KR102608920B1 - Agent for improving sickness behavior symptoms - Google Patents

Abstract

Provision of the Sikhness Behavior symptom improver.
A chicness behavior symptom improvement agent that uses soy hydrolyzate as an active ingredient.

Description

SICKNESS BEHAVIOR SYMPTOMS {AGENT FOR IMPROVING SICKNESS BEHAVIOR SYMPTOMS}

The present invention relates to a security behavior symptom improving agent.

It is generally known that infection or inflammation causes physiological and mental changes such as decreased appetite, weight loss, fatigue, depression, and mood depression, and these symptoms are called sickness behavior. (Non-patent Documents 1 and 2).

The cause of chicness behavior has not been completely elucidated, and its treatment has not been established.

It has been reported that zaltoprofen, a non-steroidal anti-inflammatory drug, is effective as a treatment for sickness behavior (Patent Document 1).

Japanese Patent Publication No. 2001-233771

SA Family Pract 2003 ; 45(9):15-18 Phytomedicine 14 (2007) ; SVI 27-31

However, although zaltoprofen administration suppresses weight loss, reduction in food intake, and elevation of serum ALT, symptoms such as fatigue, decreased performance, and depressive symptoms, which are the main symptoms of chicness behavior, do not improve, leading to improvement in the patient's QOL. wasn't enough.

In addition, when applying antidepressants such as Paxil, in addition to the strong central action, there is concern about strong side effects such as liver damage, and zaltoprofen also has few side effects, but there is a possibility of liver function disorders.

Therefore, the object of the present invention is to provide a new security behavior symptom improving agent that is safe and can improve behavioral decline, depressive symptoms, etc.

Accordingly, the present inventor first studied to develop an animal model that does not cause clear liver damage, and as a result of administering a certain amount of concanavalin A using ddY male mice, not BALB/c mice, it was found that there was no clear effect on the liver. We succeeded in creating a model that does not show liver damage and reduces the amount of voluntary movement in depressed patients. As a result of careful examination using this model, it was found that liver hydrolyzate improves the decrease in depressive-type spontaneous movement, which is one of the symptoms of secret behavior, and also improves the activity of brain tyrosine hydrolytic enzyme, which is the rate-limiting enzyme of dopamine biosynthesis. It was found that the degradation was improved. Based on this knowledge, it was discovered that liver hydrolyzate is useful as an agent for improving symptoms of sickness behavior, an agent for improving behavioral decline, and an activator of brain tyrosine hydroxylase, and the present invention was completed.

That is, the present invention provides the following [1] to [12].

[1] A chicness behavior symptom improvement agent that uses soy hydrolyzate as an active ingredient.

[2] An agent that improves symptoms selected from depression, mood swings, mental fatigue, and decreased behavioral ability, using soy hydrolyzate as an active ingredient.

[3] A brain tyrosine hydroxylase activator that uses liver hydrolyzate as an active ingredient.

[4] Use of soy hydrolyzate to manufacture the Seekness Behavior symptom improvement agent.

[5] Use of soy hydrolyzate to produce an agent for improving symptoms selected from depression, mood swings, mental fatigue, and behavioral impairment.

[6] Use of soy lysates for the preparation of brain tyrosine hydroxylase activator.

[7] Soy hydrolyzate to improve chicness behavior symptoms.

[8] Soy hydrolyzate to improve symptoms selected from depression, mood swings, mental fatigue, and decreased performance.

[9] Soy hydrolyzate to activate tyrosine hydroxylase in the brain.

[10] A method for improving the symptoms of dark behavior, characterized by administering an effective amount of liver hydrolyzate.

[11] A method for improving symptoms selected from depression, mood swings, mental fatigue, and decreased behavioral ability, characterized by administering an effective amount of liver hydrolyzate.

[12] A method of activating brain tyrosine hydroxylase, characterized by administering an effective amount of liver hydrolyzate.

According to the present invention, it is possible to improve symptoms of decreased behavioral ability, such as depressive-type decreased behavioral ability and decreased behavioral ability due to mental fatigue, which are representative symptoms of chicness behavior. The symptom improvement effect is thought to be due to the action of improving the decrease in dopamine production by activating tyrosine hydroxylase in the brain. In addition, it is thought that this tyrosine hydroxylase activation action returns to the normal range and there is no excessive activation.

Figure 1 is a diagram showing changes in AST and ALT levels in model animals of the present invention.
Figure 2 is a diagram showing the effect of liver hydrate (LH) on the decrease in spontaneous exercise amount caused by ConA administration.
Figure 3 is a diagram showing the effect of liver hydrate (LH) on the decrease in brain tyrosine hydroxylase (TH) activity caused by ConA administration.

The active ingredient of the Sikhness Behavior symptom improving agent of the present invention is liver hydrolyzate. Soy sauce hydrolyzate, also called soy sauce hydrolyzate, soy sauce extract, soy sauce decomposition extract, or liver hydrolyzate, is obtained by hydrolyzing soy sauce with digestive enzymes, etc., and is used as a medicine to improve liver function. As the raw material for soy sauce, fresh soy sauce from beef, pork, bonito, whale, etc. is used. The obtained hydrolyzate is preferably used after being concentrated. Preferably, soy sauce hydrolyzate, which is specified as the above-mentioned pharmaceutical, is used.

Soy sauce hydrolyzate contains low-molecular-weight peptides as the main ingredient and various amino acids, nucleotides, vitamins, minerals, etc. More specifically, 19 to 78% by mass of amino acids, 17 to 73% by mass of peptides and proteins, 1.8 to 11% by mass of sugars, 0.005 to 0.04% by mass of lipids, 0.7 to 2.5% by mass of nucleic acids, 1.6 to 5.4% by mass of minerals, vitamins. It is preferable to contain 0.03 to 0.2% by mass and 0.8% by mass or less of glutathione. Additionally, amino acids 23 to 65 mass%, peptides and proteins 20 to 61 mass%, saccharides 2.2 to 8.6 mass%, lipids 0.006 to 0.035 mass%, nucleic acids 0.9 to 2.1 mass%, minerals 1.9 to 4.5 mass%, vitamins 0.04 to 0.15 mass%. It is more preferable to contain 0.7% by mass or less of glutathione, 29 to 52% by mass of amino acids, 25 to 49% by mass of peptides and proteins, 2.8 to 6.9% by mass of saccharides, 0.008 to 0.03% by mass of lipids, and 1.1 to 1.7% by mass of nucleic acids. It is more preferable to contain 2.4 to 3.6 mass% of minerals, 0.05 to 0.12 mass% of vitamins, and 0.6 mass% or less of glutathione.

Among these components, the amino acid composition is Ala 17 to 68 mg/g, Arg 0.6 to 4.4 mg/g, Asp 9 to 48 mg/g, Cystine 5 mg/g or less, Glu 18 to 63 mg/g, Gly 10. ~ 39 mg/g, His 3 ~ 17 mg/g, Ile 14 ~ 56 mg/g, Leu 26 ~ 98 mg/g, Lys 15 ~ 65 mg/g, Met 0.3 ~ 20 mg/g, Phe 13 ~ 46 ㎎/g, Pro 10 ∼ 48 ㎎/g, Ser 12 ∼ 49 ㎎/g, Thr 12 ∼ 45 ㎎/g, Trp 3 ∼ 13 ㎎/g, Tyr 1.6 ∼ 41 ㎎/g, Val 18 ∼ 71 ㎎/ g is preferable. Additionally, Ala 21 to 57 mg/g, Arg 0.8 to 3.6 mg/g, Asp 11 to 40 mg/g, Cystine 4 mg/g or less, Glu 22 to 53 mg/g, Gly 13 to 32 mg/g, His 4 ~ 14 mg/g, Ile 17 ~ 47 mg/g, Leu 32 ~ 82 mg/g, Lys 18 ~ 54 mg/g, Met 0.4 ~ 17 mg/g, Phe 15 ~ 38 mg/g, Pro 12 ~ 40 mg/g, Ser 15 to 41 mg/g, Thr 14 to 38 mg/g, Trp 3.8 to 11 mg/g, Tyr 1.9 to 34 mg/g, Val 21 to 59 mg/g are more preferable, and Ala 26 ~ 45 mg/g, Arg 1 ~ 2.9 mg/g, Asp 14 ~ 32 mg/g, Cystine 3 mg/g or less, Glu 27 ~ 42 mg/g, Gly 16 ~ 26 mg/g, His 5 ~ 11 ㎎/g, Ile 21 ~ 40 mg/g, Leu 40 ~ 66 mg/g, Lys 22 ~ 43 mg/g, Met 0.5 ~ 14 mg/g, Phe 19 ~ 31 mg/g, Pro 15 ~ 32 mg/ g, Ser 18 to 33 mg/g, Thr 18 to 30 mg/g, Trp 4.8 to 8.4 mg/g, Tyr 2.4 to 27 mg/g, Val 27 to 48 mg/g.

It is known that liver hydrolyzate has an effect of improving liver function, but its action on models that do not show liver failure, that is, its action on secret behavior or action on behavioral deterioration is not known at all.

As shown in the examples described later, liver hydrolyzate has the effect of activating tyrosine hydroxylase (TH) in the brain striatum in a sickness behavior model animal that does not exhibit liver dysfunction, and also has the effect of activating depressive-type tyrosine hydroxylase (TH) in the brain striatum. Significantly improves the decrease in spontaneous movement. Therefore, liver hydrolyzate is useful as an agent to improve symptoms of sickness behavior, an agent to improve symptoms selected from depression, mood swings, mental fatigue, and decreased behavioral ability, and as an activator of brain tyrosine hydroxylase. Here, since tyrosine hydroxylase is the rate-limiting enzyme of dopamine production, it is believed that the effect of improving the decrease in spontaneous exercise in the depressive type is due to the promotion of dopamine production in the brain striatum. Therefore, liver hydrolyzate is effective for symptoms of chicness behavior such as depression, mood swings, mental fatigue, and decreased behavioral ability.

Here, mental fatigue is fatigue caused by social factors such as stress, and is different from physical fatigue.

In addition, since the secret behavior model used in the examples was a model that did not cause liver damage, it was unexpected that liver hydrolyzate had an effect of improving the hide behavior symptoms in this model.

The security behavior symptom improving agent of the present invention can be administered by oral administration, transdermal administration, enteral administration, intravenous administration, etc., but oral administration is more preferable. Preparations for oral administration include solutions, tablets, powders, fine granules, granules, capsules, etc., but solutions and tablets are preferred, and liquid preparations are more preferred.

These oral preparations include excipients such as lactose, mannitol, corn starch, and crystalline cellulose, binders such as cellulose derivatives, gum arabic, and gelatin, disintegrants such as calcium carboxymethyl cellulose, lubricants such as talc and magnesium stearate, Solubilizers such as nonionic surfactants, coagulants, sweeteners, stabilizers, pH adjusters, water, ethanol, propylene glycol, glycerin, etc. can be used. Additionally, coating agents such as hydroxymethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, and methacrylate copolymer may be used.

Additionally, other active ingredients may be added to the skin behavior symptom improving agent of the present invention. Other active ingredients include vitamin B type ₁ ; Thiamine, thiamine nitrate, thiamine hydrochloride, fursultiamine, bisbentiamine, benfotiamine, thiamine disulfide, dicethiamine, thiamine propyl disulfide and their derivatives, vitamin B ₂ ; Riboflavin and derivatives and their salts, vitamin B ₃ ; Niacin, nicotinic acid, nicotinic acid amide and derivatives and their salts, vitamin B ₅ ; Panthenol, pantothenic acid and derivatives and their salts, vitamin B ₆ ; Pyridoxine and derivatives and their salts, vitamin B class ₁₂ ; Cyanocobalamin and derivatives, salts thereof, and other vitamins; Vitamin A, Vitamin C, Vitamin E, Vitamin K, Vitamin P, diisopropylamine dichloroacetate, taurine, chondroitin sulfate, royal jelly, caffeine, turmeric, white thistle, dandelion, dandelion, burdock, garlic, chrysanthemum, Western Yarrow, gardenia, sesame seeds, panax ginseng, asparagus, onion, chicory, medicinal sage, Korean thistle (artichoke), goji berry, leguminous and iris family plants, perennial orchid, Elba de Passarinho (Struthantus Flexicaulis Mart), Examples include cetesanguria (Cuphea balsamona Cham.), arborvitae, black tea, resveratrol, catechins, berberine, rosemary, soybean extract, and metformin.

In addition, the Sikhness Behavior symptom improving agent of the present invention can be used as a quasi-pharmaceutical product, food for specified health purposes, functional food, sports drink, rehabilitation drink, pet food, etc. in addition to pharmaceuticals.

The content of liver hydrolyzate in the skin behavior symptom improving agent of the present invention, etc. varies depending on the dosage form, but is usually preferably 0.001 to 10% by mass and more preferably 0.001 to 5% by mass in terms of dry weight. In addition, the daily dosage of liver hydrolyzate in the skin behavior symptom improving agent of the present invention is preferably 100 mg to 12000 mg, more preferably 180 mg to 6000 mg, and 400 to 3600 mg in dry weight. It is more desirable. Additionally, it is preferable to administer the liver hydrolyzate for two or more consecutive days.

Example

Next, the present invention will be described in detail with reference to examples, but the present invention is not limited to these at all.

(1) Method

In the experiment, ddY male mice weighing 28 to 32 g were used. The amount of spontaneous movement was evaluated using the Supermax Apparatus ^TM (manufactured by Muromachi Machinery Co., Ltd.). Immunohistochemical staining was analyzed using MapAnalyzer ^™ (manufactured by Yamato Scientific Co., Ltd.), which can simultaneously measure quantity and distribution of tyrosine hydroxylase (TH) levels in the mouse striatum using fluorescent dye-labeled antibodies. (n=4 ~ 6). The administration method was first to administer water or liver hydrolyzate orally, and 30 minutes later, physiological saline solution or concanavalin A (ConA) was administered intravenously, followed by fasting and abstinence for 24 hours. After 1.5 hours, water or liver hydrolyzate was orally administered, and spontaneous movement was measured 60 minutes later (n=4 to 6).

(2) Results

AST and ALT levels of this animal model are shown in Figure 1. In Figure 1, the animal model did not show hepatic impairment.

The amount of spontaneous movement was significantly decreased by the administration of ConA (12.5 mg/kg, i.v.), and was improved to the level of the saline solution-administered control group by the administration of liver lysate (30, 100 mg/kg, p.o.) (Figure 2). The TH level in the striatum was significantly decreased in the ConA-administered group compared to the physiological saline solution-administered group, and the decrease in TH level caused by ConA administration was improved by administration of liver hydrolyzate (100 mg/kg, p.o.) (Figure 3).

From the above results, it was revealed that liver lysate improves the secret behavior by protecting the expression level of TH in the nucleus accumbens and caudate nucleus of the brain.

The components and amino acid composition contained in the used soy sauce hydrolyzate are shown in Table 1.

(%) Total Amino Acids, Peptides and Proteins 75 amino acid 34.89 peptides and proteins 40.11 total sugars 5.7 lipids 0.02 total nucleic acid bases 1.35 mineral 2.89 moisture 2.08 vitamin 0.1 glutathione 0.42 amino acid (mg/g) Ala 31.8 Arg 1.2 Asp 17.6 Cystine 2.5 Glu 35 Gly 19.7 His 9 Ile 26 Leu 48.3 Lys 27.3 Met 0.6 Phe 23.7 Pro 18.8 Ser 22.5 Thr 22.4 Trp 7 Tyr 2.9 Val 32.6

Claims (12)

A pharmaceutical composition for improving symptoms of sickness behavior selected from depression, mood depression, mental fatigue, and decreased behavioral ability due to mental fatigue, containing soy hydrolyzate as an active ingredient. A food composition containing soy hydrolyzate as an active ingredient for improving chicness behavior symptoms selected from depression, mood swings, mental fatigue, and decreased behavioral ability due to mental fatigue. A quasi-drug composition containing soy hydrolyzate as an active ingredient for the improvement of chicness behavior symptoms selected from depression, mood depression, mental fatigue, and decreased behavioral ability due to mental fatigue. The composition according to any one of claims 1 to 3, wherein the improvement of the symptoms is due to activation of tyrosine hydroxylase in the brain. delete delete The composition according to any one of claims 1 to 3, wherein the symptom is a decrease in behavioral ability due to mental fatigue. delete delete delete delete delete