Memory improvement agent

Abstract

The present invention provides a novel memory disorder ameliorating agent. A PKC [gamma] activity inhibitor is useful as an active ingredient of a dysmnesia ameliorating agent.

Description

Technical Field

[0001] This invention relates to memory impairment improvers. Background Technology

[0002] Memory impairment is known to result primarily from irreversible neurodegeneration, such as Alzheimer's disease. Since the primary cause of memory impairment is irreversible, it is essentially not something that can be improved; the only approach is to slow its progression.

[0003] On the other hand, known memory impairments can also occur due to other causes. These include, for example, depression, psychological trauma, stress, and brain fog.

[0004] For example, Non-Patent Literature 1 describes memory impairment as a neuropsychological symptom of depression, with brain function recovering in a manner consistent with clinical recovery. Furthermore, memory impairment is also present as a symptom of brain fog, a condition that has rapidly increased in sequelae of COVID-19 infection. Non-Patent Literature 2 describes a high proportion of cases where brain fog gradually recovers over time, and Non-Patent Literature 3 describes that, although individual differences exist, more than half of those with this sequelae experience symptom improvement within 5 months. Moreover, Non-Patent Literature 4 describes that the main symptom of dissociative amnesia caused by psychological trauma or stress is memory impairment inconsistent with normal amnesia, and that most patients are able to recover lost memories and eliminate forgetting. In other words, these memory impairments caused by other reasons are predictably recoverable symptoms, which is fundamentally different from the memory impairments primarily caused by irreversible neurodegeneration mentioned above.

[0005] Existing technical documents Non-patent literature Non-Patent Literature 1: Okamoto Yasumasa: The Pathological-Related Brain Basis of Depression, Journal of Psychosomatic Medicine, Vol. 111, No. 11 (2009), pp. 1330-1344 Non-Patent Literature 2: What is the rapidly increasing brain fog in Kumiko Arai's COVID-19 sequelae? Its differences from dementia and amnesia, [online], 2023 / 2 / 13, [retrieved April 12, 2023], Internet<URL:https: / / nishiharu-clinic.com / 2023 / 02 / 13 / korona-bureinfogu / > Non-Patent Literature 3: What is the "brain fog" in Hideaki Hatsumura's COVID-19 sequelae?, [online], 2022 / 10 / 13, [retrieved on April 12, 2023], Internet <URL: https: / / utu-yobo.com / column / brain-fog / > Non-patent literature 4: David Spiegel, MSD Manual Professional Version 08. Mental Disorders / Dissociative Disorders Group / Dissociative Amnesia, [online], March 2021, Merck & Co., Inc., Rahway, NJ, USA, [retrieved on April 12, 2023], Internet <URL: https: / / www.msdmanuals.com / ja-jp / %E3%83%97%E3%83%AD%E3%83%95%E3%82%A7%E3%83%83%E3%82%B7%E3%83%A7%E3%83%8A%E3%83%AB / 08-%E7%B2%BE%E7%A5%9E%E9%9A%9C%E5%AE%B3 / %E8%A7%A3%E9%9B%A2%E7%97%87%E7%BE%A4 / %E8%A7%A3%E9%9B%A2%E6%80%A7%E5%81%A5%E5%BF%98> SUMMARY

[0006] PROBLEMS TO BE SOLVED BY THE INVENTION In order to improve memory disorders, treatment to remove the main cause of the onset is generally performed. That is, in order to improve memory disorders with depression, psychological trauma, stress as the main cause, treatment against the main cause is required, and the kinds of agents used in these treatments generally must be carefully applied considering the risk of side effects. In addition, for the brain fog of the sequelae of the novel coronavirus infection disease, since there is no clear cause, the treatment method is not clear. Under such a background, a new ingredient that brings an effect based on a clear mechanism of action against memory disorders is desired.

[0007] Therefore, an object of the present application is to provide a memory disorder improver with a clear mechanism of action.

[0008] MEANS FOR SOLVING THE PROBLEMS The present inventors found that, as an independent model of memory disorders, a DGK γ knockout mouse, which shows hyperphosphorylation (PKC γ activity abnormality) in the brain, improves memory disorders by administering a PKC β activity inhibitor, normalizing PKC γ activity in the brain. The present application was completed based on this insight and further repeated research. γ

[0009] That is, the present application provides the application of the following disclosed means.

[0010] Item 1. A memory disorder improver that normalizes PKC​γ an active ingredient.

[0011] Item 2. The memory disorder improver according to item 1, wherein the PKC γ the active ingredient is a flavonoid selected from the group consisting of Scutellarin, baicalin, Baicalein, Luteolin, Apigenin, Apigenin glucoside, and salts thereof.

[0012] Item 3. The memory disorder improver according to item 1 or 2, wherein the memory disorder improver is used for improving a memory disorder not caused by β accumulation of amyloid.

[0013] Item 4. The memory disorder improver according to any one of items 1 to 3, wherein the memory disorder improver is used for improving a memory disorder not caused by general anesthesia exposure.

[0014] Item 5. The memory disorder improver according to any one of items 1 to 4, wherein the memory disorder improver is used for improving a memory disorder not caused by cerebral infarction.

[0015] Item 6. A food product comprising the memory disorder improver according to any one of items 1 to 5.

[0016] Item 7. A PKC γ active inhibitor for use in the manufacture of a memory disorder improver.

[0017] Item 8. A PKC γ active inhibitor for use in a memory disorder improver.

[0018] Item 9. A method for improving a memory disorder, comprising the step of administering an effective amount of a PKC γ active inhibitor to a subject in need of improvement of a memory disorder.

[0019] Effects of the Invention According to the present invention, it is possible to provide a novel memory disorder improver whose mechanism of action is clear. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 shows results of confirming the memory disorder improving effect of a PKC γ active inhibitor administered orally to mice by Y-maze test.

[0021] Figure 2 shows results of confirming the memory disorder improving effect of a PKC γResults of PKC activity in the cerebral cortex of mice to which the activity inhibitor was administered.

[0022] Figure 3 Results showing confirmation of PKC γ activity of various flavonoids by immunoblotting.

[0023] Figure 4 Results showing confirmation of PKC γ activity of various flavonoids by immunoblotting. DETAILED DESCRIPTION

[0024] 1. Memory disorder improver The memory disorder improver of the present application is characterized by containing, as an effective ingredient, a PKC γ activity inhibitor.

[0025] 1-1. Active ingredient As the PKC γ activity inhibitor, there is no particular limitation as long as it is a compound having an action of inhibiting phosphorylation of PKC γ . As the preferred PKC γ activity inhibitor used in the present application, there can be mentioned scutellarein (the following Formula (1)), baicalin (the following Formula (2)), baicalein (the following Formula (3)), luteolin (the following Formula (4)), apigenin (the following Formula (5)), apigenin glucoside (the following Formula (6)), and salts thereof, and the like flavonoids.

[0026] [Chemical Formula 1]

[0027] [Chemical Formula 2]

[0028] In addition, as the salt, there is no particular limitation as long as it is a pharmaceutically or food-chemically acceptable salt, and for example, there can be mentioned an alkali metal salt such as a sodium salt, and the like.

[0029] In the memory disorder improver of the present application, these PKC γ activity inhibitors can be contained singly or in combination. Among these PKC γ activity inhibitors, there can be preferably mentioned scutellarein, baicalin, luteolin, apigenin, more preferably baicalin, luteolin, and further preferably baicalin.

[0030] As the PKC γThe blending amount of the active inhibitor is not particularly limited and can be appropriately set according to the formulation form and / or specific use of the memory disorder improver, and for example, 40 to 100% by weight, preferably 60 to 90% by weight can be mentioned.

[0031] 1-2. Other ingredients The memory disorder improver of the present application can further contain, within a range not impairing the effects of the present application, additives and / or bases corresponding to the formulation form and use, in addition to the above-mentioned effective ingredient, or can not contain them. As such additives and bases, there are no particular limitations as long as they are pharmaceutically acceptable, and for example, excipients, binding agents, disintegrating agents, lubricants, isotonic agents, plasticizers, dispersants, emulsifiers, co-solvents, wetting agents, stabilizers, suspending agents, adhesives, gelling agents, coating agents, glossing agents, water, oils and fats, waxes, hydrocarbons, fatty acids, higher alcohols, esters, water-soluble polymers, surfactants, metal soaps, lower alcohols, polyhydric alcohols, pH adjustors, buffers, antioxidants, anti-UV agents, preservatives, flavoring agents, fragrances, powders, thickening agents, coloring agents, chelating agents, sweeteners, and the like can be mentioned. These additives can be used singly or in combination of two or more. Further, the content of these additives and bases can be appropriately set according to the kind of the additives and bases used, the formulation form and use of the memory disorder improver of the present application, and the like.

[0032] Further, the memory disorder improver of the present application can contain, within a range not impairing the effects of the present application, other nutritional ingredients and / or pharmacological ingredients, in addition to the above-mentioned effective ingredient, or can not contain them. As such nutritional ingredients and pharmacological ingredients, there are no particular limitations as long as they are pharmaceutically acceptable, and for example, antacids, stomachics, digestives, intestinal regulators, antispasmodics, mucosal repair agents, anti-inflammatory agents, astringents, antiemetics, antitussives, expectorants, anti-inflammatory enzyme agents, sedative hypnotics, antihistamines, caffeine, cardiac diuretics, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, crude drug extracts, vitamins, menthol, and the like can be mentioned. These nutritional ingredients and / or pharmacological ingredients can be used singly or in combination of two or more. Further, the content of these ingredients can be appropriately set according to the kind of the ingredients used.

[0033] 1-3. Preparation form The memory disorder improver of the present application is not particularly limited in form and properties as long as it contains the above-mentioned effective ingredient.

[0034] As the administration method of the memory disorder improver of the present application, either of oral administration and non-oral administration is included. Therefore, the memory disorder improver of the present application can be prepared as an oral agent, an injection agent, an infusion agent, a nasal drop agent, or the like. Among them, the memory disorder improver of the present application is preferably an oral agent which is easy to be administered (ingested) daily and / or continuously.

[0035] In addition, the memory disorder improver of the present application can be in a liquid form or in a solid form. As examples of the liquid form, there are mentioned a liquid agent, a beverage agent, an emulsion agent, a suspension agent, an alcoholic agent, a syrup agent, an elixir agent (including a soft extract agent, etc.), and the like, and as examples of the solid form, there are mentioned a tablet, a pill, a powder, a fine granule, a granule, a tablet, a capsule (including a hard capsule and a soft capsule), a lozenge, a chewable agent, a dry extract agent, and the like. In the case where the memory disorder improver of the present application is in a solid form, a sustained or slow-release dosage form can be prepared, or the memory disorder improver can be mixed with water or the like at the time of administration or ingestion.

[0036] The memory disorder improver of the present application can also be used as an additive or the like for imparting added value to foods, pharmaceuticals, quasi-pharmaceuticals, and the like. As the foods to which the memory disorder improver of the present application is added, there are mentioned general foodstuffs, health functional foods (including specified health foods, nutrition functional foods, and functional labeling foods, etc.). Among them, as the effective ingredient of the memory disorder improver of the present application, since flavonoids which can be ingested as a food ingredient are contained, it is preferable to be used in a health functional food which is easy to be ingested daily and / or continuously, and in addition, since the memory disorder improver of the present application exerts an effect of normalizing PKC γ phosphorylation (PKC γ activity-based normalization), it is particularly preferable to be used in a specified health food or a functional labeling food.

[0037] 1-4. Manufacturing method As the production method of the memory disorder improver of the present application, the above-mentioned effective ingredient and other ingredients which are added as necessary are used, and according to various forms and properties and purposes of use, the usual preparation procedures which have been known heretofore are followed.

[0038] 1-5. Use The memory disorder improver of the present application is used for improving memory disorders by normalizing PKC γ activity. As the memory disorder, there is no particular limitation as long as it is a memory disorder caused by inhibition of PKC γ activity. For example, there are mentioned memory disorders caused by aging, depression, psychological trauma, stress, and / or brain fog, etc. Note that in the memory disorder improver of the present application, the memory disorder is preferably not a memory disorder caused by an irreversible neurodegenerative disease and βa memory disorder caused by any of the accumulation of amyloid, a memory disorder not caused by exposure to general anesthesia (particularly isoflurane), and a memory disorder not caused by cerebral infarction.

[0039] In addition, in the memory disorder, the object of the memory is not particularly limited, and a spatial memory (i.e., a memory required in an action of searching for a target, going to a destination, returning to the original place, etc.) is preferable.

[0040] 1-6. Dosage The amount of the memory disorder improver of the present application is, for example, 0.1 g / day / 60 kg or more, preferably 0.3 g / day / 60 kg or more, more preferably 0.5 g / day / 60 kg or more, and further preferably 1 g / day / 60 kg or more, in terms of the amount of the PKC γ activity inhibitor for a human.

[0041] The method of administration (ingestion) of the memory disorder improver of the present application is not particularly limited, and, for example, it can be performed orally or non-orally once or a plurality of times a day, and it is preferable to be performed orally once or 2 to 3 times a day.

[0042] 2. PKC γ Inhibitors of activity The PKC γ activity inhibitor used in the memory disorder improver of the present application described above is not particularly limited, and, for example, a compound selected from the group consisting of baicalein (the above-described formula (2)), baicalein (the above-described formula (3)), luteolin (the above-described formula (4)), apigenin (the above-described formula (5)), apigenin glucoside (the above-described formula (6)), and salts thereof can be used. The PKC γ activity inhibitory action of these is unknown. Therefore, the present application also provides a PKC γ activity inhibitor, which uses, as an effective ingredient, a compound selected from the group consisting of baicalein, baicalein, luteolin, apigenin, apigenin glucoside, and salts thereof. These PKC γ activity inhibitors can be used for improving any symptoms caused by abnormality of PKC γ activity.

[0043] Example Hereinafter, an example will be shown, and the present application will be more specifically described, but the present application is not limited to this.

[0044] [Experimental Example 1] (memory disorder model mouse) The present inventors have found that, among 10 subtypes of diacylglycerol kinases (DGK) found in mammals, one subtype DGK β, particularly in the hippocampus, cerebral cortex, and striatum of the brain, and sharply increase during the period of development of neural networks, and are expressed specifically in nerves, promoting growth of synapses. Mice in which this DGK β is knocked out (DGK β KO mice) are used as a model of memory impairment. Note that this model of memory impairment is not a mouse that shows accumulation of A β in the brain, is not a model of irreversible neurodegenerative disease, is not a mouse exposed to general anesthesia with isoflurane or the like, and is not a model of cerebral infarction.

[0045] To the model of memory impairment, scutellarein, which is an inhibitor of PKC γ activity, is orally administered at a dose of 100 mg per mouse for 10 days. Also, to normal mice, scutellarein, which is an inhibitor of PKC γ activity, is orally administered at a dose of 100 mg per mouse for 10 days.

[0046] (memory impairment evaluation system) A Y-maze device is used. The Y-maze is a device in which three arms of the same size are connected radially at intervals of 120°, and is used for a spontaneous alternation test, which is one of tests for evaluation of spatial memory. As an index for evaluation of spatial memory, the value obtained by dividing the number of times of entering different arms consecutively by the value obtained by subtracting 1 from the total number of times of entering arms, and multiplying the result by 100 (Alternations) is used. The lower the Alternations, the higher the degree of memory impairment.

[0047] (results) The results are shown in Figure 1 . In the figure, WT indicates the results of normal mice, KO indicates the results of the model of memory impairment, - indicates the results of mice to which scutellarein was not administered, and + indicates the results of mice to which scutellarein was administered. Also, the numerical values written in the form of "WT-: 5" and the like indicate the number of mice (the same applies to the following figures). As shown in Figure 1 , in the group of the model of memory impairment (KO) to which scutellarein was not administered (-), the value of Alternations was significantly low, and memory impairment was observed. Furthermore, it was confirmed that, by administering scutellarein (+), the value of Alternations was significantly high, and the memory impairment in the group of the model of memory impairment (KO) was improved to a level close to that of normal mice (WT).

[0048] Note that the cerebral cortex and hippocampus of mice to which scutellarein was administered were subjected to immunoblotting, and the activation of PKC was evaluated. The results are shown in Figure 2 (cerebral cortex) and Figure 3 (hippocampus).

[0049] As shown in Figure 2 and Figure 3 , in the memory disorder model mice (KO) group to which no scutellarein was administered (-), abnormal activity of PKC γ in the cerebral cortex and hippocampus was observed, and, in contrast, in the memory disorder model mice (KO) group to which scutellarein was administered (+), the activity of PKC γ was confirmed to be improved to the normal level.

[0050] [Experiment 2] The PKC γ activity inhibitory action of various flavonoids was tested. As the various flavonoids, specifically, scutellarein (Scu), baicalein (Bai), luteolin (Lut), and apigenin (Api) were used, respectively. The plasmid encoding GFP-PKC γ was introduced into COS7 cells by electroporation, and cultured for 48 hours, whereby GFP-PKC γ was expressed. After the cells were treated with TPA (12-O-Tetradecanoylphorbol-13-acetate, an activator of PKC γ ) and each flavonoid, the cells were ground, and the proteins were subjected to SDS-PAGE. Then, immunoblotting was performed on PKC γ and phosphorylated PKC γ (activated form).

[0051] The obtained electrophoresis results (n = 2) are shown in Figure 4 . As shown in Figure 4 , not only for scutellarein (Scu), but also for baicalein (Bai), luteolin (Lut), and apigenin (Api), PKC γ activity inhibitory action was confirmed. According to this result, in the case where baicalein (Bai), luteolin (Lut), and apigenin (Api) are administered to the memory disorder model mice of Experiment 1, the same memory disorder improving effect can be reasonably extrapolated.

Claims

1. A memory impairment improver, characterized in that, with PKC γ inhibitors as active ingredients.

2. The memory disorder improver according to claim 1, wherein The PKC The memory disorder improver is for improving a memory disorder not caused by exposure to general anesthesia. The activity inhibitor is a flavonoid selected from the group consisting of scutellarein, baicalein, baicalin, luteolin, apigenin, apigenin glucoside, and salts thereof.

3. The memory disorder improver according to claim 1, wherein The memory disorder improver is for improving a memory disorder not caused by β an accumulation of amyloid.

4. The memory disorder improver according to claim 1, wherein The memory disorder improver is for improving a memory disorder not caused by cerebral infarction.

5. The memory disorder improver according to claim 1, wherein A memory disorder improver comprising the memory disorder improver according to claim 1.

6. A food product, characterized by, ​

Images