CN110840873A

CN110840873A - Application of docosapentaenoic acid in preparing medicine for preventing and treating schizophrenia

Info

Publication number: CN110840873A
Application number: CN201911193896.9A
Authority: CN
Inventors: 宋采; 李舒蕊; 胡雪琼; 张永平; 张才
Original assignee: Guangdong Ocean University; Shenzhen Research Institute of Guangdong Ocean University
Current assignee: Guangdong Ocean University; Shenzhen Research Institute of Guangdong Ocean University
Priority date: 2019-11-28
Filing date: 2019-11-28
Publication date: 2020-02-28

Abstract

The invention discloses application of docosapentaenoic acid in preparation of drugs for preventing and treating schizophrenia. The invention provides a new application of docosapentaenoic acid (DPA) in preparing a medicament for preventing and/or treating schizophrenia. The invention discovers that the survival rate of lymphocytes of patients with fine differentiation can be remarkably improved by 150 mu M DPA, and the contents of 3-methyl-4-hydroxybenzene glycol, dopamine and metabolites thereof, and serotonin and metabolites thereof are obviously increased after DPA treatment; in addition, the abnormal expression of dopamine receptors DRD1, DRD2, DRD4 and serotonin receptor 5HTR1A is obviously reduced, and the level of serotonin receptor 5HTR2A is increased to a certain extent, which shows that the docosapentaenoic acid can effectively relieve the symptoms of schizophrenia, has the advantages of safety, effectiveness, no toxic or side effect and the like, and has good popularization and application prospects.

Description

Application of docosapentaenoic acid in preparing medicine for preventing and treating schizophrenia

Technical Field

The invention belongs to the technical field of medicines. More particularly, relates to the application of docosapentaenoic acid in preparing medicaments for preventing and treating schizophrenia.

Background

Schizophrenia is a serious mental disease whose pathogenesis is not clear, the clinical manifestations of schizophrenia greatly affect the sensory perception, thinking, emotion, will, behavior, cognitive function and the like of patients, and about three-fold patients cannot be treated and improved. The cause of schizophrenia is quite complex, but the most widely used at present is the neurotransmitter hypothesis, which considers that the cause of schizophrenia is an imbalance in the neurotransmitter ratio in patients, in particular an abnormality in dopamine and serotonin. Numerous studies have shown that the single-limb transmitter system in brain, especially dopamine and serotonin systems, are closely related to the normal mental activities of human body, and the disturbance of the two systems can cause various neuropsychiatric diseases such as schizophrenia, neuropathic pain, mania, anxiety, various depression, Parkinson's disease and the like.

The current clinically used drugs are mainly traditional antipsychotics (such as dopamine D)₂Receptor antagonists) and atypical antipsychotics (e.g., D)₂/5-HT_2aDual antagonists) in which conventional antipsychotics are gradually eliminated due to their tendency to cause extrapyramidal symptoms (EPS), and atypical antipsychotics are in a wide variety, but conventional drugs are relatively single in their regulation of neurotransmitters and their receptors, have clinically significant side effects, and none of them has an absolute advantage for the improvement of the overall spectrum of schizophrenia, and most of them have improvement of one of positive or negative symptoms, or have reduced side effects. The treatment of schizophrenia also brings great physical damage to patients. Therefore, a novel medicine with low toxic and side effects, quick response and wide treatment spectrum is searchedAnti-schizophrenic drugs have been the focus of research in the pharmaceutical industry worldwide.

In the field of medical technology, the technical problems solved by the substitution and modification of the substituent on the main chain or side chain and the technical effects brought by the substitution and modification are unpredictable, and the slight substitution or modification of any substituent on the main chain or side chain of the compound can cause the modified compound not to have the function before modification, and the technical effects are unpredictable even if the modified compound still has the original function. Docosapentaenoic acid (DPA) is a long-chain unsaturated fatty acid which is present in human colostrum, is a main component of human brain tissue and nerve cells, is high in DPA content in human milk and seal oil, and is deficient in fish oil and various foods. Patent document CN1233955A discloses a pharmaceutical preparation for the treatment of schizophrenia and/or tardive dyskinesia, in which oils comprising eicosapentaenoic acid (EPA) and/or Stearidonic Acid (SA) are used in amounts of more than 20%, preferably more than 40%, more preferably more than 70% by weight of the total fatty acids present (preferably of the total unsaturated fatty acids). In this patent EPA reduces schizophrenia by inhibiting the activity of phospholipase a 2. EPA (eicosapentaenoic acid) and SA (stearidonic acid) are fatty acids containing 20 and 18 carbon atoms, respectively, and in fact they have been shown to be effective in inhibiting the activity of phospholipase A2 (Finnen, Biochem Soc. Trans 1991; 19: 915). In contrast, DHA (docosahexaenoic acid) is a fatty acid containing 22 carbon atoms, and it does not inhibit phospholipase as does other fatty acids containing 22 carbon atoms. EPA has been found to be broadly effective in the treatment of schizophrenia. The EPA group was significantly better than the placebo group, whereas the DHA group was not significantly different from the placebo group (p <0.02 in both cases), and there was no significant effect of DHA in clinical studies on the treatment of schizophrenia. However, docosapentaenoic acid is not currently used in studies relating to the treatment of schizophrenic lymphocytes.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides the application of docosapentaenoic acid in preparing medicaments for preventing and treating schizophrenia, which comprises toxic and side effects of treating schizophrenia, resisting extrapyramidal reactions caused by schizophrenia medicaments and the like. Docosapentaenoic acid alleviates the symptoms of schizophrenia by improving lymphocyte survival, neurotransmitter content and aberrant expression of neurotransmitter receptors and produces no or greatly reduced extrapyramidal reactions and other lipid and carbohydrate metabolic abnormalities in the course of the improvement. Experiments show that the application of the docosapentaenoic acid alone can achieve a certain curative effect and keep very low side reaction, thereby being capable of well improving the treatment compliance.

The purpose of the invention is realized by the following technical scheme:

the invention relates to application of docosapentaenoic acid or pharmaceutically acceptable salts or prodrugs thereof in preparing medicaments for preventing and/or treating schizophrenia.

The invention also relates to application of the docosapentaenoic acid or the pharmaceutically acceptable salt or the prodrug thereof in preparing an auxiliary medicament for preventing and/or treating schizophrenia.

The docosapentaenoic acid or a pharmaceutically acceptable salt thereof or a prodrug of docosapentaenoic acid in the present invention can be obtained directly from the market or synthesized by a conventional compound synthesis method in the prior art using commercially available raw materials. The docosapentaenoic acid of the present invention may be synthesized by one of ordinary skill in the art in view of the prior art. The synthesized docosapentaenoic acid may be further purified by column chromatography, high performance liquid chromatography or crystallization.

The prodrug of docosapentaenoic acid means a substance which can be converted into docosapentaenoic acid or a salt thereof in vivo. The prodrug generally refers to a substance that, when administered by an appropriate method, undergoes a metabolic or chemical reaction in the subject to convert it to docosapentaenoic acid or a salt thereof.

The pharmaceutically acceptable salts of eicosapentaenoic acid are salts which are physiologically acceptable, especially when applied as a medicament to humans and/or mammals; comprises the salt obtained by addition reaction of docosapentaenoic acid and organic salt or inorganic salt. In a preferred embodiment, the pharmaceutically acceptable salt is a salt containing a pharmaceutically acceptable anion, and includes hydrochloride, hydramine, hydrarginia, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, rosate, tartrate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate.

In a preferred embodiment, the docosapentaenoic acid reduces schizophrenia by improving lymphocyte survival, neurotransmitter content, and/or aberrant expression of neurotransmitter receptors.

In a preferred embodiment, the application object includes, but is not limited to, animals such as humans. By "animal" in the context of the present invention is meant any animal that benefits from the improvement or reduction of loss or other deterioration of the mental system of the animal, including humans, birds (avians), bovine (bovine), canine (Canine), equine (equine), feline (feline), caprine (hicrine), wolfine (lupine), murine (murine), ovine (ovine), and porcine (porcine), and preferably domesticated animals. Animals domesticated therein include animals such as dogs, cats, birds, rabbits, guinea pigs, ferrets, hamsters, mice, gerbils, recreational horses, cows, goats, sheep, donkeys, pigs, and more exotic species fed by humans.

In a preferred embodiment, the neurotransmitter includes a metabolite of norepinephrine, dopamine or a metabolite thereof, serotonin or a metabolite thereof; the neurotransmitter receptors comprise dopamine receptors DRD1 or DRD2 or DRD4, and serotonin receptors 5HTR1A or 5HTR 2A. Experiments show that the lymphocyte survival rate of patients with seminal emission can be improved remarkably when the concentration of DPA is more than 150 mu M, and the cell survival rate is increased by 138.32%; moreover, compared with the normal group, the norepinephrine-induced metabolites 3-methyl-4-hydroxyphenyl glycol, dopamine and its metabolites, and serotonin and its metabolites in peripheral blood lymphocytes of the patients with fine resolution are all significantly reduced, and after DPA treatment, the contents of 3-methyl-4-hydroxyphenyl glycol, dopamine and its metabolites, serotonin and its metabolites are all significantly increased; in addition, compared with a normal group, the dopamine receptors DRD1, DRD2, DRD4 and the serotonin receptor 5HTR1A of the patients with fine details are remarkably increased, the serotonin receptor 5HTR2A is remarkably decreased, under the action of DPA, the abnormal expression of the dopamine receptors DRD1, DRD2, DRD4 and the serotonin receptor 5HTR1A is remarkably decreased, and the level of the serotonin receptor 5HTR2A is increased to a certain extent, so that the docosapentaenoic acid can effectively relieve the symptoms of schizophrenia, does not generate or greatly reduce extrapyramidal reactions and other lipid and sugar metabolism abnormal reactions in the improvement process, and has wide application prospects in the aspect of treating the schizophrenia.

In a preferred embodiment, the effective dose concentration of docosapentaenoic acid is 150-500. mu.M, preferably 150-200. mu.M.

The invention also relates to a pharmaceutical composition or an auxiliary pharmaceutical composition for treating schizophrenia, which comprises an effective amount of docosapentaenoic acid or a free salt or a prodrug thereof, and a pharmaceutically acceptable carrier.

Wherein said pharmaceutically acceptable carrier does not destroy the pharmaceutical activity of the docosapentaenoic acid of the present invention, is generally recognized by health professionals as being useful for this purpose and as an inactive ingredient of a medicament. A compilation of pharmaceutically acceptable carriers can be found in the handbook of Pharmaceutical excipients (handbook of Pharmaceutical excipients, 2 nd edition, edited by A.Wade and P.J.Weller; published by American Pharmaceutical Association, Washington and Pharmaceutical Press, London, 1994), and the like.

The medically acceptable carrier includes, but is not limited to: lecithin, aluminum stearate, alumina, ion exchange materials, tween or other surfactants, serum proteins, buffer substances such as phosphates, glycine, sorbic acid, water, salts, electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, magnesium silicate, mixtures of saturated fatty acid partial glycerides, and the like.

Other conventional pharmaceutical adjuvants such as binder (e.g. microcrystalline cellulose), filler (e.g. starch, glucose, anhydrous lactose and lactose beads), disintegrant (e.g. crosslinked PVP, croscarmellose sodium, low-substituted hydroxypropylcellulose), lubricant (e.g. magnesium stearate), and absorption enhancer, adsorption carrier, flavoring agent, sweetening agent, excipient, diluent, wetting agent, etc.

In one preferred embodiment, the composition is formulated in the form of a liquid or solid formulation. Preferably, the phenylpyruvic acid and the pharmaceutical composition thereof can be prepared into tablets, capsules, pills, powder, granules, syrups, solutions, injections, sprays, aerosols or patches according to actual needs.

Dododopentenic acid and compositions thereof may be prepared according to conventional methods in the art and may be administered by the gastrointestinal or parenteral route.

Preferably, the parenteral administration route is selected from injection, respiratory administration, dermal administration, mucosal administration or luminal administration. The administration route may be oral, sublingual, intramuscular or subcutaneous, intravenous, etc. Wherein the parenteral medicament can be selected from injection, spray, aerosol, patch, etc.; the preparation for gastrointestinal administration can be selected from tablet, capsule, powder, granule, pill, solution or syrup.

In a preferred embodiment, the docosapentaenoic acid as the only active ingredient accounts for 0.0001% to 90%, preferably 0.001% to 50%, further preferably 0.01% to 20%, and more preferably 0.1% to 10% of the total weight of the formulation.

In another preferred embodiment, in the composition of the present invention, docosapentaenoic acid is used as one of the active ingredients to constitute the composition together with other active ingredients. Wherein the docosapentaenoic acid is 0.0001-50% (preferably 0.01-20%, more preferably 0.1-10%) of the total weight as one of the active ingredients. The other active ingredients can be chlorpromazine, haloperidol or clozapine which are commonly used as anti-schizophrenia medicines.

Compared with the prior art, the invention has the beneficial effects that:

experiments show that the lymphocyte survival rate of patients with seminal emission can be improved remarkably when the concentration of DPA is more than 150 mu M, and the cell survival rate is increased by 138.32%; moreover, compared with the normal group, the norepinephrine-induced metabolites 3-methyl-4-hydroxyphenyl glycol, dopamine and its metabolites, and serotonin and its metabolites in peripheral blood lymphocytes of the patients with fine resolution are all significantly reduced, and after DPA treatment, the contents of 3-methyl-4-hydroxyphenyl glycol, dopamine and its metabolites, serotonin and its metabolites are all significantly increased; in addition, compared with a normal group, the dopamine receptors DRD1, DRD2, DRD4 and the serotonin receptor 5HTR1A of the patients with fine details are remarkably increased, the serotonin receptor 5HTR2A is remarkably decreased, under the action of DPA, the abnormal expression of the dopamine receptors DRD1, DRD2, DRD4 and the serotonin receptor 5HTR1A is remarkably decreased, and the level of the serotonin receptor 5HTR2A is increased to a certain extent, so that the docosapentaenoic acid can effectively relieve the symptoms of schizophrenia, does not generate or greatly reduce extrapyramidal reactions and other lipid and sugar metabolism abnormal reactions in the improvement process, and has wide application prospects in the aspect of treating the schizophrenia. Moreover, the docosapentaenoic acid is safe and easy to obtain, has small addition amount, high physiological activity, and has the advantages of safety, convenience, effectiveness and the like.

Drawings

FIG. 1 is a graph of the effect of DPA on the survival of peripheral blood lymphocytes in normal humans.

FIG. 2 is a graph of the effect of DPA on the survival of peripheral blood lymphocytes from patients with seminal plasma.

FIG. 3 is a graph of the improvement of 150 μ M DPA in the levels and ratios of denervating neurotransmitters and their metabolites in peripheral blood lymphocytes from schizophrenic patients.

FIG. 4 is a graph of the improvement of dopamine receptor mRNA expression in peripheral blood lymphocytes from schizophrenic patients with 150 μ M DPA.

Detailed Description

The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.

Unless otherwise indicated, reagents and materials used in the following examples are commercially available.

[ cells used in the present invention ]: the peripheral venous blood of a schizophrenia patient is collected and separated in a third civil hospital in Zhanjiang city of Guangdong province, and the used culture medium is RPMI 1640 culture medium, 10% FBS and 1% double antibody, the parameters of the culture box are 37 ℃, and the concentration of carbon dioxide is 5%.

TABLE 1 Main reagents

Name of reagent	Manufacturer of the product
		Human peripheral blood mononuclear cell separation liquid	Tianjin City tertiary ocean biological product science and technology Limited liability company
n-3DPA	MCE Corp Ltd
		RPMI 1640 medium	Gibco, USA
Fetal bovine serum	Gibco, USA
		Double antibody	Gibco, USA
Trizol	Nanjing Nodezan Biotech Co
		Reverse transcription kit	Nanjing Nodezan Biotech Co., Ltd
SYBR Green dyes	Nanjing Nodezan Biotech Co., Ltd
		CCK8	Japan Donglian chemical Co Ltd
EDTA-NA2	Beijing Solaibao Tech & ltTech & gt Ltd
		Perchloric acid	Tianjin city Tongxin chemical plant
Heptane sulfonic acid sodium salt	Michelin chemical reagents Ltd
		Dipotassium hydrogen phosphate	Tianjin Fuchen chemical reagent Co Ltd
Citric acid	Tianjin Beichen Square reagent factory
		Anhydrous sodium acetate	Guangdong Guanghua science & technology Ltd
Triethylamine	Xilong chemical corporation
		HPLC methanol	Guangzhou chemical reagent plant
0.45 μm filter membrane	Guangzhou Bi Xi Luo Tech Co Ltd

TABLE 2 Main instruments

Name of instrument	Manufacturer of the product
		Inverted microscope	Olympus Corp
Fluorescent quantitative PCR instrument	Bio-Rad Ltd
		High-speed refrigerated centrifuge	Beckman Co Ltd
Enzyme-linked immunosorbent assay (ELISA) instrument	Bio-Tek Co
		Ultramicro nucleic acid quantitative instrument	DeNovix, USA
High performance liquid chromatography	Agilent, USA

Example 1

1. And (3) treating and culturing the cells:

venous blood was collected from the schizophrenic patients and the normal control group in a fasting state at about 6 am using EDTA anticoagulated vacuum blood collection tubes. Then, the mixture was centrifuged at 1800 rpm for 10min at 4 ℃ to remove plasma, the same volume of 1640 medium was added to the remaining blood cells, and then a fraction of twice the volume of the blood cells (3: 1 ratio of fraction 1 to fraction 2) was added slowly to a 50mL centrifuge tube, and then the blood cells were added slowly. Then centrifuging for 30min at the rotating speed of 500g/min, taking the upper layer white annular lymphocyte to a centrifuge tube of 15mL, adding 1640 culture medium to 13mL of cleaning cells, and centrifuging for 10min at the rotating speed of 400g/min at the temperature of 4 ℃. The supernatant was discarded and the cells washed repeatedly once. The cell number was recorded by a cell counter and lymphocytes with a cell viability of 95% or more were collected for further culture.

2. DPA toxicity by CCK8 method:

the obtained normal human lymphocytes are prepared to have a concentration of 2 × 10⁶Each ml of cell suspension was seeded in 96-well plates, 100 μ l per well, with 5 duplicate wells per set. The test was divided into CT group (lymphocytes of normal persons), SZ group (lymphocytes of schizophrenia patients), and DPA drug treatment group (DPA concentration of 10, 20, 30, 40, 50, 100, 150, 200. mu.M). After inoculating cells, placing the 96-well plate in an incubator to balance for 3 hours, adding DPA with different concentrations according to groups when the cell state is stable and the parameters of the incubator are 37 ℃ and the carbon dioxide concentration is 5%, and continuously culturing for 48 hours to detect the toxicity of the DPA to the cells. During detection, 10% of CCK8 reagent is added into each hole in volume fraction for reaction for 4 hours, the OD value of each hole is measured at the wavelength of 450nm, and the cell viability is calculated.

3. Determination of DPA concentration:

the obtained lymphocytes of the patient and the normal person are made into cells with the concentration of 2 multiplied by 10⁶Each ml of cell suspension was seeded in 96-well plates, 100 μ l per well, with 5 duplicate wells per set. The lymphocytes of normal persons were set as normal control group (CT group), and the lymphocytes of patients with fine fraction were set as drug-treated group (DPA concentration of 10, 20, 30, 40, C,50. 100, 150, 200 μ M) and untreated group (schizophrenic patient group, SZ group). After inoculating cells, placing the 96-well plate in an incubator to balance for 3 hours, wherein the parameters of the incubator are 37 ℃, the carbon dioxide concentration is 5%, and when the cell state is stable, adding or not adding DPA with different concentrations according to groups, and continuously culturing for 48 hours, and then detecting the cell viability. A10% volume fraction of CCK8 reagent was added to each well for 4 hours, and the OD value of each well was measured at a wavelength of 450nm, and the cell viability was calculated. The concentration with the highest cell viability was taken as the drug treatment concentration.

4. Detection of monoamine neurotransmitters in peripheral blood lymphocytes:

preparing a tissue lysate: weighing disodium ethylene diamine tetraacetate (EDTA-Na)₂)0.01861g (weighing error is controlled within 1%), 50mL of ultrapure water is added, 5mL of perchloric acid is slowly added, and finally the volume is made 100mL with ultrapure water. Preparing perchloric acid precipitator: 27.3864g of dipotassium hydrogen phosphate and EDTA-Na were weighed₂0.0744g (weighing error controlled within 1%) was dissolved in ultrapure water and the volume was adjusted to 100 mL. Collecting the separated lymphocytes 2X 10⁶Adding 100 mu L of tissue lysate into a 1.5mL centrifuge tube, fully and uniformly blowing to break cells and release neurotransmitter, and placing on ice for 10 minutes to fully crack. Centrifuging at 14000r/min for 15 minutes at 4 ℃, sucking the supernatant into a 1.5mL centrifuge tube, and mixing the supernatant with the supernatant according to a volume fraction ratio of 1: 1 adding perchloric acid precipitant, mixing uniformly and carrying out ice bath for 10 minutes. Centrifuge at 14000r/min for 15 minutes at 4 ℃ and carefully aspirate the supernatant using a 1mL syringe. The supernatant was filtered through a 0.45 μ M aqueous membrane into a liquid phase dedicated vial for use. Preparing an aqueous mobile phase: 10.507g of citric acid, 4.1015g of anhydrous sodium acetate, 0.101125g of sodium heptanesulfonate and EDTA-Na are weighed₂0.18612g, was dissolved in 1L of ultrapure water, and 0.69mL of triethylamine was added thereto. The aqueous mobile phase was filtered with 0.45 μ M aqueous membrane, methanol was filtered with 0.22 μ M organic membrane, and the two mobile phases were degassed in an ultrasonic cleaner for 5min to remove air bubbles. The chromatographic column adopts a C18 column, and the volume fraction ratio of the mobile phase is citric acid-sodium acetate buffer solution: methanol (87: 13), flow rate 1.0mL/min, sample size 20. mu.L, FLD detector, detection wavelength: transmitted waveA length of 330nm and an excitation wavelength of 280 nm.

5. PCR method for detecting neurotransmitter receptor expression in peripheral blood lymphocytes:

collecting the separated lymphocytes 5X 10⁵Adding the mixture into a 1.5mL centrifuge tube, adding 500 mu L Trizol into the centrifuge tube, blowing and fully mixing the mixture by using a pipette gun, and cracking the mixture for 10min at normal temperature. Then 200. mu.L of chloroform was added thereto, followed by vigorous shaking for 15 seconds to emulsify the whole mixture into white, and the mixture was allowed to stand at room temperature for 10 min. Centrifuging at 12000g/min for 15min at 4 ℃. Taking the supernatant, putting the supernatant into a new 1.5mL centrifuge tube, adding isopropanol with the same volume as the supernatant, standing the mixture for 30min at room temperature, centrifuging the mixture for 10min at the temperature of 4 ℃ at the rotating speed of 12000g/min, and discarding the supernatant. 0.5mL of 75% ethanol was added, the sample was washed several times by gentle inversion, then centrifuged at 12000g/min for 10min at 4 ℃ and the supernatant carefully decanted off one side of the tube, and this step was repeated 3 times. Air-drying mRNA in the centrifuge tube in a clean bench, adding 20 μ L sterile DEPC water to dissolve mRNA precipitate, and obtaining mRNA solution. mRNA concentration, OD, was measured using a trace nucleic acid quantifier₂₆₀/OD₂₈₀Repeat 3 times with 1.8 to 2.0, and average. The concentration of mRNA was adjusted to 700ng in a 20. mu.l reaction system, and the reaction solution was added to synthesize cDNA by reverse transcription. The cDNA was diluted 15-fold by volume, and 6. mu.L of SYBR fluorescent dye, 0.48. mu.L of primer and 3.5. mu.L of template cDNA 2. mu. L, DEPC water were added to a fluorescent quantitative PCR tube, and the content of neurotransmitter receptor was measured by a real-time fluorescent quantitative PCR instrument.

6. Data processing:

data processing statistical analysis was performed using GraphPad Prism 7. The mean. + -. standard error (X. + -. SEM) of the data for the cell fraction, and the mean. + -. standard error (X. + -. SD) of the remaining data. Data were analyzed using t-test, with P <0.05 indicating statistical significance.

7. Analysis of results

(1) As can be seen from fig. 1, DPA at all concentrations was not toxic to normal human peripheral blood lymphocytes.

(2) As can be seen from FIG. 2, the lymphocyte survival rate of the patients with seminal emission (SZ group) is lower than that of the normal human lymphocytes, which indicates that the lymphocytes of the patients with schizophrenia are damaged to a certain extent, and when the DPA concentration reaches 150 μ M, the lymphocyte survival rate of the patients with schizophrenia can be improved very obviously, the cell survival rate is increased by 138.32%, which is the same as that of the 200 μ M group, and reaches a very significant (P < 0.01) level compared with the untreated group, so that 150 μ M is selected as the optimal concentration for drug treatment.

(3) As can be seen from fig. 3, the content of Noradrenaline (NE) in peripheral blood lymphocytes of the patients with sperm fraction did not change significantly compared to the normal control group (CT), but the metabolite 3-methyl-4-hydroxyphenylglycol (MHPG) thereof decreased significantly by 24.58%, and the content of MHPG increased by 18.20% after 150 μ M DPA treatment. The content of excitatory neurotransmitters Dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) and their metabolites, dihydroxyphenyl acetic acid (DOPAC) and 5-oxindole acetic acid (5-HIAA), were significantly reduced by 46.40%, 70.94%, 85.28% and 86.34%, respectively. After 150 μ M DPA treatment, the content rose by 78.77%, 230.74%, 474.95% and 613.82%, respectively. Wherein, P<0.05,**P<0.01,***P<0.001,****P<Ct group 0.0001 vs;^#P<0.05,^##P<sz group 0.01vs.

(4) As can be seen from fig. 4, the dopamine receptors DRD1, DRD2, DRD4 and serotonin receptor 5HTR1A of the patients with fine fractions were increased to different degrees, 36.55%, 14.75%, 305.52% and 220.64% respectively, and reached significance (P < 0.05) compared to the normal Control (CT). In addition to 5HTR2A, aberrant expression of neurotransmitter receptors was significantly improved (P < 0.05) by 150 μ M DPA, with decreases of 25.50%, 11.39%, 47.43%, and 56.46%. Compared with the normal control group, the serotonin receptor 5HTR2A of the patients with the fine scores is reduced by 73.65 percent, and the serotonin receptor 5HTR2A level is improved to a certain extent after the treatment of 150 mu M DPA.

The above results indicate that it is possible to develop DPA as a new drug to improve schizophrenia levels. DPA can relieve the pathological state of peripheral lymphocytes of schizophrenia patients by improving the neurotransmitter content of lymphocytes and the abnormal expression of neurotransmitter receptors, can effectively relieve the symptoms of schizophrenia and does not generate or greatly reduce extrapyramidal reactions and other lipid and sugar metabolism abnormal reactions in the improvement process, and has wide application prospect in the aspect of treating schizophrenia.

Example 2

Tablets containing the following mass fraction components may be produced in a conventional manner:

example 3

Granules containing the following mass fraction components may be produced in a conventional manner:

wherein the composition is prepared from docosapentaenoic acid and chlorpromazine in a weight ratio of 1.5: 1.

Example 4

Capsules containing the following components may be produced in a conventional manner:

example 5

Microspheres comprising the following components may be produced in a conventional manner:

90 wt% of the pharmaceutical composition

5 wt% of chitosan

Hyaluronic acid 5 wt%

Wherein the composition consists of docosapentaenoic acid and haloperidol in a weight ratio of 1: 1.

Example 6

Oral liquids containing the following components may be produced in a conventional manner:

docosapentaenoic acid 1 wt%

49.5 wt% of glucose

49.5 wt% of deionized water

Example 7

10 wt% of the pharmaceutical composition

45 wt% of glucose

45 wt% of deionized water

Wherein the composition is prepared from docosapentaenoic acid and clozapine in a weight ratio of 2: 1.

The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, so that any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention are within the scope of the technical solution defined by the claims of the present invention, unless departing from the technical solution of the present invention.

Claims

1. Application of docosapentaenoic acid or pharmaceutically acceptable salt or prodrug thereof in preparing medicines for preventing and/or treating schizophrenia.

2. Application of docosapentaenoic acid or pharmaceutically acceptable salt or prodrug thereof in preparing adjuvant drugs for preventing and/or treating schizophrenia.

3. Use according to claim 1 or 2, wherein the prodrug of docosapentaenoic acid is a substance which is convertible in vivo to docosapentaenoic acid or a salt thereof.

4. The use according to claim 1 or 2, wherein the pharmaceutically acceptable salt is a salt comprising a pharmaceutically acceptable anion, including a hydrochloride, hydrabamate, hydrarginate, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, rosate, tartrate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate.

5. Use according to claim 1 or 2, characterized in that the docosapentaenoic acid reduces schizophrenia by improving the survival rate of lymphocytes, neurotransmitter content and/or abnormal expression of neurotransmitter receptors.

6. The use of claim 5, wherein said neurotransmitter comprises a metabolite of norepinephrine, dopamine or a metabolite thereof, serotonin or a metabolite thereof; the neurotransmitter receptors comprise dopamine receptors DRD1 or DRD2 or DRD4, and serotonin receptors 5HTR1A or 5HTR 2A.

7. Use according to claim 1 or 2, wherein the effective dose concentration of docosapentaenoic acid is 150 to 500 μ Μ.

8. A pharmaceutical composition or adjuvant pharmaceutical composition for the treatment of schizophrenia comprising an effective amount of docosapentaenoic acid or a free salt or prodrug thereof and a pharmaceutically acceptable carrier.

9. The composition of claim 8, wherein the composition is formulated as a liquid formulation or a solid formulation.

10. The composition of claim 8, wherein the docosapentaenoic acid is present as an active ingredient in an amount of from 0.0001% to 90% by weight of the total formulation.