Application of quercetin or derivatives thereof in preparation of medicine for preventing and / or treating offspring neurodevelopment disorder diseases caused by respiratory virus infection during pregnancy

Abstract

The invention relates to the technical field of medical application, in particular to application of quercetin or derivatives thereof in preparation of drugs for preventing and / or treating offspring neurodevelopment disorder diseases caused by respiratory virus infection during pregnancy. The medicine comprises quercetin or a pharmaceutically acceptable quercetin derivative of the quercetin, and the quercetin derivative is a compound for improving the solubility or bioavailability of the quercetin through structural modification. The medicine blocks fetal microglial cell activation and macrophage subgroup imbalance induced by viruses by targeting maternal decidua natural killer cells (dNK), and treats filial generation neurodevelopment disorder diseases caused by infection of various pregnancy respiratory viruses such as influenza viruses, respiratory syncytial viruses (RSV), coronaviruses and the like. And the quercetin derivative can improve the bioavailability of quercetin through glycosylation, esterification or prodrug modification and the like, and has a wide clinical application prospect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical applications, specifically to the use of quercetin or its derivatives in the preparation of medicaments for the prevention and / or treatment of neurodevelopmental disorders in offspring caused by respiratory viral infections during pregnancy. Background Technology

[0002] Maternal health during pregnancy is crucial for the normal development of the fetal central nervous system. Numerous epidemiological studies have shown that viral infections during pregnancy significantly increase the risk of offspring developing neurodevelopmental disorders (NDDs). Autism Spectrum Disorder (ASD), one of the most common NDDs, has a global prevalence of approximately 1%. Individuals with ASD typically exhibit impairments in social interaction, language communication difficulties, and repetitive, stereotyped behaviors, usually requiring lifelong medical care and social support, and have become a significant burden on global public health.

[0003] Currently, the pathogenesis of NDDs such as autism remains unclear, and effective prevention and intervention methods are lacking. In recent years, maternal immune activation (MIA) has been considered a key link between infection during pregnancy and neurodevelopmental disorders in offspring. Influenza A virus, especially the H1N1 subtype, is a common respiratory pathogen. Infection during pregnancy has been confirmed by multiple studies to cause systemic inflammatory responses in the mother and induce structural and immune dysfunction of the placental barrier, thereby interfering with the immune homeostasis of fetal brain tissue.

[0004] Quercetin is a natural plant flavonoid widely found in fruits and vegetables, possessing excellent anti-inflammatory, antioxidant, and immunomodulatory activities. Chinese invention patent application CN112022845 A discloses the application of quercetin in the preparation of drugs against the novel coronavirus, marking the first time quercetin has been used to treat infections caused by the novel coronavirus. Research has found that quercetin can effectively inhibit the proliferation of the novel coronavirus within cells, thus enabling its use in treating pneumonia caused by the novel coronavirus. This expands the application range of quercetin and provides a new approach to the prevention and treatment of the novel coronavirus. Chinese invention patent application CN115364090 A discloses the application of quercetin in the preparation of drugs for cognitive impairment caused by epilepsy. Quercetin can reduce the neurotoxicity caused by glutamate and improve cell activity. Clinical trials have demonstrated a close correlation between neuronal death caused by epilepsy and neuronal ferroptosis. Further animal and cell experiments have demonstrated that quercetin can protect neurons by regulating neuronal ferroptosis, thereby treating cognitive impairment caused by epilepsy. However, none of the above inventions involve the use of quercetin or its derivatives in the preparation of drugs for the prevention and / or treatment of neurodevelopmental disorders in offspring caused by respiratory viral infections during pregnancy. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides the use of quercetin or its derivatives in the preparation of drugs for the prevention and / or treatment of neurodevelopmental disorders in offspring caused by respiratory viral infections during pregnancy. This invention utilizes H1N1 influenza virus infection to realistically simulate viral and bacterial infection of the pregnant mother to achieve maternal immune activation (MIA). The invention then detects the neuronal structure, macrophage status, glial cell status, and expression of pro-inflammatory factors in the offspring, and determines the disease status of the offspring through behavioral changes, thereby enabling research on MIA-related mental illnesses in offspring.

[0006] This invention is achieved through the following technical solutions: The first aspect of the invention relates to the use of quercetin or derivatives thereof in the preparation of a medicament for the prevention and / or treatment of neurodevelopmental disorders in offspring caused by respiratory viral infections during pregnancy, said medicament comprising quercetin or a pharmaceutically acceptable derivative thereof, said derivative being a compound whose solubility or bioavailability of quercetin is improved by structural modification.

[0007] Preferably, the respiratory viruses during pregnancy include influenza virus, respiratory syncytial virus, coronavirus, or parainfluenza virus.

[0008] More preferably, the influenza virus includes influenza A virus (H1N1) and influenza B virus.

[0009] Preferably, the structural modification of the quercetin derivative is selected from one or more of the following methods: (a) Introducing a glycosyl, phosphate, or sulfonic acid group at the hydroxyl site of quercetin; (b) Modified by esterification or etherification; (c) Formation of prodrug.

[0010] Preferably, the quercetin is a compound with the chemical name 3,3′,4′,5,7-pentahydroxyflavone, and its structure is shown below: .

[0011] Preferably, the neurodevelopmental disorder is a neurodevelopmental disorder in offspring caused by respiratory viral infection during pregnancy.

[0012] Preferably, the neurodevelopmental disorder is selected from autism, intellectual disability, developmental speech or language disorder, autism spectrum disorder, developmental learning disability, developmental motor coordination disorder, attention deficit hyperactivity disorder, stereotyped movement disorder, primary tic or tic disorder, secondary neurodevelopmental syndrome, other specific neurodevelopmental disorders, or unspecified neurodevelopmental disorders.

[0013] Preferably, the drug can inhibit the activation of maternal decidual NK cells, reduce their secretion of extracellular granzyme B (GzmB), and decrease its transfer to the fetus.

[0014] Preferably, the drug can neutralize GzmB activity and regulate the immune environment of fetal brain tissue by promoting the expression of GzmB inhibitory factors such as Serpin3n in placental or decidual tissue.

[0015] Preferably, the drug can regulate the balance of macrophage subsets and microglia homeostasis in the fetal brain, thereby improving fetal neuroimmune abnormalities.

[0016] Preferably, the drug can upregulate the expression of PTN and VEGFA in maternal decidual NK cells.

[0017] Preferably, the drug comprises one or more pharmaceutically acceptable adjuvants selected from antiviral agents, immunomodulators, antioxidants, and stabilizers.

[0018] Preferably, the dosage form of the drug is an injection, infusion, powder, tablet, or capsule.

[0019] Inflammation during pregnancy is caused by viral infections during pregnancy, such as influenza virus, novel coronavirus, Zika virus, etc., which activate the maternal immune system, leading to an increase in type I interferon levels and decidual NK cell expression at the maternal and fetal interfaces.

[0020] Neurodevelopmental disorders are mainly characterized by autistic-like behaviors.

[0021] The beneficial effects of this invention are as follows: This invention is the first to propose quercetin or its derivatives as a drug for the prevention and treatment of neurodevelopmental disorders in offspring caused by inflammation during pregnancy. Experiments have confirmed that oral administration of quercetin after infection during pregnancy significantly improves infection-induced activation of macrophages in offspring brains, and alleviates autism-related symptoms such as social impairment, stereotyped behaviors, and anxiety in offspring. This is of great significance for the development of drugs for the prevention and treatment of neurodevelopmental disorders in offspring caused by inflammation during pregnancy. Attached Figure Description

[0022] Figure 1 The images show the staining of choroid plexus macrophages in E18.5 embryos of control (orally administered saline and infected) and experimental (orally administered quercetin and infected) mice at E9.5 of pregnancy after H1N1 intranasal infection-induced maternal immune activation modeling. Green fluorescence represents macrophages, and red fluorescence represents the macrophage activation marker CD68. Figure 2 The images show the staining of meningeal macrophages in E18.5 embryos of mice in the control group (administered saline and infected) and the experimental group (administered quercetin and infected) at E9.5 after H1N1 intranasal infection-induced maternal immune activation model. Green fluorescence represents macrophages, and red fluorescence represents the macrophage activation marker CD68. Figure 3 The images show the staining of microglia in the E18.5 embryos of mice in the control group (administered saline and infected) and the experimental group (administered quercetin and infected) at E9.5 of pregnancy after H1N1 intranasal infection-induced maternal immune activation model. Green fluorescence represents microglia. Figure 4 Mice in the control group (administered saline and infected) and mice in the experimental group (administered quercetin and infected) underwent maternal immune activation modeling by intranasal H1N1 infection at gestation E9.5. Adult mice were then subjected to open field behavioral experiments. Figure 5 The mice in the control group (administered saline and infected) and the experimental group (administered quercetin and infected) were subjected to H1N1 intranasal infection-induced maternal immune activation model at gestation E9.5. The mice were then subjected to social behavior experiments in adulthood. Figure 6 Mice in the control group (administered saline and infected) and mice in the experimental group (administered quercetin and infected) underwent H1N1 intranasal infection-induced maternal immune activation modeling at gestation E9.5. Adult mice were then subjected to a marble-burying behavior experiment. Figure 7Flow cytometry plot of placental decidua at E13.5 after H1N1 intranasal infection-induced maternal immune activation model was established in control mice (administered saline and infected) and experimental mice (administered quercetin and infected) at E9.5 of pregnancy. Figure 8 The control group (gavage with saline and infection) and the experimental group (gavage with quercetin and infection) mice were modeled with maternal immune activation induced by H1N1 intranasal infection at E9.5 gestation. The WB of the amniotic fluid at E13.5 harvest is represented and statistically analyzed. Figure 9 The control group (or mice infected with saline or not infected by gavage) and the experimental group (or mice infected with quercetin by gavage) were infected with H1N1 via nasal drop at E9.5 of pregnancy. The results of decidual NK cell sequencing at E13.5 were obtained. The left figure shows the enrichment of upregulated genes in the H1N1 infection group compared with the saline group, and the right figure shows the enrichment of downregulated genes in the quercetin treatment group compared with the H1N1 group. Figure 10 The sequencing results of human decidual NK cells in the control group (saline or IFNβ stimulation) and the experimental group (co-stimulated with IFNβ and quercetin) are shown. The left figure shows the enrichment pathway of upregulated genes in the IFNβ stimulation group compared with the saline group, and the right figure shows the enrichment pathway of downregulated genes in the quercetin treatment group compared with the IFNβ stimulation group. Figure 11 Western blot results of JAK1, STAT1, P-JAK1, and P-STAT1 in human decidual NK cells from the control group (physiological saline or IFNβ stimulation) and the experimental group (IFNβ and quercetin co-stimulation). Figure 12 Western blot results of human decidual NK cells SERPINA3 in the control group (physiological saline or IFNβ stimulation) and the experimental group (IFNβ and quercetin co-stimulation); Figure 13 Human decidual NK cells were used as a control group (stimulated with physiological saline or IFNβ) and an experimental group (stimulated with IFNβ and quercetin). PTN , VEGFA The qPCR results. Detailed Implementation

[0023] The present invention will be further described below with reference to specific embodiments, and the advantages and features of the present invention will become clearer as a result. However, these embodiments are merely exemplary and do not constitute any limitation on the scope of the present invention. Those skilled in the art should understand that modifications or substitutions can be made to the details and form of the technical solutions of the present invention without departing from the spirit and scope of the present invention, but all such modifications and substitutions fall within the protection scope of the present invention.

[0024] The experimental methods used in the following examples are all conventional methods, such as multiplex immunohistochemistry, open field assays, and social interaction assays. They were performed according to the techniques and conditions described in the literature in this field or according to the product instructions. The reagents and materials involved in the examples are all commercially available.

[0025] Laboratory animals: The 8-week-old wild-type C57BL / 6 female and male mice used in this embodiment were purchased from Shanghai Silex Company. All mice were housed at the SPF-grade Laboratory Animal Center of the University of Science and Technology of China (USTC). The mouse housing and experimental procedures were strictly carried out in accordance with the USTC Laboratory Animal Management Regulations and were approved by the USTC Ethics Committee.

[0026] Experimental reagents: Quercetin (Catalog No.: 117-39-5, MERCK Sigma), AlphaAntichymotrypsin Monoclonal antibody (Catalog No.: 66078-1-Ig, Proteintech), Stat1Antibody Rabbit mAb (Catalog No.: 14994, CST), Phospho-Stat1 Rabbit mAb (Catalog No.: 9167, CST), Jak1 Rabbit mAb (Catalog No.: 3344, CST), Phospho-Jak1Rabbit mAb (Catalog No.: 74129, CST).

[0027] Example 1: Establishment of a maternal immune activation-induced offspring NDD model Eight-week-old wild-type C57BL / 6 female mice were mated with wild-type C57BL / 6 male mice. Vaginal plugs were examined the following day as a marker of successful mating. The date of successful mating was recorded as E0.5, based on the gestational age. Pregnant female mice at E9.5 (9.5 days post-gestation) (B6-pregn) were given intranasal drops of 16HA H1N1 to induce immune activation, thus successfully establishing a maternal immune activation model. An equal volume of physiological saline was administered intranasally as a non-immune activation model.

[0028] Example 2: Quercetin administered to mice by gavage Using H1N1-infected pregnant female mice (B6-pregn) obtained in Example 1, it was confirmed that immune activation was induced in the mice.

[0029] A non-immune activation control group (Saline + DMSO, or Control group for short) was set up. Pregnant female mice (B6-pregn) were administered DMSO by gavage at E11.5 and E12.5, and decidua was collected at E13.5. Pregnant female mice (B6-pregn) were administered DMSO by gavage at E12.5 and E15.5, and fetal brain or adult behavioral samples were collected at E18.5. An immune-activated control group (H1N1 + DMSO, or H1N1 group) was set up. Pregnant female mice (B6-pregn) at E11.5 and E12.5 were administered DMSO by gavage, and decidua was collected at E13.5. Pregnant female mice (B6-pregn) at E12.5 and E15.5 were administered DMSO by gavage, and fetal brain or adult behavioral data was collected at E18.5. An immune-activated experimental group (H1N1 + quercetin, or Quercetin group) was set up. Pregnant female mice (B6-pregn) at E11.5 and E12.5 were administered quercetin 200 μg / day by gavage, and decidua was collected at E13.5. Pregnant female mice (B6-pregn) at E12.5 and E15.5 were administered quercetin 200 μg / day by gavage, and fetal brain or adult behavioral data was collected at E18.5.

[0030] Example 3: Multiple recombinant chemical assays to detect changes in embryonic cerebral cortex structure and macrophages Using the pregnant female mice from Example 2, E18.5 mouse embryos were extracted, including three pregnant mice each from the Control group, H1N1 group, and H1N1+quercetin group; four fetal mice from the Control group; eight fetal mice from the H1N1 group; and six fetal mice from the H1N1+quercetin group. Fetal brains were isolated and fixed with 4% paraformaldehyde, then embedded in paraffin, sectioned, and antigen-retrieval was performed using sodium citrate antigen retrieval solution at pH 6.0. Staining was performed using Thermo Fisher Scientific multi-recombinant cytokinesis kits (B40922, B40923, B40926). Finally, images were taken using a fluorescence microscope (3D-Histech). Iba1 antibody (CST, catalog number 17198) was used to label embryonic brain microglia and macrophages, and CD68 antibody (CST, catalog number 97778) was used to label activated microglia and macrophages. The final results were statistically analyzed using ImageJ. Increased CD68 expression in embryonic macrophages indicates a neurodevelopmental disorder.

[0031] Maternal immune activation also leads to increased activation of embryonic brain macrophages and microglia. Compared with the control group, H1N1-infected mice showed enhanced CD68 expression in E18.5 embryonic brain macrophages, exhibiting an activated phenotype. These macrophages were primarily located in the meningeal and choroid plexus (ChP) regions. In contrast, the quercetin-treated group showed increased IBA1 expression. + CD68 +The proportion of double-positive cells was significantly reduced, which significantly alleviated the abnormal activation of embryonic brain macrophages and the increase of periventricular microglia caused by H1N1 infection.

[0032] For details, please see [link / details]. Figures 1-3 .

[0033] Example 4: Behavioral testing of F1 generation mice The offspring (F1 generation) of the mice in Example 2 were used. F1 male mice were subjected to behavioral tests such as socialization test, open field test, and marble burying test at 6-12 weeks of age. There were 8 F1 mice in each of the Control group, H1N1 group, and H1N1+quercetin group.

[0034] Social Experiment: A simplified social interaction test was conducted in an open area (40 × 40 × 30 cm) with two empty wire cages placed diagonally. Mice were first allowed free movement in the area for 5 minutes to acclimatize. In the subsequent 5-minute test phase, the mice's social preferences were assessed by allowing them to interact with one empty cage (labeled "Empty Cage") and another cage containing an unfamiliar, age- and sex-matched mouse of the same species (labeled "Mouse 1"). The interaction time between the mice and each cage was precisely recorded using EthoVision XT software. In the final 5-minute phase, a new unfamiliar mouse (labeled "Mouse 2") was added to the previously empty cage to assess social novelty preferences. The interaction time between the mice and both Mouse 1 and Mouse 2 was then recorded and analyzed using EthoVision XT software.

[0035] Open field test: Mice were placed in an open field (50 cm × 50 cm) and allowed to explore freely for 5 minutes while their activity was recorded by a camera. The time spent by mice in the central area (20 cm × 20 cm) of the open field was recorded using the EthoVision XT (Noldus) animal motion tracking system. This test was used to assess anxiety-related behavioral characteristics in mice.

[0036] Marble Burial Test: A 5 cm thick layer of corn cob bedding was evenly laid in an open cage (35 cm × 20 cm), and 20 marbles were evenly placed on top. Mice were then placed inside and allowed to move freely. After 10 minutes, the mice were removed, and the number of marbles buried at least two-thirds of the way down in the corn cob bedding was counted. This test was used to assess stereotyped repetitive behaviors in mice and to reflect their anxiety-related behavioral characteristics.

[0037] Data Analysis: Statistical difference analysis and graphing were performed using GraphPad Prism 8.0 software. One-way ANOVA was used for univariate analysis of differences among multiple groups; two-way ANOVA was used for multivariate analysis of differences among multiple groups. Data are presented as mean ± standard error (mean ± SEM). A statistically significant difference was defined as p < 0.05 (* represents p < 0.05; ** represents p < 0.01; *** represents p < 0.001; **** represents p < 0.0001; ns represents no significant difference). See below for detailed results. Figure 4-Figure 6 .

[0038] The results showed that maternal immune activation induced autism-like behavioral symptoms in offspring. Compared with the control group, offspring in the H1N1 infection group exhibited significantly impaired social skills and social novelty, increased anxiety symptoms, and increased stereotyped and repetitive behaviors—phenotypes similar to those of human autism, indicating a neurodevelopmental disorder. Quercetin treatment significantly alleviated the behavioral abnormalities in offspring induced by polyIC treatment.

[0039] These results demonstrate that H1N1 infection can lead to neuroimmunological diseases and autistic behaviors in offspring, and that quercetin treatment can effectively alleviate abnormal brain development and macrophage activation during the embryonic period, while also reducing autism-related behavioral symptoms in adulthood.

[0040] Example 5: Detection of GZMB protein levels in the decidua and amniotic fluid of pregnant mice and decidual transcriptome sequencing Using the pregnant female mice from Example 2, decidua and amniotic fluid were collected for experimental flow cytometry, Western blotting, and transcriptome sequencing.

[0041] Flow cytometry: Decidual tissue was harvested from E13.5 female mice, with three mice each in the Control, H1N1, and H1N1+quercetin groups. After being minced, the decidual tissue was enzymatically digested in culture medium with 1 mg / mL collagenase (Sigma-Aldrich) at 37°C, followed by continuous shaking and incubation for 45 minutes. The cell suspension was then filtered through a 200-mesh sieve and centrifuged at 4°C. The resulting pellet was resuspended in 40% Percoll, centrifuged again, and then treated with erythrocyte lysis buffer on ice for 2 minutes. Finally, the cells were washed and resuspended in culture medium. For surface staining, cells were pre-blocked with serum to inhibit Fc receptors and then incubated with fluorescently labeled antibodies at 4°C for 30 minutes. For intracellular staining of GzmB in decidual NK cells (dNK), surface labeling was performed first, followed by fixation and permeabilization with Foxp3 / transcription factor staining buffer (eBioscience), and then incubation with GzmB and other intracellular antibodies. No in vitro stimulation was performed. Data were acquired using a FACSCelesta flow cytometer (BD Biosciences) and analyzed using FlowJo software (Tree Star). See below for detailed results. Figure 7 . Amniotic fluid Western blotting: GzmB in amniotic fluid from five E13.5 pregnant mice (Control group, H1N1 group, and H1N1+quercetin group, five samples each) was analyzed by Western blot. Ponceau staining was used as a loading control. Amniotic fluid was heated at 98°C for 16 minutes in Dual Color SDS-PAGE loading buffer (6X, Beyotime, P0298) containing protease and phosphatase inhibitors (Proteintech) before SDS-PAGE electrophoresis. Proteins were then transferred to PVDF membranes, blocked with 5% skim milk at room temperature for 1 hour, and incubated overnight at 4°C with primary antibody diluted with Beyotime antibody dilution buffer. After washing, the membranes were incubated with HRP-labeled secondary antibody at room temperature for 1 hour. Protein signals were detected by chemiluminescent autoradiography. The dilution ratios of the primary and secondary antibodies were 1:1000 and 1:10,000, respectively. See below for detailed results. Figure 8 .

[0042] Mouse dNK transcriptome sequencing: Decidual cells were harvested from E13.5 female mice, with two mice each from the Control group, H1N1 group, and H1N1+quercetin group. Decidual tissue was minced and enzymatically digested in culture medium with 1 mg / mL collagenase (Sigma-Aldrich) at 37°C with continuous shaking for 45 minutes. The cell suspension was then filtered through a 200-mesh sieve and centrifuged at 4°C. The resulting pellet was resuspended in 40% Percoll, centrifuged again, and then treated with erythrocyte lysis buffer on ice for 2 minutes. Finally, the cells were washed and resuspended in culture medium. Cells were stained with FACS antibody and sorted using a BD FACSAria III flow cytometer. Mouse decidual NK cells (dNK) were defined as CD45⁺ NK1.1⁺ CD3⁻ CD19⁻ and collected for subsequent Smart-seq analysis. Total RNA was extracted using the RNeasy Mini Kit (Qiagen), and strand-specific libraries were constructed using the TruSeq StrandedTotal RNA Sample Preparation Kit (Illumina). Poly(A)+ mRNA was enriched using oligo(dT) magnetic beads, then cleaved and reverse transcribed into cDNA. After end repair, adapter ligation, and PCR amplification, the libraries were purified, quantified using Qubit 2.0, and their quality was verified on an Agilent Bioanalyzer 2100. Qualified libraries were clustered using cBot and sequenced on an Illumina NovaSeq 6000 platform. Sequencing reads were aligned using HISAT2, and gene expression levels were calculated using StringTie. Expression data were normalized using the TMM method and expressed in FPKM format. Differentially expressed genes were screened using edgeR software, and FDR correction was performed using the Benjamini–Hochberg method. GeneOntology (GO) analysis of differentially expressed genes was performed using the DAVID database (http: / / david.abcc.ncifcrf.gov / ), and the results were visualized using the Bioinformatics online platform (https: / / www.bioinformatics.com.cn). See below for detailed results. Figure 9 .

[0043] Example 6: Human decidual NK cell in vitro stimulation qPCR, followed by transcriptome sequencing and Western blot experiments. Fresh human decidual tissue was minced and digested in RPMI 1640 medium with 1 mg / mL type IV collagenase at 37°C with shaking for 45 minutes. The cell suspension was filtered through a 200-mesh sieve and then centrifuged using a Percoll density gradient to enrich lymphocytes. The cells were then cultured at 37°C for 2 hours to allow stromal cells and macrophages to adhere; non-adherent monocytes were collected, centrifuged (450 × g, 10 min), and resuspended in MACS buffer.

[0044] After incubation with the antibody mixture, the cells were sorted by magnetic beads (MACS) using an LS column. The efflux fraction containing decidual NK cells (dNK) was collected, washed, and counted.

[0045] dNK cells used for transcriptome sequencing (3 patient cells per group) and qCPR (left, 7 patient cells per group; right, 5 patient cells per group) were cultured for 6 hours under the following three conditions: control group, interferon-1 stimulation group (IFN-β, 125 ng / mL), and interferon-1 + quercetin combined stimulation group (Quercetin + IFN-β; IFN-β, 125 ng / mL; Quercetin, 40 μg / mL). Samples used for Western blot analysis were incubated for 16 minutes under the same treatment conditions. Figure 11 Cells from 6 patients in each group; Figure 13 (8 patients in each group). See details below. Figures 10-13 .

[0046] The above detailed description is a specific description of one of the feasible embodiments of the present invention. This embodiment is not intended to limit the patent scope of the present invention. All equivalent implementations or modifications that do not depart from the present invention should be included within the scope of the technical solution of the present invention.

Claims

1. The use of quercetin or its derivatives in the preparation of drugs for the prevention and / or treatment of neurodevelopmental disorders in offspring caused by respiratory viral infections during pregnancy, characterized in that: The drug comprises quercetin or a pharmaceutically acceptable derivative thereof, wherein the derivative is a compound that improves the solubility or bioavailability of quercetin through structural modification.

2. The use according to claim 1, characterized in that: The respiratory viruses mentioned during pregnancy include influenza virus, respiratory syncytial virus, coronavirus, or parainfluenza virus.

3. The use according to claim 1, characterized in that: The structural modification of the quercetin derivative is selected from one or more of the following methods: (a) Introducing a glycosyl, phosphate, or sulfonic acid group at the hydroxyl site of quercetin; (b) Modified by esterification or etherification; (c) Formation of prodrug.

4. The use according to claim 1, characterized in that: The neurodevelopmental disorder mentioned above is a neurodevelopmental disorder in offspring caused by respiratory viral infection during pregnancy.

5. The use according to claim 1, characterized in that: The neurodevelopmental disorders mentioned are selected from autism, intellectual disability, developmental speech or language disorder, autism spectrum disorder, developmental learning disability, developmental motor coordination disorder, attention deficit hyperactivity disorder, stereotyped movement disorder, primary tic or tic disorder, secondary neurodevelopmental syndrome, other specific neurodevelopmental disorders, or unspecified neurodevelopmental disorders.

6. The use according to claim 1, characterized in that: The drug can inhibit the activation of maternal decidual NK cells, reduce their secretion of extracellular granzyme B, and decrease its transfer to the fetus.

7. The use according to claim 1, characterized in that: The drug can regulate the immune environment of fetal brain tissue by promoting the expression of GzmB inhibitory factors such as Serpin3n in placental or decidual tissues, neutralizing GzmB activity.

8. The use according to claim 1, characterized in that: The drug can regulate the balance of macrophage subsets and microglia homeostasis in the fetal brain, and improve fetal neuroimmune abnormalities.

9. The use according to claim 1, characterized in that: The drug can upregulate the expression of PTN and VEGFA in maternal decidual NK cells.

10. The use according to any one of claims 1-9, characterized in that: The drug comprises one or more pharmaceutically acceptable excipients selected from antiviral agents, immunomodulators, antioxidants, and stabilizers; the drug is in the form of an injection, infusion, powder, tablet, or capsule.

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