JP6913461B2 - Sickness behavior symptomatology improver - Google Patents

Description

The present invention relates to a thickness behavior symptomatology improving agent.

It is generally known that during infections and inflammation, physiological and psychological changes such as loss of appetite, weight loss, tiredness, depression, and depression are induced, and these symptoms are sickness behaviors (sickness behavior). It is called sickness behavior) (Non-Patent Documents 1 and 2).

The cause of sickness behavior has not been completely elucidated, and no cure has been established.

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

Japanese Unexamined Patent Publication No. 2001-233771

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

However, although saltoprofen administration suppresses weight loss, decrease in food intake, and increase in ALT in serum, symptoms such as fatigue, decreased activity, and depressive symptoms, which are major symptoms of sickness behavior, have not been improved. It was not sufficient for improving the patient's QOL.
In addition, when antidepressants such as paxil are applied, there are concerns about strong side effects such as liver damage in addition to strong central action, and zaltoprofen has been shown to have the possibility of liver dysfunction, although there are few side effects. ..
Therefore, an object of the present invention is to provide a new sickness-behavior symptomatology improving agent that is safe and can improve behavioral deficiency, depressive symptom, and the like.

Therefore, the present inventor first examined to develop a model that does not cause clear liver damage as an animal model, and found that a fixed amount of concanavalin A was administered using ddY male mice instead of BALB / c mice. , We succeeded in creating a model in which depression-like locomotor activity is reduced without showing clear liver damage. When studied diligently using this model, liver hydrolase improves depression-like locomotor activity, which is one of the symptoms of sickness behavior, and tyrosine hydrolase activity in the brain, which is the rate-limiting enzyme for dopamine biosynthesis. Found to improve the decline in. Based on these findings, we have found that liver hydrolyzate is useful as a sickness behavior symptom improver, a behavioral decline improver, and a tyrosine hydroxylase activator in the brain, and completed the present invention.

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

[1] A sickness behavior symptom improving agent containing a liver hydrolyzate as an active ingredient.
[2] An agent containing liver hydrolyzate as an active ingredient, which is selected from depression, depression, mental fatigue, and decreased behavior.
[3] A tyrosine hydroxylase activator in the brain containing a liver hydrolyzate as an active ingredient.
[4] Use of liver hydrolyzate for the production of sickness behavior symptomatology improver.
[5] Use of liver hydrolyzate to produce a symptom-improving agent selected from depression, depression, mental fatigue and decreased behavior.
[6] Use of liver hydrolyzate for the production of intracerebral tyrosine hydroxylase activator.
[7] Sickness behavior A liver hydrolyzate for improving symptoms.
[8] Liver hydrolyzate for improving symptoms selected from depression, depression, mental fatigue and decreased behavior.
[9] Liver hydrolyzate for activating tyrosine hydroxylase in the brain.
[10] A method for improving sickness behavior symptoms, which comprises administering an effective amount of liver hydrolyzate.
[11] A method for improving symptoms selected from depression, depression, mental fatigue, and decreased behavior, which comprises administering an effective amount of liver hydrolyzate.
[12] A method for activating tyrosine hydroxylase in the brain, which comprises administering an effective amount of a liver hydrolyzate.

According to the present invention, it is possible to improve behavioral deficiency symptoms such as depression-like behavioral deficiency and mental fatigue-induced dyskinesia, which are typical symptoms of sickness behavior. The symptomatological improvement effect is considered to be due to the effect of improving the decrease in dopamine production by activating tyrosine hydroxylase in the brain. Furthermore, this tyrosine hydroxylase activating action returns to the normal range, and it is considered that there is no overactivation.

It is a figure which shows the change of the AST and ALT level of the model animal of this invention. It is a figure which shows the effect of the liver hydrolyzate (LH) on the decrease of the locomotor activity by the administration of ConA. It is a figure which shows the effect of the liver hydrolyzate (LH) on the decrease of the tyrosine hydroxylase (TH) activity in the brain by the administration of ConA.

The active ingredient of the sickness behavior symptomatology improving agent of the present invention is a liver hydrolyzate. Liver hydrolyzate, also called liver hydrolyzate, liver extract, liver decomposition extract, or liver hydrolyzate, is obtained by hydrolyzing the liver with digestive enzymes and is used as a drug for improving liver function. It is a thing. As the raw material liver, fresh liver such as cow, pig, bonito, and whale is used. The obtained hydrolyzate is preferably concentrated and used. Preferably, a liver hydrolyzate defined as the above-mentioned pharmaceutical product is mentioned.

The liver hydrolyzate contains various amino acids, nucleotides, vitamins, minerals and the like with a small molecule peptide as a main component. More specifically, amino acids 19 to 78% by mass, peptides and proteins 17 to 73% by mass, sugars 1.8 to 11% by mass, lipids 0.005 to 0.04% by mass, nucleic acids 0.7 to 2.5% by mass. %, 1.6 to 5.4% by mass of inorganic substances, 0.03 to 0.2% by mass of vitamins, and 0.8% by mass or less of glutathione are preferably contained. In addition, amino acids 23 to 65% by mass, peptides and proteins 20 to 61% by mass, sugars 2.2 to 8.6% by mass, lipids 0.006 to 0.035% by mass, nucleic acids 0.9 to 2.1% by mass. , 1.9 to 4.5% by mass of inorganic substances, 0.04 to 0.15% by mass of vitamins, 0.7% by mass or less of glutathione, more preferably 29 to 52% by mass of amino acids, 25 to 49% by mass of peptides and proteins. Mass%, sugars 2.8 to 6.9% by mass, lipids 0.008 to 0.03% by mass, nucleic acids 1.1 to 1.7% by mass, inorganic substances 2.4 to 3.6% by mass, vitamins 0. Those containing 05 to 0.12% by mass and 0.6% by mass or less of glutathione are more preferable.

Among these components, the amino acid composition is Ala 17-68 mg / g, Arg 0.6-4.4 mg / g, Asp 9-48 mg / g, Cystine 5 mg / g or less, Glu 18-63 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, Ph 13-46 mg / g, Pro 10-48 mg / g, Ser 12-49 mg / g, Thr 12-45 mg / g, Trp 3-13 mg / g, Tyr 1.6-41 mg / g, Val 18-71 mg / g are preferable. In addition, 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 to 14 mg / g, Ile 17-47 mg / g, Leu 32-82 mg / g, Lys 18-54 mg / g, Met 0.4-17 mg / g, Ph 15-38 mg / g, Pro 12-40 mg / g, Ser 15 ~ 41 mg / g, Thr 14-38 mg / g, Trp 3.8-11 mg / g, Tyr 1.9-34 mg / g, Val 21-59 mg / g are more preferable, 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 mg / g, Ile 21-40 mg / g, Leu 40- 66mg / g, Lys 22-43mg / g, Met 0.5-14mg / g, Ph 19-31mg / g, Pro 15-32mg / g, Ser 18-33mg / g, Thr 18-30mg / g, Trp 4 8.8 to 8.4 mg / g, Tyr 2.4 to 27 mg / g, and Val 27 to 48 mg / g are more preferable.

Liver hydrolyzate is known to have an effect of improving liver function, but its action on a model showing no liver damage, that is, its action on sickness behavior and its action on behavioral decline are not known at all.

As shown in Examples below, liver hydrolyzate has the effect of activating tyrosine hydroxylase (TH) in the striatum of the brain in a sickness-behavior model animal that does not show liver damage, and is depressive. Significantly improves the decrease in locomotor activity. Therefore, the liver hydrolyzate is useful as a sickness-behavior symptom-improving agent, a symptom-improving agent selected from depression, depression, mental fatigue and decreased behavior, and a tyrosine hydroxylase activator in the brain. Here, since the tyrosine hydroxylase is a rate-determining enzyme for dopamine production, it is considered that the effect of improving the depression-like decrease in locomotor activity is due to the promotion of dopamine production in the brain striatum. Therefore, liver hydrolyzate is effective for symptoms of sickness behavior such as depression, depression, mental fatigue, and decreased activity.
Here, mental fatigue is fatigue caused by social factors such as stress, and is different from physical fatigue.
Since the thickness behavior model used in the examples is a model that does not cause liver damage, it was unexpected that the liver hydrolyzate had the effect of improving the thickness behavior symptoms in such a model.

The sickness-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. Examples of the preparation for oral administration include liquid preparations, tablets, powders, fine granules, granules, capsules and the like, but liquid preparations and tablets are preferable, and liquid preparations are more preferable.

These orally-administered preparations include excipients such as lactose, mannitol, corn starch and crystalline cellulose, binders such as cellulose derivatives, gum arabic and gelatin, disintegrants such as carboxymethyl cellulose calcium, talc and magnesium stearate. Such lubricants, dissolution aids such as nonionic surfactants, flavoring agents, sweeteners, stabilizers, pH adjusters, water, ethanol, propylene glycol, glycerin and the like can be used. Further, a coating agent such as hydroxymethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, and methacrylate copolymer may be used.

In addition, other active ingredients may be added to the sickness behavior symptom improving agent of the present invention. Other active ingredients include vitamin B ₁ ; thiamine, thiamine nitrate, thiamine hydrochloride, fursultiamine, bisbenchamine, benphothiamine, thiamine disulfide, disetiamine, thiaminepropyl disulfide and derivatives _{thereof, vitamin B 2} ; riboflavin and Derivatives and their salts, vitamins B ₃ ; niacin, nicotinic acid, nicotinic acid amides and derivatives and their salts, vitamin B ₅ ; pantenol, pantothenic acid and derivatives and their salts, vitamin B ₆ ; pyridoxin and Derivatives and their salts, Vitamin B ₁₂ ; Cyanocovalamin and derivatives and their salts, other vitamins; Vitamin A, Vitamin C, Vitamin E, Vitamin K, Vitamin P, Diisopropylamine dichloroacetate, Taurine, Chondroitin sulfate, Royal jelly , Caffeine, Ukon, Maria Azami, Dandelion, Western Dandelion, Gobo, Garlic, Kiku, Western Nokogirisou, Kuchinashi, Goma, Tanana Carrot, Asparagus, Onion, Thicoli, Medicinal Salvia, Korean Azami (Artichoke), Kuco, Bean Plants of the family / Ayame family, Miyama quail, Elba de Pasarinho, Setesangria, Agamega wrinkles, tea, resveratrol, catechins, velverin, rosemary, bean extract, metformin and the like.

Further, the sickness behavior symptom improving agent and the like of the present invention can be used not only as pharmaceuticals, but also as quasi-drugs, foods for specified health use, functional foods, sports drinks, rehabilitation drinks, pet foods and the like.

The content of the liver hydrolyzate in the thickness behavior symptomatology improving agent of the present invention varies depending on the administration form, but is usually preferably 0.001 to 10% by mass, more preferably 0.001 to 5% by mass as a dry weight. .. The daily dose of the liver hydrolyzate in the sickness behavior symptomatology improving agent of the present invention is preferably 100 mg to 12000 mg, more preferably 180 mg to 6000 mg, and even more preferably 400 to 3600 mg as a dry weight. In addition, the liver hydrolyzate is preferably administered continuously for 2 days or more.

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

(1) Method For the experiment, ddY male mice weighing 28 to 32 g were used. The spontaneous momentum was ^{evaluated using a Super Mex device TM} (manufactured by Muromachi Kikai Co., Ltd.). ^{Immunohistochemical staining was analyzed by MapAnalyzer TM} (manufactured by Yamato Scientific Co., Ltd.), which can simultaneously measure the quantification and distribution of tyrosine hydroxylase (TH) levels in the striatum of mice using an antibody labeled with a fluorescent dye. (N = 4 to 6). First, water or liver hydrolyzate was orally administered, and 30 minutes later, physiological saline or concanavalin A (ConA) was intravenously administered, and the patient was fasted and fasted for 24 hours. Water or liver hydrolyzate was orally administered 1.5 hours later, and locomotor activity was measured 60 minutes later (n = 4-6).

(2) Results Figure 1 shows the AST and ALT levels of this animal model. From FIG. 1, the animal model showed no liver damage.
Spontaneous momentum was significantly reduced by administration of ConA (12.5 mg / kg, iv), and by administration of liver hydrolyzate (30,100 mg / kg, po) at the level of the control saline-administered group. (Fig. 2). The TH level in the striatum was significantly decreased in the ConA-administered group as compared with the physiological saline-administered group, and the decrease in TH level due to ConA administration was improved by the administration of liver hydrolyzate (100 mg / kg, po). (Fig. 3).
From the above results, it was found that the liver hydrolyzate improves the thickness behavior by protecting the TH expression level in the nucleus accumbens and caudate nucleus in the brain.

Table 1 shows the components and amino acid compositions contained in the liver hydrolyzate used.

Claims (1)

A human brain tyrosine hydroxylase activator containing liver hydrolyzate as an active ingredient and having a total serum protein of more than 6.5 g / dl and no liver damage.

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