JP2016003187A - Schizophrenia therapeutic agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a schizophrenia therapeutic agent having improved biological safety.SOLUTION: A schizophrenia therapeutic agent includes Bifidobacterium bacteria as an active ingredient.

Description

  The present invention relates to a therapeutic agent for schizophrenia comprising a Bifidobacterium genus bacterium as an active ingredient.

Schizophrenia is a mental illness that shows various symptoms such as hallucinations and delusions. The incidence is as high as about 1 in 100, and it can be said that this is one of the diseases that everyone can experience.
Schizophrenia symptoms are roughly classified into positive and negative symptoms.
Positive symptoms refer to symptoms such as hallucinations, delusions, attenuating thoughts, tension symptoms, hyperactivity, and bizarre behavior, mainly appearing in the acute phase of schizophrenia.
Negative symptoms, on the other hand, refer to symptoms such as autism, catalepsy (passive attitude taken passively), and emotional bluntness, and are symptoms that appear mainly during the schizophrenia depletion period (non-patented). Reference 1).

  As the pathology of schizophrenia, the dopamine excess hypothesis, glutamate lowering hypothesis, neurodevelopmental disorder hypothesis, and the like have been proposed.

The dopamine excess hypothesis is a hypothesis that dopaminergic nervous system runaway in the brain is the cause of schizophrenia.
The dopamine hypothesis was the most popular hypothesis for the cause of schizophrenia, but studies using the postmortem brain of schizophrenia patients have reported cases that did not reach the hypothesis. It is falling.
However, it is thought that the pathological condition is that the dopaminergic nervous system is out of control in the brains of schizophrenic patients through animal experiments and brain imaging studies.
Therefore, therapeutic agents that suppress excessive enhancement of the dopaminergic nervous system are also used in the treatment of schizophrenia (Non-patent Document 1).

  Several characteristics of schizophrenia that cannot be explained by the dopamine excess hypothesis have been pointed out in recent years. Under such circumstances, the hypothesis supported is the glutamic acid lowering hypothesis. From animal experiments and genomic studies, evidence that links schizophrenia and reduced function of the glutamate nervous system has accumulated, and now it is one of the leading hypotheses replacing the dopamine hypothesis (Non-patent Document 1).

The neurodevelopmental disorder hypothesis explains the etiology of schizophrenia in two stages.
The neurodevelopmental disorder hypothesis is that the first stage is a factor that impairs neurodevelopment during the fetal period (first hit), and that adolescent sexual maturity and neurotransmitter abnormalities overlap as the second stage (second hit). This is a hypothesis of developing ataxia (Non-patent Document 1).
As a factor causing the first hit in this hypothesis, overexpression of brain-derived nerve growth factor (BDNF) has been reported (Non-patent Document 2).

  Thus, although various hypotheses have been proposed for the pathology of schizophrenia, the current situation is that it is not clear.

Conventionally, in the treatment of schizophrenia, dopamine D2 receptor blockers such as haloperidol, which is a first generation typical antipsychotic agent, dopamine D2 receptors, such as olanzapine, which is a second generation atypical antipsychotic agent, and serotonin 2A receptor blockers have been used.
However, side effects such as obesity, hyperglycemia, and diabetic ketoacidosis have been reported for haloperidol and the like, and for olanzapine and the like (Non-Patent Documents 3 to 7).

  By the way, Bifidobacterium is a Gram-positive obligate anaerobic gonococcus, commonly called Bifidobacterium, and is widely known to have an intestinal action that restores the balance of the intestinal flora. . Bifidobacterium genus is not only an intestinal regulating action, but also prevents / improves / treats metabolic disorders associated with aging (Patent Document 1), prevents or improves arthritis (Patent Document 2), and improves constipation. (Patent Document 3) and the like are known to exhibit various physiological activities.

In addition, among Bifidobacterium bacteria, Bifidobacterium longum ATCC BAA-999 has a preventive action against allergic diseases in infants (Patent Document 4), and alleviates hay fever. It has been reported that there is a possibility of contribution (Non-Patent Document 8).
However, it has never been known that Bifidobacterium has a therapeutic action for schizophrenia.

JP 2014-55194 A JP 2012-158568 A JP 2012-158561 A JP 2014-65669 A JP 2011-544523 A JP 2010-152387 A

Clinical Study 2004 November issue, 2004 Gifu Pharmaceutical University Bulletin 54, 61-62, 2005 Schizophrenia treatment and patient description. Guide to Diseases and Drugs 2003, Vol. 54, pages 287-304. 2003 The American Journal of Psychiatry, 160, 1209-1222, 2003 Neuropsychopharmacology, Vol. 28, No. 8, pp. 1400-1411, 2003 Diabetes Care, 27, 596, 2004 Clinical Psychopharmacology, Vol. 8, No. 12, 2151-2164, 2005 Applied and Environmental Microbiology, Vol. 74, No. 21, pages 6814-6817, 2008 Parkinson's Diseases: Diagnostics and Clinical Management (2002), Parkinson's Diseases (Diagnostics and Clinical Management), 2002 Pharmacology Biochemistry and Behavior, Vol. 39, pp. 699-703, 1991. Pharmacology Biochemistry and Behavior

As described above, antipsychotics such as haloperidol and olanzapine are useful for the treatment of schizophrenia, but have side effects and require careful use.
Therefore, the problem to be solved by the present invention is to provide a therapeutic agent for schizophrenia that is highly safe for a living body.

As a result of intensive research efforts, the present inventors have found for the first time that Bifidobacterium bacteria have a therapeutic effect on schizophrenia.
As mentioned above, there are many unclear points about the pathology of schizophrenia, and there is no knowledge that enterobacteria such as Bifidobacterium are useful for the treatment of schizophrenia, so this discovery It was unexpected.

  That is, this invention which solves the said subject is a schizophrenia therapeutic agent which uses a Bifidobacterium genus bacterium as an active ingredient.

  Foods containing Bifidobacterium have been confirmed to be safe from more than 30 years of food experience. Therefore, the therapeutic agent for schizophrenia of the present invention is effective in the treatment of schizophrenia, but has almost no side effects and is highly safe.

The therapeutic agent for schizophrenia of the present invention is preferably used for improving positive symptoms of schizophrenia.
As shown in the test examples described later, the Bifidobacterium bacterium that is an active ingredient of the therapeutic agent for schizophrenia of the present invention exhibits a high improvement effect on the positive symptoms of schizophrenia.
Therefore, the therapeutic agent for schizophrenia of the present invention is particularly useful for improving positive symptoms of schizophrenia.

In the present invention, Bifidobacterium longum ATCC BAA-999 can be preferably used as a bacterium belonging to the genus Bifidobacterium.
Bifidobacterium longum ATCC BAA-999 has an excellent therapeutic effect on schizophrenia.

  The therapeutic agent for schizophrenia of the present invention has almost no side effects even when taken and is highly safe. Moreover, the therapeutic agent for schizophrenia of the present invention is particularly effective in improving positive symptoms of schizophrenia.

The figure showing the result of a test example. The bar graph which shows the total of the frequency | count of the standing | starting action which occurred in 1 minute from 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, and 60 minutes after administering apomorphine hydrochloride, respectively. The figure showing the result of a test example. Line graphs showing the number of rising actions that occurred in 1 minute from 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, and 60 minutes after administration of apomorphine hydrochloride are shown.

  Next, a preferred embodiment of the present invention will be described in detail. However, the present invention is not limited to the following preferred embodiments, and can be freely changed within the scope of the present invention.

“Treatment” in the present invention includes alleviation (amelioration) of symptoms and treatment of a disease.
ADVANTAGE OF THE INVENTION According to this invention, the therapeutic effect of schizophrenia can be acquired by producing or ingesting the Bifidobacterium bacterium which is an active ingredient on a daily basis, hardly producing a side effect.

  In the present invention, Bifidobacterium can be used by separating from various samples including Bifidobacterium, and commercially available strains and deposited strains can also be used.

  Bifidobacterium belonging to the genus Bifidobacterium which is an active ingredient in the present invention can be used without particular limitation, and can be used as Bifidobacterium longum or Bifidobacterium indium. Phantis (Bifidobacterium infantis), Bifidobacterium animalis (Bifidobacterium animalis), Bifidobacterium bifidoum (Bifidobacteria bifedium), Bifidobacterium blebet ) And Bifidobacteria And the like can be exemplified beam shoe cathodic Tenu error Tam (Bifidobacterium pseudocatenulatum).

  Specifically, Bifidobacterium longum ATCC BAA-999, Bifidobacterium breve ATCC 15700, Bifidobacterium infantis ATCC 15697, etc. may be used as the genus Bifidobacterium in the present invention. it can.

  These strains are generally available from the American Type Culture Collection (address 12301 Parklawn Drive, Rockville, Maryland 20852, United States of America).

  Bifidobacterium longum ATCC BAA-999 is also commercially available from specialized suppliers, for example from Morinaga Milk Industry, Japan under the trademark BB536.

  In a preferred embodiment of the present invention, Bifidobacterium longum ATCC BAA-999 is used as the Bifidobacterium.

The therapeutic agent for schizophrenia of the present invention can be administered to mammals including humans.
The administration form may be any form that allows the Bifidobacterium to reach the intestine, and either oral administration or parenteral administration may be selected according to the patient's symptoms and the like.

The therapeutic agent for schizophrenia of the present invention can be appropriately formulated into a predetermined dosage form according to the administration method.
As a dosage form of the therapeutic agent for schizophrenia of the present invention, in the case of oral administration, Bifidobacterium is provided as a solid preparation such as powder, granule, tablet, capsule, etc. in the form of lyophilized powder. It is also possible to coat the freeze-dried powder of Bifidobacterium genus with oil or the like and provide it in the form of a solution such as a solution, syrup, suspension, emulsion, etc. .
In addition, enteral administration and parenteral administration are also possible. For parenteral administration, for example, suppositories, sprays and the like can be mentioned.
Formulation can be appropriately performed by a known method according to the dosage form.

At the time of formulation, only the active ingredient may be formulated, or a formulation carrier may be blended as appropriate.
When a pharmaceutical carrier is blended, the content of the active ingredient in the therapeutic agent for schizophrenia of the present invention is usually 0.01 to 30% by mass, preferably 0.1 to 10% by mass.

In addition, the content of Bifidobacterium in the therapeutic agent for schizophrenia (CFU / g: CFU represents Coloy forming units) is usually 1 × 10 ⁶ to 1 × 10 ¹² CFU / g, preferably 1 It is * 10 < ⁷ > -5 * 10 < ¹¹ > CFU / g.

As the preparation carrier, various conventional organic or inorganic carriers can be used depending on the dosage form.
For example, as a carrier in the case of a solid preparation, excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents and the like can be mentioned.

  Examples of excipients include sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbit; starch derivatives such as corn starch, potato starch, α-starch, dextrin and carboxymethyl starch; crystalline cellulose, hydroxypropylcellulose, hydroxypropyl Cellulose derivatives such as methylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium; gum arabic; dextran; pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium magnesium metasilicate; phosphate derivatives such as calcium phosphate; And carbonate derivatives thereof; and sulfate derivatives such as calcium sulfate.

  Examples of the binder include gelatin, polyvinyl pyrrolidone, and Magrogol in addition to the above excipients.

  Examples of the disintegrant include, in addition to the above excipients, chemically modified starch or cellulose derivatives such as croscarmellose sodium, sodium carboxymethyl starch, and crosslinked polyvinylpyrrolidone.

  Lubricants include: talc; stearic acid; stearic acid metal salts such as calcium stearate and magnesium stearate; colloidal silica; waxes such as bee gum and gallow; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; Carboxylic acid sodium salts such as sodium sulfate; sulfates such as sodium sulfate; leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid and silicic acid hydrate; starch derivatives and the like .

  Examples of the stabilizer include paraoxybenzoic acid esters such as methyl paraben and propyl paraben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; acetic anhydride; sorbic acid and the like.

  Examples of the flavoring agent include sweeteners, acidulants, and fragrances.

  Examples of the carrier in the case of a solution for oral administration include a solvent such as water and a flavoring agent.

The dose of the Bifidobacterium genus varies depending on the dosage form of the therapeutic agent for schizophrenia, patient's symptoms, age, etc., but is usually 2 × 10 ⁶ CFU / kg body weight or more per day, preferably 2 × 10 ^7. ˜2 × 10 ⁹ CFU / kg body weight can be used as a guide. The administration can be performed once or several times a day, and the administration period is preferably continued for several days or more.

The therapeutic agent for schizophrenia of the present invention is preferably used for improving positive symptoms of schizophrenia.
Here, positive symptoms of schizophrenia are symptoms that mainly appear in the acute phase of schizophrenia, and hallucinations, hallucinations, hallucinations, delusions, confusion, attenuating thoughts, tension symptoms, hyperactivity, strange behaviors and abnormalities It refers to symptoms such as involuntary movements.

In addition, as shown in the test examples described later, Bifidobacterium bacteria are particularly useful for improving symptoms caused by excessive enhancement of the dopaminergic nervous system.
Therefore, the present invention is particularly preferably used for amelioration of symptoms caused by excessive enhancement of the dopaminergic nervous system.

  Here, symptoms caused by excessive enhancement of the dopaminergic nervous system include hallucinations, hallucinations, hallucinations, delusions, confusion, tension symptoms, hyperactivity, strange behavior, and abnormal involuntary movements.

<Test example>
Next, a test example is shown and the therapeutic effect of the schizophrenia by Bifidobacterium is demonstrated. In this test example, Bifidobacterium longum ATCC BAA-999 was tested for its effect to improve the positive symptoms of schizophrenia.

  Positive symptoms of schizophrenia are symptoms that appear mainly in the acute phase of schizophrenia, and hallucinations, hallucinations, hallucinations, delusions, confusion, attenuated thinking, tension symptoms, hyperactivity, strange behavior, and abnormal involuntary movements Say the symptoms. It is widely known that dopamine hypersecretion, that is, excessive enhancement of the dopaminergic nervous system is observed in the brain of patients who develop positive symptoms (Non-patent Document 1).

On the other hand, apomorphine is a dopamine receptor agonist and is used as a therapeutic agent for Parkinson's disease whose pathological condition is a decrease in dopamine production in the brain. And it is known that apomorphine induces symptoms such as abnormal involuntary movement, confusion, hallucination, hallucination, and hallucination by excessively enhancing the dopaminergic nervous system (Non-patent Document 9).
In other words, apomorphine causes a neurological reaction in the brain similar to that of schizophrenic patients, and induces symptoms similar to the positive symptoms of schizophrenia.

  For these reasons, the positive behavior of schizophrenia is generally modeled on the standing behavior induced by the administration of apomorphine to mice (non-patented). Document 10, Patent Documents 5 and 6).

Therefore, in this test example, the effect of improving the positive symptoms of schizophrenia was evaluated by observing the effect of repeated oral administration of Bifidobacterium longum ATCC BAA-999 on apomorphine-induced standing behavior using mice. Went by.
Hereinafter, details of this test example will be described.

(1) Experimental material [1. Animal used]
In this test example, 4-week-old ddY male mice (Japan SLC) were used.

[2. Drugs used]
Apomorphine hydrochloride solution (0.05 mg / mL) for subcutaneous administration was prepared by dissolving apomorphine hydrochloride (Sigma Aldrich) in physiological saline (Otsuka Pharmaceutical).

A cell sample for oral administration (1 × 10 ⁹ CFU / 0.2 mL) is obtained by dissolving Bifidobacterium longum ATCC BAA-999 (trademark BB536, Morinaga Milk Industry) in physiological saline (Otsuka Pharmaceutical). Prepared.

(2) Test method After pre-breeding the mice for 4 to 7 days in an almost constant environment (temperature 22 ± 2 ° C., humidity 55 ± 10%) in a 12-hour light-dark cycle (lights from 8 am to 8 pm) One animal was put in each cage, and the test breeding was carried out for 2 weeks.

During the test breeding period, the prepared bacterial cell sample was orally administered once a day at 0.2 mL (1 × 10 ⁹ CFU). In the control group, 0.2 mL of physiological saline was orally administered.

One day after the end of the two-week test breeding period, the prepared apomorphine hydrochloride solution was subcutaneously administered at 10 mL (0.5 mg) per kg of mouse weight and transferred to the observation cage.
From 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, and 60 minutes after administration of apomorphine hydrochloride, the number of rising behaviors that occurred per minute was measured.

(3) Results Table 1 and FIGS. 1 and 2 show the number of rising behaviors of the mouse measured by the above method. The Mann-Whitney U test was used for the significant difference test.

  From Table 1 and FIG. 1, the mice that were orally administered the bacterial cell samples during the test breeding period tended to have a lower total number of rising behaviors induced by apomorphine hydrochloride than the mice in the control group. I understand.

  In particular, in 1 minute 10 minutes after the administration of apomorphine hydrochloride, it was found that the mice that had been orally administered with the bacterial cell sample had a significantly lower number of rises per minute than the mice in the control group (Table 1). 1 and FIG. 2).

  From this result, it was found that Bifidobacterium longum ATCC BAA-999 has an action of suppressing the rising behavior induced by apomorphine.

As described above, apomorphine is a dopamine receptor agonist and induces the rising behavior of mice by excessively enhancing the dopaminergic nervous system.
Therefore, from the results of this test example, it was found that Bifidobacterium longum ATCC BAA-999 is useful for improving symptoms caused by excessive enhancement of the dopaminergic nervous system.

Further, as described above, apomorphine-induced standing behavior using mice is used as a model for positive symptoms of schizophrenia.
Therefore, it was revealed in this test example that Bifidobacterium longum ATCC BAA-999 has an effect of improving positive symptoms of schizophrenia.

  From the above, it was found that the therapeutic agent for schizophrenia of the present invention containing Bifidobacterium as an active ingredient is useful for improving symptoms caused by excessive enhancement of the dopaminergic nervous system.

  Moreover, it turned out that the therapeutic agent for schizophrenia of this invention is useful for improvement of the positive symptom of schizophrenia.

  And since improvement of the positive symptom of schizophrenia is indispensable in the treatment of schizophrenia, it turned out that the therapeutic agent for schizophrenia of this invention is useful for the treatment of schizophrenia.

The present invention can provide a highly safe therapeutic agent for schizophrenia without side effects.

Claims (3)

A therapeutic agent for schizophrenia comprising Bifidobacterium as an active ingredient. The therapeutic agent for schizophrenia according to claim 1, which is used for improving positive symptoms of schizophrenia. The schizophrenia therapeutic agent according to claim 1 or 2, wherein the Bifidobacterium genus bacterium is Bifidobacterium longum ATCC BAA-999.