use of such methods in "at risk" individuals, including individuals unaffected by or not otherwise afflicted with neurodegenerative diseases or conditions such as those described above, for the purpose of preventing, minimizing, or delaying the development of such diseases or conditions over time.
  • the methods of the present disclosure preferably include continuous, daily administration of the compositions as described herein.
  • Such preventive methods may be directed at adults or others, particularly older adults, who are susceptible to developing neurodegenerative diseases due to hereditary considerations, environmental considerations, and the like.
  • the individual desirably consumes at least one serving of the nutritional composition daily, and in some embodiments, may consume two, three, or even more servings per day.
  • Each serving is desirably administered as a single, undivided dose, although the serving may also be divided into two or more partial or divided servings to be taken at two or more times during the day.
  • the methods of the present disclosure include continuous day after day administration, as well as periodic or limited administration, although continuous day after day administration is generally desirable.
  • the methods of the present disclosure are preferably applied on a daily basis, wherein the daily administration is maintained continuously for at least 3 days, including at least 5 days, including at least 1 month, including at least 6 weeks, including at least 8 weeks, including at least 2 months, including at least 6 months, desirably for at least about 18-24 months, desirably as a long term, continuous, daily, dietary supplement.
  • the exemplified products are nutritional products prepared in accordance with manufacturing methods well known in the nutrition industry for preparing nutritional liquids (e.g., emulsions and clear liquids) and powders.
  • Examples 1-5 illustrate nutritional emulsions of the present disclosure, the ingredients of which are listed in the table below. All ingredient amounts are listed as kg per 1000 kg batch of product, unless otherwise specified.
  • Examples 6-10 illustrate nutritional emulsions of the present disclosure, the ingredients of which are listed in the table below. All ingredient amounts are listed as kg per 1000 kg batch of product, unless otherwise specified.
  • Table 2 Nutritional Emulsions
  • Examples 11-15 illustrate nutritional clear liquids of the present disclosure, the ingredients of which are listed in the table below. All ingredient amounts are listed as kg per 1000 kg batch of product, unless otherwise specified. Table 3: Clear Liquids
  • Examples 16-20 illustrate nutritional powders of the present disclosure, the ingredients of which are listed in the table below. These products are prepared by spray drying methods in separate batches, and are reconstituted with water prior to use to the desired target ingredient concentrations. All ingredient amounts are listed as kg per 1000 kg batch of product, unless otherwise specified.
  • Vitamin premix 1.0 1.0 1.0 1.0 1.0
  • Zinc sulfate monohydrate 0.057 0.057 0.057 0.057 0.057 0.057
  • mice Male albino Wistar rats (Harlan Sprague-Dawley, Inc., USA), 2-3 months old, were individually housed in polycarbonate cages with Bed-O-Cob® bedding in a temperature-controlled room (25°C) with a 12-hour light/dark cycle.
  • the rats i.e., test subjects
  • the rats were handled beginning the day after arrival, allowed free access to water, and provided with a control diet (standard rodent diet AIN 93 G, available from Harlan, USA) or with test diets (AIN 93 G with respective amounts of PS-DHA added) shown below for two weeks prior to water maze testing and throughout the testing period.
  • Water Maze Test To determine the effects of the test diets on spatial reference learning, water maze tests were performed in a circular pool (diameter: 180 cm, height: 76 cm) made of black plastic. The pool was filled to a depth of 35 cm of water (maintained at 25.0 ⁇ 1.0°C). The pool was located in a large room with a number of extra-maze visual cues including geometric images (e.g., squares, triangles, circles etc.) hung on the wall, ambient lighting, approximately 25-30 Lux (lumen/m ), and black curtains, used to hide the experimenter (visually) and the resting test subjects. Water Maze Test: To determine the effects of the test diets on spatial reference learning, water maze tests were performed in a circular pool (diameter: 180 cm, height: 76 cm) made of black plastic. The pool was filled to a depth of 35 cm of water (maintained at 25.0 ⁇ 1.0°C). The pool was located in a large room with a number of extra-maze visual cue
  • the rat was given a score of 90 seconds and then physically placed on the platform and also allowed the 30-second rest period. In either case the rat was subsequently returned to its home cage. Latency in seconds (A) and distance swam in centimeters (B) to locate a hidden platform over 14 consecutive days (sessions) corresponded to the measure of memory acquisition. Effect of PS-DHA in enhancing memory acquisition is depicted in FIG. 1 A.
  • Probe Trials Twenty-four hours following the last hidden platform trial (i.e., day 15 of testing), a probe trial was conducted in which the platform was removed from the pool to measure spatial bias and the recall memory of the previous platform location. This was accomplished by measuring the percentage of time spent in the previous target quadrant and the number of crossings over of the previous platform location. The time spent in target quadrant corresponded to an estimate of the strength of the recall memory of the previous platform location. The number of crossings over of the previous platform location was correlated to the strength of memory retention. Effect of Curcumin in enhancing the recall memory is shown in FIG. IB.
  • a rat was successful on its own accord, it was then given a series of 4 additional trials (with a 1.0-minute intertrial interval) and the latency (in seconds) to locate the platform was recorded. The platform was moved on each trial to a different quadrant (the subject was always entered from the opposite quadrant) until the test was conducted once in all 4 quadrants.
  • PS-DHA administration at 90mg/Kg body weight had a significant lowering effect on latency in seconds (A) and distance swam in centimeters (B) to locate a hidden platform, and therefore PS- DHA had a significant enhancing effect on memory acquisition.
  • neuronal activation leads to pre-synaptic release of glutamate resulting in the activation of post-synaptic AMPA and NMD A receptors.
  • Activation of post-synaptic AMPA receptors results in the flow of Na + ions, causing the depolarization of post-synaptic neuron. This depolarization abolishes the blocking
  • NMD A receptors by Mg , resulting in the opening of NMD A receptor channels for Na + and Ca 2+ ions.
  • Ca 2+ influx through NMD A receptors is known to trigger
  • CaMKII Ca /calmodulin-dependent protein kinase
  • NMDAR dependant hippocampal LTP was used as a physiological marker to assess the efficacy of Curcumin and PS-DHA in enhancing cognitive function.
  • NMDAR dependant LTP was recorded on hippocampal brain slices in vitro.
  • mice were housed and used in accordance to the French and European legislations for animal care. The mice were sacrificed by fast decapitation, without previous anaesthesia. The brain was quickly removed and soaked in ice-cold oxygenated buffer with the following composition:
  • Hippocampus slices 350 ⁇ were cut with a Macllwain tissue- chopper and incubated at room temperature for at least 60 minutes in Artificial Cerebro-Spinal Fluid (ACSF) having the following composition:
  • PS-DHA was prepared as a 60, 30 or 15 mM stock solution in a mix (10% Cremphor El (ref: C5135, Sigma, batch: 1439553 13509161) - 5% ethanol (ref: 20820.293, VWR, batch: 07K210530)-85% ACSF) from powder on each day of experimentation. This stock solution was then 1000X diluted into ACSF to reach the final 60, 30 or 15 ⁇ concentration.
  • Curcumin was prepared as a 30, 15 or 5 mM Stock solution in DMSO, this solution was then 10X diluted in ACSF containing 1 eq. NaOH (i.e. 300, 150 or 50 ⁇ NaOH, ref: 28 244.295, VWR, batch: 0601507). This solution was finally 100X diluted in ACSF to reach the final 30, 15 or 5 ⁇ concentration.
  • D-AP5 (ref: Asc-271, ASCENT, batch: APN08163-1-1) was dissolved as a 30 mM stock solution in water, aliquoted and stored at -20°C until use. Aliquots were thawed and vortexed each day of experiment and then 1000X or 10000X diluted in ACSF to reach the final concentration of 30 ⁇ or 3 ⁇ .
  • NBQX (ref: Asc-045, ASCENT, batch: APN07044-8-3) was dissolved as a 10 mM stock solution in water, aliquoted and stored at -20°C until use. Aliquots were thawed and vortexed each day of experiment and then 1000X diluted in ACSF to reach the final concentration of 10 ⁇ .
  • a 350- ⁇ thick mouse hippocampal slice was disposed on the multi- electrode array (100 ⁇ distant electrodes). One electrode was chosen to stimulate Schaeffer collaterals at the CA3/CA1 interface. An I/O curve was performed to monitor evoked-responses for stimulations between 100 and 800 ⁇ , by 100 ⁇ steps. The stimulus was a monopolar biphasic current pulse (negative for 60 ⁇ and then positive for 60 ⁇ ), settled to evoke 40% of the maximal amplitude response (as determined with the I/O curve) and applied every 30 seconds to evoke "responses" (i.e. field Excitatory Post Synaptic Potentials; fEPSP) in the CA1 region.
  • fEPSP field Excitatory Post Synaptic Potentials
  • Evoked-responses were recorded if they satisfied quality criteria described in Standard Operating Procedures: correct location, stable baseline (fluctuation within +/- 10 % during ten consecutive minutes), amplitude > 100 ⁇ after background noise subtraction.
  • the fEPSP from selected electrodes were simultaneously sampled at 5 kHz and recorded on the hard disk of a PC until offline analysis.
  • fEPSP amplitudes of selected electrodes were compiled online (with MC Rack program) to monitor and to follow the good performance of the experiments. Data was plotted in a standard spreadsheet file for off-line analysis. The fEPSP resulted from glutamatergic synaptic transmission consecutive to afferent pathway stimulation.
  • the slices were continuously perfused with ACSF solutions (bubbled with 95% 0 2 -5% C0 2 ) at the rate of 3 mL/min with a peristaltic pump (ME A chamber volume: ⁇ 1 mL). Complete solution exchange in the ME A chamber was achieved 20 seconds after the switch of solutions.
  • the perfusion liquid was continuously pre-heated at 37°C just before reaching the MEA chamber with a heated-perfusion cannula (PH01, Multichannel Systems, Reutlingen,
  • the temperature of the MEA chamber was maintained at 37 +/- 0.1 °C with a Peltier element located in the MEA amplifier headstage.
  • weak tetanic frequency stimulation one trains of 100 Hz stimulations for 0.1 seconds
  • the effect of PS-DHA at 2.5 ⁇ on NMDAR dependent hippocampal LTP induced by weak titanic frequency stimulation is also shown in FIG. 3B and in the table below. Weak stimulation resulted in weak potentiation that normally occurs during short term memory formation.
  • Curcumin and PS-DHA showed significant enhancement of hippocampal LTP by modulating the NMDAR activity.
  • Curcumin and PS-DHA showed a synergistic effect in enhancing hippocampal LTP by modulating the NMDAR activity.
  • NMDAR neurodegenerative diseases
  • Glutamate is the major excitatory neurotransmitter in the brain that activates the major ion channel receptors such as NMDAR and AMPAR that contribute to synaptic plasticity.
  • NMDAR and AMPAR major ion channel receptors
  • NMDA is a specific agonist of NMDAR that is capable of causing the excitotoxic neuronal death due to
  • NMDA was applied in the presence of different concentrations of Curcumin and PS-DHA in a
  • Hippocampal neurons were plated in 96-well plates and cultured for 10 days. NMDA and glutamate neurotoxicity assays were performed as detailed below. All preincubation experiments were performed in neurobasal medium

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Abstract

L'invention concerne des compositions nutritionnelles comprenant une combinaison de curcumine et/ou de curcumine biodisponible et d'acide phosphatidylsérine-docosahexaènoïque. La combinaison améliore les performances cognitives chez un individu, et, dans un mode de réalisation, elle améliore un trouble cognitif et/ou un dysfonctionnement du cerveau associé à un déclin cognitif lié à l'âge ou un déclin cognitif dû à une maladie neurodégénérative. Cette combinaison est également efficace pour améliorer l'acquisition de la mémoire, la rétention de la mémoire et la remémoration chez un individu.
PCT/US2012/068456 2011-12-08 2012-12-07 Compositions nutritionnelles comprenant de la curcumine et de l'acide phosphatidylsérine-docosahexaènoïque pour améliorer la cognition Ceased WO2013086327A1 (fr)

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EP2806866B1 (fr) * 2012-01-26 2018-11-28 Fidia Farmaceutici S.p.A. Compositions pharmaceutiques contenant du sel de sodium de la phosphatidylsérine et du curcumine
CN112888320A (zh) * 2018-11-05 2021-06-01 雀巢产品有限公司 使用姜黄素和ω-3脂肪酸的组合用于细胞能量的组合物和方法

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Publication number Priority date Publication date Assignee Title
EP2806866B1 (fr) * 2012-01-26 2018-11-28 Fidia Farmaceutici S.p.A. Compositions pharmaceutiques contenant du sel de sodium de la phosphatidylsérine et du curcumine
DE102013220974A1 (de) * 2013-10-16 2015-04-16 Briu Gmbh Zusammensetzung zur oralen Administration von Curcumin
CN112888320A (zh) * 2018-11-05 2021-06-01 雀巢产品有限公司 使用姜黄素和ω-3脂肪酸的组合用于细胞能量的组合物和方法

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