CN109223785A - Kynurenic acid or derivatives thereof improves chronic psychiatric in preparation stress application in related pathologies damage medicine - Google Patents
Kynurenic acid or derivatives thereof improves chronic psychiatric in preparation stress application in related pathologies damage medicine Download PDFInfo
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- CN109223785A CN109223785A CN201811269300.4A CN201811269300A CN109223785A CN 109223785 A CN109223785 A CN 109223785A CN 201811269300 A CN201811269300 A CN 201811269300A CN 109223785 A CN109223785 A CN 109223785A
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- kynurenic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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Abstract
Improving chronic psychiatric in preparation the invention discloses kynurenic acid or derivatives thereof stress application in related pathologies damage medicine.Compared with the existing technology, improving chronic psychiatric in preparation the invention discloses kynurenic acid or derivatives thereof stress application in related pathologies damage medicine, the present invention confirmed by correlative study, it is oral give kynurenic acid play the role of good improvements chronic psychiatric stress correlation human communication disorders, maincenter inflammatory conditions, spleen immune disorder.
Description
Technical field
Improving chronic psychiatric in preparation the invention discloses kynurenic acid or derivatives thereof stress related pathologies damage medicine
Application in object, belongs to technical field of new application of medicine.
Background technique
Chronic psychiatric psychological stress is generally existing in the crowd of modern society, be found with a variety of diseases (such as mental disease,
Coronary heart disease, inflammatory bowel disease) disease incidence increase or recurrence it is closely related.Research shows that chronic psychiatric psychological stress can cause
Maincenter and periphery endocrine-inflammation-immune response imbalance, reduce, gastrointestinal dysfunction with depressed, ability of learning and memory
Etc. systemic abnormal symptom.With further speeding up for rhythm of life, chronic social psychological behavior is relevant social and economical
Burden will be further exacerbated by, and be found effective intervention means and be had become science and social concern urgently to be resolved.
More and more evidences shows that the change of endogenous small molecule metabolites under chronic psychiatric psychological stress participates in
The occurrence and development of multiple organ dysfunction exception.It is different that balance by restoring metabolic pathway or its network can contribute to improvement mood
Often, multiple pathology links such as blood vessel endothelium injury, intestinal inflammatory, so that being effective against chronic psychiatric stress bring health damage
Evil.Therefore, correct the regulating strategy of endogenous small molecule metabolic imbalance improve chronic psychiatric stress be in terms of related pathologies process
It has potential application.
Kynurenic acid is internal kynurenin in kynurenine aminotransferase (kynurenine
Aminotransferase, KAT) effect under metabolite, document report its can act on n-methyl-D-aspartic acid
Receptor (N-methyl-D-aspartate receptor, NMDAR), alpha 7 nicotinic type cholinergic recepter (α 7nicotine
Cholinergic subtype alpha 7receptor, α 7nAChR) and g protein coupled receptor (G-protein coupled
Receptor 35, GPR35), there is certain neural activity and immunoregulation effect.Current basis and clinical research show
Kynurenic acid level occurs abnormal under a variety of Central Nervous System Diseases states.The important physiological disposition feature of one of kynurenic acid
It is poor to the permeability of physiologic barrier, and the kynurenic acid in peripheral circulation can not pass through blood-brain barrier.It is necessary based on drug
The efficient traditional understanding for being distributed in intracerebral and adjusting maincenter pathogenesis, current report are focused on being administered by intracerebral injection
Or increases the method for its precursor kynurenine levels and adjust its intracerebral level to adjusting the diseases such as cognitive disorder.
Summary of the invention
Goal of the invention: improving chronic psychiatric in preparation object of the present invention is to open kynurenic acid or derivatives thereof stress phase
The application in pathology damage drug is closed, the present invention is confirmed by correlative study, has good improvement after kynurenic acid is oral
Chronic psychiatric stress related human communication disorders, maincenter inflammatory conditions, spleen immune disorder effect.
Technical solution: to achieve the above object of the invention, the invention adopts the following technical scheme:
Kynurenic acid or derivatives thereof improves chronic psychiatric in preparation stress application in related pathologies damage medicine.
The kynurenic acid chemical name is 4- oxyquinoline -2- formic acid (4-hydroxyquinoline-2-carbo
Xylic acid), molecular formula C10H7NO3, molecular weight 189.17g/mol, chemical structural formula is as follows:
The improvement chronic psychiatric stress related pathologies damage, refer to improve chronic psychiatric stress-induced social activity hide and
The immunologic derangement at the positions such as brain and spleen.
The drug is using kynurenic acid as drug made by single component.
Alternatively, the drug is with kynurenic acid or derivatives thereof for active constituent, in addition pharmaceutically acceptable auxiliary
Material, made drug.
The dosage form of the drug be conventional tablet, conventional capsule agent, oral solution, syrup, particle, dripping pill, oral disnitegration tablet,
Sustained release tablets, controlled release tablet, Duracaps, Extencap, injection or infusion solution.
Pharmaceutically acceptable auxiliary material of the present invention refers to that the various routines needed for being added when preparing different dosage forms are auxiliary
Material, such as diluent, binder, disintegrating agent, glidant, lubricant, corrigent, inclusion material, adsorbent material etc. are with routine
Formulation method is prepared into any common preparation.
Technical effect: compared with the existing technology, the invention discloses kynurenic acids or derivatives thereof to improve slowly in preparation
Property Psychomotor test Battrey related pathologies damage medicine in application, the present invention confirms that kynurenic acid has well by correlative study
Improvement chronic psychiatric stress related human communication disorders, maincenter inflammatory conditions, spleen immune disorder effect.
Detailed description of the invention
Fig. 1: kynurenic acid to chronic social activity stress after mouse social avoidance behaviour influence, Control is normal right
According to a group mouse, CSDS is chronic social stress group mouse, CSDS+KA be chronic social activity stress in give KA mouse, CSDS only gives
Give blank solvent；The result shows that KA can obviously increase mouse in central social region residence time (figure A, #p < 0.05,
Compared with CSDS group) and number (figure B, #p < 0.05, compared with CSDS group).
Fig. 2: kynurenic acid to chronic social activity stress in mouse brain proinflammatory monocytes infiltration influence, Control
For normal control group mice, CSDS is chronic social stress group mouse, CSDS+KA be chronic social activity stress in give KA mouse,
CSDS is only given blank solvent；The result shows that KA can significantly reduce hippocampus Ly6ChiProinflammatory monocytes infiltration (figure A,
CD11b+Ly6ChiCell divides group to scheme；Scheme B, Ly6ChiThe statistical chart of proinflammatory monocytes ratio, p < 0.05 *).
Fig. 3: influence of the kynurenic acid to the mouse maincenter inflammatory mediator disorder of chronic social stress-induced, Control
For normal control group mice, CSDS is chronic social stress group mouse, CSDS+KA be chronic social activity stress in give KA mouse,
CSDS is only given blank solvent；The result shows that KA can significantly reduce hippocampus inflammatory factor Ccl2 (figure A, #p < 0.05, with
CSDS group compares) and Il6 (figure B, #p < 0.05, compared with CSDS group) mRNA level in-site.
Fig. 4: influence of the kynurenic acid to the mouse spleen immunocyte infiltration of chronic social stress-induced, Control
For normal control group mice, CSDS is chronic social stress group mouse, CSDS+KA be chronic social activity stress in give KA mouse,
CSDS is only given blank solvent；The result shows that KA is to CD4+The ratio of T cell has no significant effect (figure A), but can dramatically increase
Chronic social activity stress CD8 in mouse spleen+T cell (figure B, p < 0.05 *) and reduce NK1.1 cell ratio (figure B, * * * p <
0.001)。
Specific embodiment
Combined with specific embodiments below, the present invention is described in more detail.
Embodiment 1: adjustment effect of the kynurenic acid to chronic social stress-induced mouse social activity avoidance behaviour
(1) material: C57BL/6J mouse (male, 8 week old) after adapting to environment 1 week, is randomly divided into three groups, is positive respectively
Normal control group (Control group, n=6), chronic social Stress model group (CSDS group, n=8) and kynurenic acid intervention group
(CSDS+KA group, n=8).Every afternoon 16:00 point by receive stress mouse be placed in attack mouse side, receive 10 minutes
Attack, is then transferred into the same mouse cage other side 24 hours；1 time is repeated above operation daily to amount to 10 days；Normal control
Only single cage raising stress without receiving social activity for group mouse.Intervention group mouse in daily stress preceding stomach-filling in 0.5 hour give dog urine quinoline
Quinoline acid (20mg/kg adjusts pH with 1M NaOH and is dissolved in pure water), by daily single.It is commented in the social experiment of progress in the 11st day
Valence.
(2) experiment is hidden in social activity: experiment is divided into two stages, and empty small mouse cage with holes is placed in the society of spacious field by the first stage
Region is handed over, mouse to be measured is put into, travels freely it in social spacious field, records track in its 150 seconds and its in social distance zone
Domain residence time then takes out mouse and small mouse cage with holes, after cleaning wiping again by the small mouse cage with holes equipped with attack mouse
Social region (same position) is put back to, same C57 mouse is placed again into social spacious field, records the movement rail in its 150 seconds
Mark and its in social region residence time, compares the difference of mouse movement track in 150s twice, while calculating social region
The residence time of (interaction zone) and number.
(3) data analysing method: experimental data is indicated with Mean ± SD, and uses GraphPad Prism 6
(GraphPad Software Inc.) software is analyzed and processed result, and data are analyzed using One-way ANOVA,
P < 0.05 indicates that data difference has statistical significance.
Embodiment 2: kynurenic acid is to the adjustment effect to chronic social stress-induced mouse maincenter inflammatory conditions
(1) material: specific method is the same as embodiment 1.
(2) separation of brain immunocyte and flow cytometry have investigated CD45 in mouse brainhiCD11b+Ly6ChiMonokaryon is thin
The infiltration of born of the same parents: after mouse is put to death, removing blood through left ventricle perfusion 20mL ice PBS solution, until liver whitens, careful separation brain
Tissue, is drawn off being placed in the nonreactive RPMI1640 culture medium of ice.It is subsequently transferred in 5mL glass homogenizer, each brain
3mL ice PBS solution is added in tissue to be homogenized, homogenate, which complements to be made with the mixing of 100%Percoll solution after 7mL, to be contained
The cell suspension (10mL) of 30%Percoll, uniform speed slow adds to above 2mL 70%Percoll separating liquid, in 18 DEG C of conditions
Lower 500g is centrifuged 30min, and 30% and the turbidity screen at 70%Percoll interface are slowly carefully removed from suction pipe, can be obtained
Lymphocyte populations.Streaming antibody is carried out at 100 μ L cell suspensions with dye solution resuspension after being washed twice with PBS solution to incubate
It educates.1 μ L anti-CD16/32 antibody is added into 100 μ L cell suspensions, closing 10min is protected from light in ice bath.It is straight without washing
The corresponding specific streaming antibody (anti-CD45-PE, anti-CD11b-APC, anti-Ly6C-FITC) of addition is connect, ice bath is protected from light
It is incubated for 45min, is then washed 3 times (400g is centrifuged 5min under the conditions of 4 DEG C) with ice PBS solution, finally with 4% paraformaldehyde weight
It is outstanding to fix, and in next day upper machine testing.Suitable channel is selected to carry out flow cytometer showed, related stream data uses FlowJo software
Analysis.
(3) the PCR analysis of hippocampus inflammatory factor mRNA: the hippocampus of mouse unilateral side is taken out into centrifuge tube, is added
Ice-bath ultrasonic is homogenized after 1.0mLTrizol, and the chloroform of 250 μ L is added after standing, is mixed by inversion 20s, quiet after fully emulsified
Set 10min；12 under the conditions of 4 DEG C, 000g is centrifuged 15min, produces colorless supernatant liquid (300 μ L) into new centrifuge tube；Add
Enter isometric isopropanol, continues to be mixed by inversion 20s, stand 10min；12,000g is centrifuged 10min under the conditions of 4 DEG C；Carefully fall
Supernatant out leaves the precipitating of centrifugation bottom of the tube；It is slowly added to 75% ethyl alcohol of ice (preparation of RNase-free water) 1mL, overturns washing
Bottom precipitation；12 under the conditions of 4 DEG C, 000g is centrifuged 5min, pours out supernatant, is placed at room temperature for 10min and 75% ethanol solution is waited to wave
Hair dissolves bottom precipitation with 10 μ L RNase-free water, can be placed on -80 DEG C until completely dissolved and saves or carry out concentration mensuration.
According to Reverse Transcriptase kit specification by 500ng mRNA reverse transcription at cDNA, then according to SYBR GREEN real-time quantitative PCR
Operation instructions require to be operated.Using Gapdh as reference gene, 2 are used-ΔΔCTPurpose in method semi-quantitative analysis difference sample
The relative different of gene expression.
Embodiment 3: adjustment effect of the kynurenic acid to chronic social stress-induced mouse spleen immunologic derangement
(1) material: specific method is the same as embodiment 1.
(2) separation of spleen immunocyte and flow cytometry: mouse spleen is placed in 70 μm of cell screen clothes, is added
2mL PBS solution is added slowly to Lympholyte-M monokaryon using 5mL syringe piston crush and grind spleen at cell suspension
In cell separating liquid (2mL, v/v 1:1), 20min is centrifuged with the speed of 1200g under room temperature, slowly removes centre with suction pipe
White opacity cell, can be obtained lymphocyte populations, be washed twice with PBS solution.If there is residual red blood cells that red blood cell can be used
Lysate removal.It is resuspended with streaming dyeing liquor and carries out streaming antibody incubation at 100 μ L cell suspensions, method is the same as embodiment 2.
Claims (5)
1. kynurenic acid or derivatives thereof improves chronic psychiatric in preparation stress application in related pathologies damage medicine.
2. application according to claim 1, which is characterized in that the improvement chronic psychiatric stress related pathologies damage, be
The social activity that finger improves chronic psychiatric stress-induced is hidden and the immunologic derangement of brain and spleen position.
3. application according to claim 1, which is characterized in that it is single that the drug, which is with kynurenic acid or derivatives thereof,
Drug made by one ingredient.
4. application according to claim 1, which is characterized in that the drug is with kynurenic acid or derivatives thereof for work
Property ingredient, in addition pharmaceutically acceptable auxiliary material, made drug.
5. application according to claim 1, which is characterized in that the dosage form of the drug be conventional tablet, conventional capsule agent,
Oral solution, syrup, particle, dripping pill, oral disnitegration tablet, sustained release tablets, controlled release tablet, Duracaps, Extencap, injection or
Infusion solution.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811269300.4A CN109223785A (en) | 2018-10-29 | 2018-10-29 | Kynurenic acid or derivatives thereof improves chronic psychiatric in preparation stress application in related pathologies damage medicine |
| PCT/CN2019/111867 WO2020088270A1 (en) | 2018-10-29 | 2019-10-18 | Application of kynurenic acid or derivative thereof in preparing drug for improving pathological damages associated with chronic psychological stress |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811269300.4A CN109223785A (en) | 2018-10-29 | 2018-10-29 | Kynurenic acid or derivatives thereof improves chronic psychiatric in preparation stress application in related pathologies damage medicine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020088270A1 (en) * | 2018-10-29 | 2020-05-07 | 中国药科大学 | Application of kynurenic acid or derivative thereof in preparing drug for improving pathological damages associated with chronic psychological stress |
| CN117045652A (en) * | 2023-08-28 | 2023-11-14 | 中国科学技术大学 | Application of kynurenic acid in preparation of medicine for relieving and/or treating bulimia nervosa |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104379136A (en) * | 2012-06-05 | 2015-02-25 | 国际干细胞公司 | Method of prevention of neurological diseases |
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| BR112015017535A2 (en) * | 2013-01-22 | 2020-02-04 | Vistagen Therapeutics Inc | dosage forms and therapeutic uses of 1-4-chloroquinurenine |
| CN106659762A (en) * | 2014-05-06 | 2017-05-10 | 西北大学 | Combinations of nmdar modulating compounds |
| WO2018205935A1 (en) * | 2017-05-09 | 2018-11-15 | 浙江大学 | Method for treating depression, and pharmaceutical composition |
| CN109223785A (en) * | 2018-10-29 | 2019-01-18 | 中国药科大学 | Kynurenic acid or derivatives thereof improves chronic psychiatric in preparation stress application in related pathologies damage medicine |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104379136A (en) * | 2012-06-05 | 2015-02-25 | 国际干细胞公司 | Method of prevention of neurological diseases |
Non-Patent Citations (3)
| Title |
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| 王铭维: "《心身疾病临床荟萃》", 30 November 2015, 中国医药科技出版社 * |
| 韩娇等: "犬尿喹啉酸与精神分裂症", 《国际精神病学杂志》 * |
| 马中富等: "《急诊医学》", 30 April 2007, 军事医学科学出版社 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020088270A1 (en) * | 2018-10-29 | 2020-05-07 | 中国药科大学 | Application of kynurenic acid or derivative thereof in preparing drug for improving pathological damages associated with chronic psychological stress |
| CN117045652A (en) * | 2023-08-28 | 2023-11-14 | 中国科学技术大学 | Application of kynurenic acid in preparation of medicine for relieving and/or treating bulimia nervosa |
| CN117045652B (en) * | 2023-08-28 | 2024-05-28 | 中国科学技术大学 | Application of kynurenic acid in preparation of medicine for relieving and/or treating bulimia nervosa |
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| WO2020088270A1 (en) | 2020-05-07 |
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