CN116236507B - Application of Akkermansia muciniphila in the relief and treatment of schizophrenia - Google Patents
Application of Akkermansia muciniphila in the relief and treatment of schizophrenia Download PDFInfo
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- 241000702462 Akkermansia muciniphila Species 0.000 title claims abstract description 38
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- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 description 1
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- PLDUPXSUYLZYBN-UHFFFAOYSA-N Fluphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 PLDUPXSUYLZYBN-UHFFFAOYSA-N 0.000 description 1
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- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 1
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- URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
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- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 description 1
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A61P3/04—Anorexiants; Antiobesity agents
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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Abstract
本发明提供嗜黏蛋白阿克曼氏菌在缓解和/或治疗精神分裂症中的应用。本发明人意外地发现，嗜黏蛋白阿克曼氏菌，特别是保藏编号为CGMCC No.22793的嗜黏蛋白阿克曼氏菌AM06和CGMCC No.22794的嗜黏蛋白阿克曼氏菌AM02，可有效地改善精神分裂症的认知功能障碍，且当与抗精神病药联用时，可有效地抑制抗精神病药引起的体重增加。
The present invention provides the use of Akkermansia muciniphila in alleviating and/or treating schizophrenia. The inventors unexpectedly found that Akkermansia muciniphila, especially Akkermansia muciniphila AM06 with a deposit number of CGMCC No. 22793 and Akkermansia muciniphila AM02 with a deposit number of CGMCC No. 22794, can effectively improve cognitive dysfunction in schizophrenia, and when used in combination with antipsychotic drugs, can effectively inhibit weight gain caused by antipsychotic drugs.
Description
Technical Field
The invention relates to application of akkermansia muciniphila, in particular to application of akkermansia muciniphila in relieving and/or treating schizophrenia.
Background
Schizophrenia (schizophrenia) is a common severe mental disorder of unknown etiology. Many diseases occur in young and young, and there are often disturbances in perception, thinking, emotion, behavior, etc., usually unconscious and intellectual disturbances. The disease course is prolonged, which accounts for more than half of the inpatients in the psychiatric department, and about half of the patients end up being mental disabilities, which brings serious burden to society, patients and families.
In the diagnostic classification and criteria of DSM-5 psychotic disorders released in 2013, diseases such as schizophrenia are first classified by lineage disorders, referred to as schizophrenic spectrum and other psychotic disorders, including schizophrenic (personality) disorders, delusional disorders, transient psychotic disorders, schizophreniform disorders, schizophrenia, schizoaffective disorders (bipolar/depressive), substance/drug-induced psychotic disorders, psychotic disorders due to other somatic diseases, stress disorders associated with other psychotic disorders, stress disorders due to other somatic diseases, unspecified stress disorders, other specific schizophrenic spectrum and other psychotic disorders, unspecified schizophrenic spectrum and other psychotic disorders. These psychotic disorders often require treatment with an antipsychotic agent.
The first generation antipsychotics (typical antipsychotics) refer to antipsychotics that act mainly on the central D2 receptor, including ① phenothiazines chlorpromazine, thioridazine, perphenazine, fluphenazine and its long-acting agents, trifluoperazine, etc., ② thioxanthenes chlorthioxanthenes and its long-acting agents, trifluothioxanthenes and its long-acting agents, telden, etc., ③ butyrylbenzenes such as haloperidol and its long-acting agents, pentafluorodide, etc., ④ benzamides such as sulpiride, etc. Phenothiazines are also classified as high potency drugs such as perphenazine, trifluoperazine, and low potency drugs such as chlorpromazine, thioridazine (potency classification applies to the first generation drugs). Such drugs have been widely used in clinical treatment of various psychosis, mainly in the treatment of various psychotic symptoms since the 50 th century of 20.
After many years of market for the first generation antipsychotics, new second generation antipsychotics have emerged, including clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and the like. Compared with phenothiazines and other medicines, the compounds have higher 5-hydroxytryptamine (5-HT) 2 receptor blocking effect, namely Dopamine (DA) -5-hydroxytryptamine receptor antagonists (SDAs), and have more selectivity on the action on the peripheral system of the brain than on the action on the striatum system.
The most obvious side effects caused by current psychotic disorder treatments are metabolic abnormalities such as weight gain and extrapyramidal reactions. The most challenging aspect in treating schizophrenic patients is the metabolic syndrome, which is more difficult to treat or reverse than other side effects caused by current therapies, especially in the long term, which makes the condition more complex. There is an urgent need to develop psychotropic drugs with greater safety.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides an application of akkermansia muciniphila in relieving and/or treating schizophrenia. The inventors have unexpectedly found that akkermansia muciniphila, in particular akkermansia muciniphila AM06 with the accession number of CGMCC No.22793 and akkermansia muciniphila AM02 with the accession number of CGMCC No.22794, can effectively improve cognitive dysfunction of schizophrenia and can effectively inhibit weight gain caused by antipsychotics when used in combination with antipsychotics.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
The invention firstly provides application of akkermansia muciniphila in preparation of medicines for relieving and/or treating schizophrenia, wherein the akkermansia muciniphila is at least one of akkermansia muciniphila AM06 with a preservation number of CGMCC No.22793 or akkermansia muciniphila AM02 with a preservation number of CGMCC No. 22794.
In some embodiments, the akkermansia muciniphila is one, two, or more of a live bacterium, an inactivated bacterium with intact morphological structure, an inactivated bacterium with incomplete morphological structure, a lysate of a thallus, a bacterial culture supernatant.
In some embodiments, the dosage form of the medicament comprises a pill, tablet, granule, capsule, oral liquid, or tube feeding formulation. The subject to which the medicament is administered is a human or animal.
The invention also provides a pharmaceutical composition comprising akkermansia muciniphila and other antipsychotics;
The other antipsychotic agent comprises at least one of phenothiazine antipsychotic agent, thioxanthene antipsychotic agent, butyryl benzene antipsychotic agent, benzamide antipsychotic agent and dopamine-5-hydroxytryptamine receptor antagonist.
Preferably, the akkermansia muciniphila is at least one of akkermansia muciniphila AM06 with the preservation number of CGMCC No.22793, akkermansia muciniphila AM02 with the preservation number of CGMCC No.22794 or akkermansia muciniphila standard strain ATCC BAA-835.
Preferably, the antipsychotic is clozapine, i.e. the pharmaceutical composition is a combination of clozapine and at least one of Alkermansia muciniphila AM06 with the preservation number of CGMCC No.22793, alkermansia muciniphila AM02 with the preservation number of CGMCC No.22794 or Alkermansia muciniphila standard strain ATCC BAA-835.
The invention also provides the use of at least one of the mucin-philin Acremonium AM06 with the preservation number of CGMCC No.22793, the mucin-philin Acremonium AM02 with the preservation number of CGMCC No.22794, or the mucin-philin Acremonium standard strain ATCC BAA-835 for preparing the medicine for reducing or reducing the weight increase caused by taking the antipsychotic medicine.
In some embodiments, the antipsychotic agent is clozapine.
The invention has the beneficial effects that:
The inventors have unexpectedly found that mucin-philin akkermansia, in particular mucin-philin akkermansia AM06 with the preservation number of CGMCC No.22793 and mucin-philin akkermansia AM02 with the preservation number of CGMCC No.22794, can effectively improve cognitive dysfunction of schizophrenia, and when used in combination with an antipsychotic agent such as clozapine, not only significantly increases the efficacy of the antipsychotic agent, but also can inhibit weight gain caused by long-term use of the antipsychotic agent and improve the quality of life of schizophrenic patients.
Drawings
FIG. 1 is a graph showing colony characteristics of Acremonium muciniphilum AM02 obtained by culturing in the method of example 1;
FIG. 2 is a graph showing the characteristics of colonies of Acremonium muciniphilum AM06 obtained by culturing in the method of example 1;
FIG. 3 is a microscopic view of the Acremonium muciniphilum AM02 obtained by culturing in the method of example 1 after gram staining;
FIG. 4 is a microscopic view of the mucin-philin Acremonium AM06 cultured by the method of example 1 after gram staining.
Strain preservation information
1)AM02:
The classification and naming are AKKERMANSIA MUCINIPHILA, the preservation unit is China general microbiological culture Collection center, the preservation address is North Star Xiyu No.1, no. 3 in the Beijing Kogyo area, the preservation date is 2021, 6 months and 28 days, and the preservation number is CGMCC No.22794.
2)AM06:
The classification and naming are AKKERMANSIA MUCINIPHILA, the preservation unit is China general microbiological culture Collection center, the preservation address is North Star Xiyu No.1, no. 3 in the Beijing Kogyo area, the preservation date is 2021, 6 months and 28 days, and the preservation number is CGMCC No.22793.
In the present application, "more" means three or more.
Detailed Description
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
EXAMPLE 1 cultivation of Acremonium muciniphilum
Alkerman's mucin-philic bacteria were streaked onto GlcNAc heme BHA plates and incubated anaerobically for 3 days. Colony morphology, staining characteristics, size, sphere shape, distribution, etc. were observed.
Colony characteristics-Achroman muciniphila, after 3 days of culture on the above medium, presents round raised, clean-edged, opaque, white, non-uniform-sized colonies, see FIGS. 1 and 2.
The microscope morphology of Alkermansia muciniphila was gram-negative bacteria, oval, single or chain-like, see FIGS. 3 and 4.
And (3) selecting a single bacterial colony, inoculating the bacterial colony into 10mL of BHI broth added with GlcNAc for fermentation culture for 48 hours (the temperature is 37 ℃), inoculating the bacterial liquid into 1L of BHI broth added with GlcNAc after the culture is finished, continuing to perform expansion culture for 24 hours, centrifuging the obtained bacterial liquid to precipitate at the rotating speed of 16000 Xg, centrifuging for 30min, removing the supernatant, and collecting the precipitate to obtain the mucin-philin Acinetobacter mud. Respectively culturing to obtain mucin-philin Acremonium AM02, AM06 and BAA-835.
EXAMPLE 2 preparation of Acremonium muciniphilum viable bacteria solution, inactivated bacteria solution and lysate
Corresponding AKK bacteria AM02, AKK bacteria AM06 and AKK bacteria ATCC BAA-835 were prepared according to the fermentation culture method of example 1.
(1) The strain was streaked onto GlcNAc heme BHA plates and incubated anaerobically for 3 days at 37 ℃.
(2) And (3) enrichment, namely selecting a single colony from the step (1), inoculating the single colony into BHI broth added with GlcNAc, carrying out enrichment culture for 48 hours at the temperature of 37 ℃, and storing the obtained bacterial liquid for later use.
(3) And (3) performing viable count on the bacterial liquid prepared in the step (2), diluting the bacterial liquid to 10 9 CFU/mL with physiological saline, and preserving the bacterial liquid for later use.
(4) And (3) the AKK bacteria inactivating bacteria liquid is prepared by taking a proper amount of bacteria mud, adding physiological saline according to the proportion of the bacteria mud to the physiological saline (m: v) =1:10, and stirring for 5-20min under the condition of 1000rpm by using a stirrer to uniformly disperse the bacteria. 100ml of the dispersed bacterial liquid is taken and placed in a sterile three-necked round bottom flask (the bacterial liquid is ensured not to adhere to the inner wall of the flask as much as possible). Placing the three-neck round bottom flask on a heating disc of a magnetic stirrer, placing a sterile stirrer, inserting a temperature electrode, setting the rotating speed to be 300-500rpm, and heating for 30min at the temperature of 70 ℃ to obtain the inactivated strain of the akkermansia muciniphila.
(5) AKK bacteria lysate, which is prepared by ultrasonic disruption. Taking 5mL of AKK bacterial live solution of 10 9 CFU/mL prepared in the step (3), carrying out ultrasonic instrument pyrolysis for 30 minutes, on for 10 seconds and Off for 10 seconds, enabling the system pyrolysis bacterial efficiency to reach 99%, centrifuging at 6000rpm, 10 minutes and 4 ℃ after pyrolysis, filtering by a 0.22 mu m filter head, and collecting filtrate, thus preparing AKK bacterial lysate of 10 9 CFU/mL, and preserving for later use.
Example 3 pharmacodynamic experiments in model of Alkermansia muciniphila therapeutically Zhuo Xiping (MK 801) induced schizophrenia
(1) Experimental design and method
Modeling and administration of animals:
SPF-class SD rats, females, 2 months of age, 100. 100 SD rats were randomly divided into a blank group, a model group, a positive drug group (clozapine 1 mg/kg), an AM02 viable bacteria group (10 9 CFU/d), an AM02 inactivated bacteria group (10 9 cell/d), an AM06 viable bacteria group (10 9 CFU/d), an AM06 inactivated bacteria group (10 9 cell/d), an AM06 cell lysate group (1 mL/d), an AM06 culture supernatant group (1 mL/d), an AM06 viable bacteria group (10 9 CFU/d) and a clozapine (1 mg/kg) combined group, 10 each. All but the blank groups of rats were given intraperitoneal injection of MK801 (0.6 mg/kg), 1 time per day for 21 consecutive days. The corresponding medicine is administrated by lavage of each rat during molding, 1 time a day, and 21 consecutive days.
Detecting the index:
Assessment of ataxia and behavior of the plates rats were assessed for ataxia and behavior of the plates 30min after the last administration. Ataxia was evaluated 1 time per 10min using a 4-level scale with reference to Hoffman scoring criteria, and notch behavior was evaluated with reference to Sams-Dodd scoring criteria. The double-blind method is used for 5 grades of scoring, average score is taken for statistics, and the higher the scoring is, the heavier the symptom is.
Morris water maze experiment, namely, on the 17 th day after administration, carrying out water maze training on the rats, setting 4 water inlet points in different quadrants, recording the time required by the rats to climb on a platform, and continuously carrying out 4 days. The platform was removed on the day of end of dosing, the swimming time in the target quadrant of the rat was recorded, and the swimming speed was calculated, repeated 4 times, and the average was taken.
(2) Experimental results
The results of the respective detection indexes are shown in table 1. The ataxia and sculpting scores increased significantly (p < 0.01) for the model group compared to the blank group, and the swimming time and swimming speed in the target quadrant decreased significantly (p < 0.01). While each akkermansia muciniphila dosing group can significantly reduce ataxia and notch score (p <0.05 or p < 0.01) to varying degrees and significantly increase swimming time and swimming speed (p <0.05 or p < 0.01) in the target quadrant. And compared with the positive medicine group and the AM06 live bacteria single acting group respectively, the AM06 live bacteria plus positive medicine combination group can improve the ataxia degree and the engraving degree of animals (p < 0.05) more remarkably, and the swimming time (p < 0.05) in the target quadrant is increased remarkably. That is, the combination group had a synergistic effect relative to the individual effect group.
Over 85% of schizophrenic patients may develop cognitive dysfunction in early stages of the disease, and improving cognitive dysfunction in schizophrenic patients can improve the quality of life and restore social function of the patients, which is of great importance to the treatment of the disease. The results show that the living bacteria, the inactivated bacteria, the thallus lysate and the culture supernatant of the AM02 and the AM06 can obviously improve the cognitive dysfunction of the schizophrenic model animal, and when the mucin-philin Acremonium and the clozapine are combined, the improvement effect of the clozapine on the cognitive function is obviously increased, and the synergistic effect is generated.
Table 1 various detection indexes (mean±sd, n=10)
Note that the difference significance p <0.05 is shown compared to the model group, and the difference significance p <0.01 is shown compared to the model group;
a Indicating significant differences p <0.05 compared to the positive drug group.
b Indicating significant differences p <0.05 compared to the AM06 live bacteria alone acting group.
Example 4 Alkermansia muciniphila for alleviating mental illness drug clozapine-induced weight gain Experimental (1) Experimental design and method
Modeling and administration of animals:
SPF-class SD rats, females, 2 months of age, 50. 50 SD rats were randomly assigned to a blank group, a model group, an AM02 viable bacteria group (10 9 CFU/one), an AM06 viable bacteria group (10 9 CFU/one), and a BAA-835 viable bacteria group (10 9 CFU/one), 10 per group. Rats in all groups except the blank group were given clozapine at 5mg/kg intragastrically 1 time per day on day 1 of the experiment, with clozapine at 25mg/kg starting on day 5 and continuing to administer clozapine 1 time per day until week 8 to induce a model of metabolic disorder. The corresponding drug was administered by lavage to each rat 1 time a day for 8 weeks while molding.
Detecting the index:
Animals were tested for body weight at weeks 0, 4, 6, 8 of the experiment.
(2) Experimental results
Table 2 body weights of rats of each group (mean±sd, n=10)
Note that * represents a difference significance p <0.05 compared to the model group, ** represents a difference significance p <0.01 compared to the model group;
# Indicating significant difference p <0.05 compared to BAA-835 viable bacteria group, ## indicating significant difference p <0.01 compared to BAA-835 viable bacteria group.
As shown in table 2, the body weight of the model animals increased significantly from week 4 (p < 0.01) compared to the blank group. While each of the mucin-philin-administered groups significantly reduced clozapine-induced weight gain (p <0.05 or p < 0.01), the effects of AM02 and AM06 on clozapine-induced weight gain were significantly better than BAA-835 (p < 0.05).
The most obvious side effects caused by current psychotic disorder treatments are metabolic abnormalities, such as weight gain, and affecting patient compliance with medication. The above results demonstrate that akkermansia muciniphila is effective in inhibiting weight gain due to prolonged administration of an antipsychotic agent such as clozapine.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
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