Application of xanthohumol substance in preparation of microglial cell selective polarization preparation

Abstract

The invention belongs to the technical field of medicines, and particularly relates to application of a xanthohumol substance in preparation of a microglial cell selective polarization preparation, the xanthohumol substance is xanthohumol or a xanthohumol derivative, and microglial cells are selectively polarized to M2 type. Experiments prove that when PolyI: C induces activation of microglial cells, expression of M2 type microglial cell surface markers YM is reduced, while after the microglial cells are subjected to xanthohumol pretreatment and then subjected to PolyI: C stimulation, activation of the microglial cells induced by PolyI: C is reduced, expression of the M2 type microglial cell surface markers YM is increased, activation of the microglial cells induced by PolyI: C is reduced, and activation of the microglial cells induced by PolyI: C is reduced. Therefore, Xn can inhibit inflammatory response by adjusting activated microglial cells to be polarized to M2.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and particularly relates to an application of a xanthohumol substance in the preparation of a microglia selective polarization preparation. Background Art

[0002] Schizophrenia, abbreviated as SZ, is a severe mental illness. Studies have shown that SZ is related to immune system disorders. In recent years, people have been exploring the relationship between immunity, inflammation and SZ, which is crucial for the development of new diagnostic and treatment methods.

[0003] Inflammation may be one of the triggering factors of mental illness. Clinical studies have shown that the levels of inflammatory factors in the peripheral blood of first-episode untreated patients are increased. Peripheral inflammation is closely related to the immune response of the central nervous system. Inflammatory factors in the peripheral blood can induce blood-brain barrier cells to produce cytokines, leading to immune activation of the central nervous system. There is a significant inflammatory response in the central nervous system of SZ patients, such as increased levels of inflammatory factors and leukocytes in the cerebrospinal fluid, and increased activation of microglia and lymphocytes. However, overactivated microglia secrete a large amount of cytokines and cytotoxic substances, causing neuronal damage. A large amount of evidence shows that excessive microglia activation is one of the important pathological mechanisms of abnormal brain structure and function in SZ patients.

[0004] The polarization of microglia after stress plays a key role in alleviating the inflammatory response of the central nervous system and promoting the repair of nerve cells. The two subtypes of microglia, M1 and M2, play both opposing and unified roles after central nervous system injury. Typical M1 microglia release proinflammatory factors and express CD16 and CD68 molecules, while M2 microglia secrete anti-inflammatory factors and express molecules such as arginase 1, CD206 and chitinase 3-like protein 3, which is also known as YM. Under pathological conditions of the central nervous system, the increase of M2 microglia can provide neuroprotection and promote neural repair and remodeling. Regulating the polarization of microglia to M2 may be an effective strategy for the treatment of SZ.

[0005] At present, the substances that promote microglia to polarize to M2 type mainly include IL-4, IL-13, transforming growth factor-β, etc. These substances can help clear pathogens in the early stage of inflammation, but they can easily cause excessive polarization of microglia. M2 microglia promote the synthesis of extracellular matrix during tissue repair. If this repair process is excessive, it may lead to the formation of fibrosis and scar tissue. In addition, if there is a pathogen infection, excessive M2 polarization may inhibit the body's immune response, making it difficult to completely eliminate the pathogen. This may lead to the persistence or recurrence of infection, posing a long-term threat to the health of the central nervous system.

[0006] In summary, there is an urgent need to provide a preparation that affects the selective polarization of microglia. Summary of the invention

[0007] The purpose of the present invention is to provide an application of xanthohumol substances in the preparation of microglia selective polarization preparations, so as to promote the polarization of M2 microglia and inhibit inflammatory response.

[0008] The technical solution adopted by the present invention is:

[0009] The present invention provides an application of a xanthohumol-like substance in the preparation of a microglia selective polarization preparation. The xanthohumol-like substance is xanthohumol or a xanthohumol derivative, and the microglia selective polarization is the polarization of microglia to M2 type.

[0010] Preferably, the xanthohumol derivative is one or more of tetrahydroxanthohumol, α,β-dihydroxanthohumol and xanthohumol C.

[0011] Preferably, the preparation uses xanthohumols as active ingredients and is supplemented with pharmaceutically acceptable excipients.

[0012] Preferably, the pharmaceutically acceptable excipient is one or more of a diluent, a disintegrant, a precipitation inhibitor, a glidant, a binder, a dispersant, a suspending agent, an isotonic agent, a thickener, an emulsifier, a preservative and a stabilizer.

[0013] Preferably, the acceptable dosage forms of the preparation include tablets, capsules, granules, injections, pills, powders, pastes or oral liquids.

[0014] Preferably, the microglial cells include one or more of HAPI cells, BV2 cells, N9 cells and MG6 cells.

[0015] The present invention provides a drug for treating mental illness caused by excessive selective polarization of microglia, the drug comprising the microglia selective polarization preparation of the present invention, a drug for treating mental illness and a pharmaceutically acceptable excipient.

[0016] Preferably, the therapeutic drugs for mental illness include one or more of chlorpromazine, risperidone, olanzapine, haloperidol and quetiapine.

[0017] Preferably, the drug is prepared from a microglia selective polarization preparation, a therapeutic drug for mental illness and a pharmaceutically acceptable excipient.

[0018] Preferably, the mental illness is one or more of schizophrenia, anxiety, depression and delirium.

[0019] The present invention also provides a drug for treating inflammatory response caused by excessive selective polarization of microglia, the drug comprising the microglia selective polarization preparation of the present invention, a drug for treating inflammatory response and a pharmaceutically acceptable excipient.

[0020] Preferably, the medicament is used to inhibit oxidative stress in microglia.

[0021] Preferably, the medicament is for reducing the release of inflammatory mediators.

[0022] Preferably, the medicament is for protecting neurons.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The present invention provides an application of a xanthohumol-like substance in the preparation of a microglia selective polarization preparation, wherein the xanthohumol-like substance is xanthohumol or a xanthohumol derivative, and the microglia selective polarization is microglia polarization to M2 type. The present invention proves through experiments that when PolyI:C induces microglia activation, the expression of M2 microglia surface marker YM is reduced, and after microglia are pretreated with xanthohumol and then stimulated with PolyI:C, PolyI:C-induced microglia activation is reduced, and the expression of M2 microglia surface marker YM is increased, so Xn may inhibit inflammatory response by regulating the polarization of activated microglia to M2.

[0025] There are two types of polarized microglia: M1 and M2. M1 microglia mainly promote the occurrence of inflammatory responses, while M2 microglia mainly play an anti-inflammatory role. The two can transform into each other, so the inflammatory response can be alleviated by regulating the M1 / M2 polarization state.

[0026] There is an obvious inflammatory response in the central nervous system of SZ patients. At the same time, the present invention also explores the improvement effect of Xn on schizophrenia-like behavior in offspring rats infected during pregnancy, proving the important role of neuroinflammation mediated by microglia activation in the pathogenesis of SZ, which provides a scientific basis for the clinical application of xanthohumol in the treatment of SZ. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 These are the levels of plasma inflammatory factors after mothers were infected with Poly I:C during pregnancy. A: TNF-α level; B: IL-6 level.

[0028] Figure 2These are the results of prepulse inhibition, open field and elevated plus maze experiments in offspring rats. A: The prepulse inhibition rate of offspring rats in PolyI:C group was significantly reduced at 70db, 80db, and 85db; B: The movement distance of offspring rats in PolyI:C group in the central area of ​​the open field was reduced; C: The number of times that offspring rats in PolyI:C group entered the open arms of the elevated plus maze was reduced; D: The time that offspring rats in PolyI:C group entered the open arms of the elevated plus maze was reduced.

[0029] Figure 3 These are the test results of the effect of Xn treatment on the body weight change and prepulse inhibition of offspring rats. A: The effect of Xn treatment on the body weight of offspring rats; B: The effect of Xn treatment on the prepulse inhibition experiment.

[0030] Figure 4 The effects of Xn treatment on the performance of offspring rats in the open field, Y maze and elevated plus maze tests. A: open field test; B: Y maze test; C: elevated plus maze test.

[0031] Figure 5 The effect of Xn on PolyI:C-induced HAPI cell activation, A: changes in TNF-α expression after Xn treatment; B: changes in YM expression after Xn treatment. DETAILED DESCRIPTION

[0032] The present invention is further described below by specific examples, but the scope of the present invention is not limited thereto. The details and forms of the technical solution of the present invention may be modified or replaced without departing from the spirit and scope of the present invention, but these modifications or replacements all fall within the protection scope of the present invention.

[0033] The inventive concept of the present invention is as follows:

[0034] The polarization of microglia after stress plays a key role in alleviating the inflammatory response of the central nervous system and promoting the repair of nerve cells. M2 microglia can reduce the inflammatory response by secreting anti-inflammatory cytokines such as IL-10 and transforming growth factor-β, preventing excessive inflammation from damaging peripheral nerve tissue; they can also remove some inflammatory mediators such as reactive oxygen and nitric oxide through phagocytosis to reduce oxidative stress and protect nerve cells from inflammatory mediators.

[0035] At present, the substances that promote microglia to polarize to M2 type mainly include IL-4, IL-13, transforming growth factor-β, etc. These substances can help clear pathogens in the early stage of inflammation, but they can easily cause excessive polarization of microglia. M2 microglia promote the synthesis of extracellular matrix during tissue repair. If this repair process is excessive, it may lead to the formation of fibrosis and scar tissue. In addition, if there is a pathogen infection, excessive M2 polarization may inhibit the body's immune response, making it difficult to completely eliminate the pathogen. This may lead to the persistence or recurrence of infection, posing a long-term threat to the health of the central nervous system.

[0036] Based on this, the present invention proposes an application of a xanthohumol substance in the preparation of a microglia selective polarization preparation, wherein the xanthohumol substance is xanthohumol or a xanthohumol derivative. Xanthohumol, referred to as Xn, is a prenylated chalcone mainly isolated from hops.

[0037] In order to enable those skilled in the art to better understand and implement the technical solution of the present invention, the present invention is further described below in conjunction with specific embodiments and drawings.

[0038] In the description of the present invention, unless otherwise specified, all reagents used are commercially available and all methods used are conventional techniques in the art.

[0039] Materials and Methods

[0040] 1) Experimental animals:

[0041] 20 SPF-grade 9-week-old female Sprague-Dawley and 10 male SD rats were purchased from Beijing Weitong Lihua Experimental Animal Center. Rats of the same sex were housed in the same cage, with 4 rats per cage, and were housed after one week of adaptation in a standard environment with a temperature of 22°C, a humidity of 50%, and a normal day-night cycle, i.e., fluorescent lights were on from 08:00 to 20:00, to prepare the animal model.

[0042] 2) Main reagents and instruments:

[0043] Poly(I:C) was purchased from Sigma, USA; RatIL-1βELISA, RatIL-6ELISA, and RatTNF-αELISA kits were purchased from Beijing Sizhengbai Biotechnology Co., Ltd.; RIPA lysis buffer, BCA protein concentration determination kit, and 5X SDS-PAGE protein loading buffer were purchased from Wuhan Biyuntian Company; protease phosphatase inhibitors were purchased from Shanghai Biyuntian Company; PAGE gel preparation kit and two-color prestained protein Marker 10kDa~180kDa were purchased from Shanghai Yamei Company; Trizol was purchased from Beijing Baoriyi Company, PrimeScript RT reagent Kit, TB Premix Ex Taq TM II was purchased from Dalian TAKARA; YM antibody was purchased from Abcam, UK; Actin antibody was purchased from CST, USA.

[0044] 3) Experimental methods:

[0045] a) Preparation of pregnancy infection model, the method is as follows:

[0046] SPF SD rats were purchased from Beijing Weitonglihua Experimental Animal Center. After one week of adaptation, they were caged in a ratio of 2:1 for female:male, and those that were successfully pregnant were enrolled. At 9.5 days of pregnancy, the pregnant rats were randomly divided into a model group, PolyI:C, and a saline group. The model group was injected with 10 mg / kg of PolyI:C via the tail vein, and the saline group was injected with an equal volume of saline. The offspring were weaned at 21 days old, and 4 were kept in each cage. In early adulthood, that is, 65 days after birth, 2 were selected from each cage for behavioral testing. The test experiments included open field, elevated plus maze, Y maze, and prepulse inhibition tests.

[0047] b) Behavioral experiment, the method is as follows:

[0048] Open field test: This experiment is a behavioral experiment used to evaluate the spontaneous activity and anxiety-like emotions of experimental animals. The experimental device is an open field of 100cm×100cm×50cm. The SpainPanLabSmart3.0 software is used to record the movement distance and time of rats in different areas. The software is used to divide the field into 16 square grids of equal area. The middle 4 square areas are divided into the central area, and the remaining areas are the peripheral areas. Behavioral tests are carried out in the order of alternating one control group and one model group. Before each round of experiments, the field is disinfected with 75% alcohol by volume to prevent the influence of odor on the behavioral results. Rats are placed in the open field area from the same corner. First, they are given 3 minutes of adaptation time. Then, the software three-point tracking method is used to record the time and distance of rats' activities in the central and peripheral areas within 30 minutes. After exporting all data, the total distance of rat movement and the time and distance spent in the central area, as well as indicators such as time percentage and distance percentage, are calculated to evaluate the spontaneous activity and anxiety-like emotions of rats.

[0049] Elevated plus maze test: This test is used to assess the anxiety level of experimental animals. The device is 40 cm above the ground and consists of two open arms and two closed arms of 60 cm × 10 cm, connected by a central platform of 10 cm × 10 cm. At the beginning of the experiment, the rat to be tested was placed in one of the closed arms, facing away from the central platform, and allowed to explore freely for 5 min. The time and number of shuttles of the experimental rats entering the open arms and closed arms were recorded using SpainPanlabSmart3.0. The anxiety index of the test rats was calculated using the formula, i.e., the activity time in the open arms / the total activity time in the open arms and closed arms × 100%; (the number of times entering the open arms) / (the total number of times entering the open arms and closed arms) × 100%.

[0050] Y-maze experiment: The Y-maze is used to evaluate the spatial memory ability of rodents. The device consists of three identical arms with an angle of 120°. There is a removable baffle near the center of each arm, and cards of different colors are attached to the end of each arm for visual marking. The three arms are randomly divided into the starting arm, the novel arm, and the other arms. The experiment is divided into two stages. The first is the acquisition experiment. In this experimental stage, the novel arm is blocked with a baffle, and the rat is placed in the starting arm and allowed to shuttle between the starting arm and the other arms for 10 minutes. This stage is to form acquired road memory, that is, familiar road routes. After 2 hours, the formal experimental process is carried out in the order of the adaptation stage. In this experimental stage, the baffle is removed, and the software is used to record the time the rat stays in the novel arm and the number of shuttles within 5 minutes to evaluate the memory function of the rat. The order of each experiment is alternating between the model group and the control group. The device is disinfected with 75% medical ethanol before each experiment.

[0051] Prepulse Inhibition (PPI): This experiment evaluates the sensorimotor gating function of rats through auditory startle reflex. All test sessions were conducted in the single-chamber seizure instrument QMC-I. First, calibrate the instrument in decibels, quality, etc. according to the calibration guide of the instrument. The rat to be tested was placed in a restrainer and adapted to the 6-dB background for 5 minutes, followed by 5 startle stimuli, 120dB white noise lasting 20ms. Then, four stimuli, 75dB, 80dB and 85dB prepulse stimulation and no stimulation, were randomly introduced, 10 times each, lasting 20ms. Then, after an interval of 100ms, a 120dB white noise was used to stimulate the startle reflex, lasting 40ms. The percentage of startle stimulus inhibition induced by each prepulse stimulus is calculated as:

[0052] The amplitude of the startle response to the average prepulse stimulation and the average stimulus startle response were calculated based on the amplitude of the heart rate change, with the unit being beats / minute.

[0053] c) Plasma collection of pregnant mice, the method is as follows:

[0054] Pregnant mice in the PolyI:C group and the normal saline group were successfully injected with PolyI:C solution and sterile normal saline through one tail vein on day 9.5 of gestation. 3 h later, 500 μl of venous blood was drawn through the other tail vein and collected into a 1.5 mL EP tube containing an anticoagulant. The blood was placed on ice and centrifuged within half an hour at 4°C, 1000 g, for 15 min. The plasma was collected and stored at -80°C for later use.

[0055] d) Enzyme-linked immunosorbent assay, the method is as follows:

[0056] First, add the gradient standard and the sample to be tested into the wells, cover them with sealing strips, adjust the constant temperature incubator to 37°C in advance, and place each reaction well in the instrument for 90 minutes; wash the plate 4 times, add 350μL of washing solution, and the time interval is 20s; add biotinylated antibody working solution, 100μL per well, seal the reaction well with sealing strips, then incubate at 37°C for 60 minutes, and wash the plate 4 times; add enzyme binding working solution, 100μL per well, seal the reaction well with sealing strips, and incubate at 37°C for 30 minutes; wash the plate 4 times; add color developer, 100μL per well, protect from light, and incubate at 37°C for 15 minutes; finally, add stop solution according to 100μL per well, mix well, and measure OD450nm within 5 minutes.

[0057] e) Western Blot, the method is as follows:

[0058] After the intervention of xanthohumol, HAPI cells were washed with PBS three times, and RIPA lysis buffer containing 1% protease inhibitors and phosphatase inhibitors was added. Lysis was performed on ice for 30 minutes, collected in a new EP tube, ultrasonically broken, centrifuged, and the supernatant was taken. The protein concentration was determined by BCA method; the loading buffer and RIPA lysis buffer were prepared into an equal mass and volume system for protein denaturation. 25μg protein was loaded into each well, separated by 10% SDS-PAGE electrophoresis, transferred to PVDF membrane, and blocked with 5% BSA at room temperature for 1h. YM and β-Actin primary antibodies were added to the corresponding target bands, incubated at 4℃ overnight, and the membrane was washed 3 times with TBST for 5min each time; added for 1h, and the membrane was washed 3 times with TBST for 5min each time; ECL luminescent liquid was added dropwise for exposure and development.

[0059] f) Xn intervention method, the method is as follows:

[0060] Adolescent offspring rats infected with PolyI:C during pregnancy were treated with Xn at a dosage of 50 mg / kg for 28 consecutive days. The weight changes of the rats were monitored every week. After the treatment, behavioral assessments such as open field, elevated plus maze, Y maze and prepulse inhibition were performed.

[0061] g) Rat microglial HAPI cell culture, PolyI:C activation and Xn treatment, the method is as follows:

[0062] PolyI:C was added to the HAPI culture medium at a concentration of 100 μg / mL. After culturing for 14 hours, the TNF-α content in the supernatant was significantly increased by ELISA. Before activating HAPI cells with PolyI:C, the cells were pretreated with gradient concentrations of Xn for 1 hour, and then HAPI cells were stimulated with PolyI:C for 14 hours, and then the changes in TNF-α content in the cell culture supernatant were detected by ELISA.

[0063] 4) Statistical methods:

[0064] GraphPad Prism 8.0 software was used for statistical analysis. The measured data that met the normal distribution were expressed as mean ± standard deviation. One-way analysis of variance was used for comparison among multiple groups, and independent sample t-test was used for comparison between two groups. P < 0.05 was considered statistically significant.

[0065] Example 1

[0066] Application of xanthohumols in the preparation of microglia selective polarization preparations

[0067] (1) Injection of PolyI:C can induce maternal immune activation during pregnancy.

[0068] PolyI:C was injected into the tail vein of 9.5-day pregnant SD rats to simulate viral infection during pregnancy, i.e., the PolyI:C group; and the control group was injected with normal saline. 3 hours after PolyI:C injection, the changes in inflammatory factors in the peripheral blood of pregnant rats were detected by ELISA. The results are as follows Figure 1 As shown, the concentrations of TNF-α and IL-6 in the plasma of pregnant mice in the PolyI:C group were significantly higher than those in the control group, indicating that PolyI:C infection during pregnancy caused the activation of the maternal immune system.

[0069] Figure 1 The experimental data of saline and Poly:C groups in A and B are expressed as mean ± standard deviation, with 8 mice in each group. The statistical analysis was performed using unpaired two-tailed t-test to detect whether the difference between the two groups was statistically significant. Compared with saline and Poly:C groups, ***P<0.001.

[0070] (2) PolyI:C infection during pregnancy causes schizophrenia-like behaviors in offspring.

[0071] The rats injected with PolyI:C and saline were subjected to subsequent experiments. The adult offspring rats were subjected to behavioral assessments such as open field, elevated plus maze and prepulse inhibition. Impaired prepulse inhibition indicates sensory gating defects, which is one of the typical symptoms of SZ patients and is the gold standard for detecting whether the SZ animal model is successfully prepared. Figure 2 As shown, the behavioral analysis results of adult offspring rats showed that in the prepulse inhibition experiment, the inhibition rate of startle stimulation to different prepulse stimuli in the adult offspring rats of the PolyI:C group was significantly lower than that in the control group; in the open field experiment, the movement distance of the adult offspring rats of the PolyI:C group in the central area was significantly reduced; in the elevated plus maze, the number and time of entering the open arm were reduced, indicating that the adult offspring rats of the PolyI:C group had schizophrenia-like behaviors such as sensory gating defects and anxiety.

[0072] (3) Xanthohumol Xn can improve the schizophrenia-like behavior of offspring rats infected during pregnancy.

[0073] The offspring rats in the normal saline group and the PolyI:C group were treated with Xn, recorded as the normal saline+Xn group and the PolyI:C+Xn group, and the Xn dosage was 50 mg / kg.

[0074] like Figure 3As shown, the weight changes of offspring rats in the PolyI:C group, saline + Xn group, and PolyI:C + Xn group were similar to those in the saline group, with no significant differences, indicating that Xn treatment did not affect the weight changes of rats. In the prepulse inhibition test PPI, after the offspring rats in the PolyI:C group were treated with Xn, the inhibition rate of prepulse stimulation of different decibels on startle stimulation increased to a certain extent, and the inhibition rate of prepulse stimulation of 80db on startle stimulation increased significantly, indicating that xanthohumol can improve the sensory gating defects of offspring rats caused by PolyI:C infection during pregnancy.

[0075] like Figure 4 As shown in the figure, in the open field test, Xn treatment can increase the percentage of the movement distance of the PolyI:C group offspring rats in the central area to the total movement distance; in the Y maze test, Xn can increase the number of times the PolyI:C group offspring rats enter the novel arm; in the elevated plus maze test, Xn can increase the number of times the PolyI:C group offspring rats enter the open arm. It can be seen that Xn treatment can improve schizophrenia-like behaviors such as anxiety and memory impairment in pregnant infected offspring rats.

[0076] (4) Xanthohumol can promote the polarization of HAPI cells induced by PolyI:C to M2 type

[0077] The results of cell experiments are as follows Figure 5 As shown in the figure, the concentration of TNF-α in the Poly I:C group was significantly higher than that in the saline group, indicating that Poly I:C treatment can induce microglial activation; after Xn treatment, the concentration of TNF-α was significantly lower than that in the Poly I:C group, indicating that Xn can inhibit Poly I:C-induced HAPI microglial activation. Poly I:C treatment reduced the expression of YM protein in cells, while Xn treatment increased the expression of YM protein.

[0078] Microglia have two types of polarization forms: M1 and M2. M1 microglia mainly promote the occurrence of inflammatory reactions, while M2 microglia mainly play an anti-inflammatory role. The two can be transformed into each other, so the inflammatory reaction can be alleviated by regulating the M1 / M2 polarization state. The present invention found that PolyI:C stimulation can inhibit the expression of YM, a surface marker of M2 microglia, while Xn pretreatment can promote the expression of YM. Therefore, Xn may inhibit the inflammatory reaction by regulating the polarization of activated microglia to M2.

[0079] SZ is a severe mental disorder that mainly develops in late adolescence or early adulthood, and clinically manifests as different symptom groups, including disruption of thinking and consciousness, social withdrawal, emotional indifference, and cognitive dysfunction. Patients have reduced social function, low clinical recovery rate, high disability rate, and unemployment rate as high as 80% to 90%, which has caused a heavy economic and social burden. The etiology of SZ is complex, and the related biological mechanisms are still unclear. In recent years, the important role of immune disorders in the onset of SZ has received widespread attention and recognition. Studies have shown that inflammation may be one of the predisposing factors of SZ. Xanthohumol is a flavonoid compound naturally present in plants, which has multiple biological activities such as anti-inflammatory, antioxidant and anti-tumor. However, the regulatory effect of xanthohumol on SZ-related immune disorders remains unclear.

[0080] Since the relationship between xanthohumol and SZ is unclear, the present invention studies the relationship between the two from the animal and cell levels. First, the analysis is conducted at the animal level. The adolescent offspring rats infected with PolyI:C during pregnancy are given Xn treatment, and then behavioral experiments such as open field, elevated cross maze, Y maze and prepulse inhibition are carried out. The experiment shows that Xn treatment can improve schizophrenia-like behaviors such as sensory gating defects, anxiety, and memory impairment in offspring rats infected during pregnancy. At the cellular level, microglia are a type of non-neuronal cells in the central nervous system that can affect the function of neurons by releasing inflammatory mediators. After activation, microglia can be polarized into two types, M1 and M2, which have pro-inflammatory and anti-inflammatory effects, respectively. Studies have shown that in SZ patients, the activation state of microglia is abnormal. In addition, some studies have also found that xanthohumol may have certain therapeutic potential for mental disorders such as schizophrenia. The present invention proves through cell experiments that the expression of M2 microglia surface marker YM is reduced when PolyI:C induces microglia activation, and after microglia are pretreated with xanthohumol and then stimulated with PolyI:C, PolyI:C-induced microglia activation is reduced, and the expression of M2 microglia surface marker YM is increased. The present invention believes that xanthohumol promotes M2 microglia polarization to inhibit inflammatory response, thereby alleviating schizophrenia-like behavior.

[0081] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0082] The above-mentioned embodiments only express several implementation methods of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the invention patent. It should be pointed out that for ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. The use of xanthohumols in the preparation of microglia selective polarization preparations, characterized in that: The xanthohumol-like substance is xanthohumol or a xanthohumol derivative, and the selective polarization of microglia is polarization of microglia to M2 type.

2. The use according to claim 1, characterized in that The xanthohumol derivative is one or more of tetrahydroxanthohumol, α,β-dihydroxanthohumol and xanthohumol C.

3. The use according to claim 1, characterized in that The preparation uses xanthohumol substances as active ingredients and is supplemented with pharmaceutically acceptable excipients.

4. The use according to claim 3, characterized in that The pharmaceutically acceptable excipient is one or more of a diluent, a disintegrant, a precipitation inhibitor, a glidant, a binder, a dispersant, a suspending agent, an isotonic agent, a thickener, an emulsifier, a preservative and a stabilizer.

5. The use according to claim 1, characterized in that The acceptable dosage forms of the preparation include tablets, capsules, granules, injections, pills, powders, pastes or oral liquids.

6. The use according to claim 1, characterized in that The microglial cells include one or more of HAPI cells, BV2 cells, N9 cells and MG6 cells.

7. A drug for treating mental illness caused by excessive selective polarization of microglia, characterized in that: The drug comprises the microglia selective polarization preparation according to claim 1, a drug for treating mental illness and a pharmaceutically acceptable excipient.

8. The drug according to claim 7, characterized in that The therapeutic drugs for mental illness include one or more of chlorpromazine, risperidone, olanzapine, haloperidol and quetiapine.

9. The drug according to claim 7, characterized in that The medicine is prepared from a microglia selective polarization preparation, a therapeutic medicine for mental illness and pharmaceutically acceptable excipients.

10. The drug according to claim 7, characterized in that The mental illness is one or more of schizophrenia, anxiety, depression and delirium.

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