Use of GLP-2 receptor agonist in preparation of drug for treating metabolic dysfunction caused by antipsychotic drugs

Abstract

Disclosed is use of a GLP-2 receptor agonist in the preparation of a drug for treating metabolic dysfunction caused by antipsychotic drugs. Also disclosed are use of a GLP-2 receptor agonist in the preparation of a drug for preventing and / or treating diseases caused by the inhibition of VMHPdyn neurons, a kit of parts comprising a GLP-2 receptor agonist and an antipsychotic drug and use thereof in the preparation of a drug for treating mental diseases, and a method for activating VMHPdyn neurons in vivo or in vitro. The present invention opens up the possibility of targeting GLP-2 receptors to treat side effects caused by antipsychotic drugs.

Description

Use of GLP-2 receptor agonists in the preparation of drugs for treating metabolic disorders caused by antipsychotic drugs

[0001] This application claims priority to Chinese patent application 202510123538X, filed on January 26, 2025. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceutical technology, specifically relating to the use of GLP-2 receptor agonists in the preparation of medicaments for treating metabolic disorders caused by antipsychotic drugs. Background Technology

[0003] GLP-2 (glucagon-like peptide-2) is a 33-amino acid single-chain polypeptide secreted by intestinal L-endocrine cells, primarily exerting its biological effects through the GLP-2 receptor (GLP-2R). GLP-2 increases intestinal blood flow, promotes small intestinal growth and nutrient absorption, inhibits gastrointestinal motility and gastric acid secretion, and reduces intestinal permeability. GLP-2 mainly regulates the growth of intestinal epithelial cells and the digestive and absorptive functions of the intestine. Several GLP-2 analogues have been developed for therapeutic applications. For example, teduglutide is clinically used to treat short bowel syndrome in adults. This drug was first approved for marketing in the European Union in 2012 (trade name GATTEX), and subsequently approved in the United States and Japan. On February 23, 2024, teduglutide was officially approved by the National Medical Products Administration (NMPA) of China for the treatment of adults and children aged 1 year and older with short bowel syndrome (SBS).

[0004] Although GLP-1 (glucagon-like peptide-1) and GLP-2 originate from the same precursor molecule, proglucagon, their distribution and functions in the body differ. GLP-1 primarily participates in blood glucose regulation, while GLP-2 mainly affects gut health and nutrient absorption. The functional difference between GLP-1 and GLP-2 lies in their binding to specific GLP-1 receptors, which are expressed in various tissues, including pancreatic β-cells, gastric mucosa, kidneys, lungs, and heart. GLP-1 exerts its main effect by stimulating glucose-dependent insulin release from the pancreas, while also slowing gastric emptying, inhibiting inappropriate postprandial glucagon release, and reducing food intake. GLP-2 primarily acts on the gut, promoting intestinal cell growth and proliferation, and playing a crucial role in gut health and nutrient absorption. These effects of GLP-2 suggest its potential application in treating certain intestinal diseases, such as short bowel syndrome. Therefore, there is no inherent correlation between GLP-1 and GLP-2.

[0005] Second-generation antipsychotics, or atypical antipsychotics (AATP), are currently used to treat various mental illnesses, such as schizophrenia. Compared to typical antipsychotics, AATP offers several significant benefits, including negative symptoms, improved cognitive function, prevention of deterioration, greater improvement in quality of life, and fewer extrapyramidal symptoms (EPS). The main side effects of second-generation antipsychotics are hypothermia, weight gain, glucose dysregulation, and dyslipidemia. These side effects are associated with potential long-term cardiovascular health risks, decreased medication adherence, and may ultimately lead to clinical deterioration. Although a deeper understanding of the biochemical effects of these drugs has been gained in recent years, the pharmacological mechanisms underlying their various therapeutic properties and associated side effects remain unclear. See HA Nasrallah, Molecular Psychiatry (2008) 13, 27–35. Many AATPs are associated with metabolic side effects, and there are numerous reports of hypothermia in newly initiated patients, which is particularly problematic in older patients and can sometimes be life-threatening. Furthermore, AATP may cause hyperglycemia and decreased insulin sensitivity within a few days. Prolonged use over several months often leads to excessive weight gain and increases the risk of type 2 diabetes and cardiovascular disease. Obesity-related metabolic syndrome is becoming a leading cause of death in schizophrenic patients taking AATP. Although adjunctive use of antihyperglycemic agents such as metformin can reduce induced weight gain in the short term, its long-term efficacy is limited, and there is currently no treatment for hypothermia. Summary of the Invention

[0006] To address the lack of an effective method for preventing and / or treating antipsychotic drug-induced metabolic dysfunction in the prior art, this invention provides the use of GLP-2 receptor agonists in the preparation of medicaments for treating metabolic dysfunction caused by antipsychotic drugs.

[0007] Metabolic dysfunction caused by antipsychotic drugs differs significantly from general metabolic dysfunction in its pathogenesis and symptoms. Antipsychotic metabolic dysfunction is drug-induced and positively correlated with drug dosage and duration of administration. Acute first-time administration is characterized by hypothermia, while chronic administration may also be accompanied by weight gain, glucose dysregulation, and dyslipidemia. In contrast, general metabolic dysfunction is usually multifactorial, involving interactions of genetics, environment, hormones, inflammation, mitochondrial function, gut microbiota, and neuroendocrine regulation. It typically does not present with hypothermia but is associated only with abnormal blood glucose and lipid metabolism, leading to obesity, hyperglycemia, and hyperlipidemia. Therefore, in clinical diagnosis, antipsychotic metabolic dysfunction and general metabolic dysfunction are distinct diseases.

[0008] The inventors have discovered that using currently known drugs for treating general metabolic disorders to treat metabolic disorders caused by antipsychotic drugs does not produce ideal therapeutic effects, especially failing to improve symptoms of hypothermia.

[0009] The inventors have discovered that GLP-2 receptor agonists, such as teduglutide, can block the inhibitory effects of antipsychotic drugs on neurons and alleviate antipsychotic drug-induced metabolic dysfunction, thereby opening up possibilities for targeting GLP-2 receptors to treat the side effects caused by antipsychotic drugs.

[0010] In this invention, "VMH" Pdyn Diseases caused by neuronal suppression can manifest as metabolic dysfunction, but they are clinically distinct from general metabolic dysfunctions. When VMH (Viral Meningococcal Hypoxia) occurs... Pdyn After neurons are acutely inhibited, the body usually presents with "hypothermia" as the most prominent symptom, which may also be accompanied by other symptoms such as weight gain, glucose imbalance and dyslipidemia.

[0011] To solve the above-mentioned technical problems, the present invention provides the following technical solution: the use of GLP-2 receptor agonists in the preparation of medicaments for the prevention and / or treatment of metabolic dysfunction caused by antipsychotic drugs.

[0012] In a specific embodiment of the present invention, the GLP-2 receptor agonist comprises an amino acid sequence as shown in SEQ ID NO:1 or 2, or comprises an amino acid sequence having at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in SEQ ID NO:1 or 2.

[0013] In a specific embodiment of the present invention, the GLP-2 receptor agonist is GLP-2 or teduglutide, or an analogue of GLP-2 or teduglutide.

[0014] In a specific embodiment of the present invention, the antipsychotic drug can inhibit VMH. Pdyn Neuron.

[0015] In a specific embodiment of the present invention, the antipsychotic drug is selected from one or more of olanzapine, clozapine, risperidone, zoltipine, serindole, ilopiperidone, quetiapine, palpanidone, asenapine, flupentixol, epipiperidone, amisulpride, flufenazine, cariprazine, lurasidone, aripiprazole, ziprasidone, and haloperidol.

[0016] In a specific embodiment of the present invention, the antipsychotic drug is selected from one or more of olanzapine, clozapine, and risperidone.

[0017] In a specific embodiment of the present invention, the metabolic dysfunction is caused by acute or chronic administration of antipsychotic drugs. Acute administration refers to a single or multiple administration of a drug within a short period of time, usually used to quickly achieve a therapeutic effect or to treat a disease or symptom urgently; in contrast, chronic administration refers to the continuous or intermittent administration of a drug over a longer period of time (such as weeks, months or even years) to treat chronic diseases or maintain a stable condition.

[0018] In a specific embodiment of the present invention, the metabolic dysfunction is manifested as one or more of the following: hypothermia, obesity, impaired glucose tolerance, impaired insulin response, hyperappetite, and sedation.

[0019] In a specific embodiment of the present invention, the metabolic dysfunction is manifested as hypothermia and / or sedation, and one or more of obesity, impaired glucose tolerance, impaired insulin response, and hyperappetite.

[0020] In a specific embodiment of the present invention, the metabolic dysfunction is manifested as hypothermia, and one or more selected from obesity, impaired glucose tolerance, impaired insulin response, hyperappetite, and sedation behavior.

[0021] To solve the above-mentioned technical problems, the technical solution provided by the present invention is: GLP-2 receptor agonists are used in the preparation of drugs for the prevention and / or treatment of VMH. Pdyn Use in drugs for diseases caused by neuronal suppression.

[0022] In a specific embodiment of the present invention, the GLP-2 receptor agonist comprises an amino acid sequence as shown in SEQ ID NO:1 or 2, or comprises an amino acid sequence having at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in SEQ ID NO:1 or 2.

[0023] In a specific embodiment of the present invention, the GLP-2 receptor agonist is GLP-2 or teduglutide, or an analogue of GLP-2 or teduglutide.

[0024] In a specific embodiment of the present invention, the VMH Pdyn Neurons can be acutely or chronically inhibited. Acute inhibition refers to VMH. Pdyn Neurons are inhibited in a short and rapid manner; chronic inhibition refers to VMH. Pdyn Neurons are suppressed for a long period of time and continuously.

[0025] In a specific embodiment of the present invention, the VMHPdyn Neurons are suppressed by antipsychotic drugs.

[0026] In a specific embodiment of the present invention, the antipsychotic drug is selected from one or more of olanzapine, clozapine, risperidone, zoltipine, serindole, ilopiperidone, quetiapine, palpanidone, asenapine, flupentixol, epipiperidone, amisulpride, flufenazine, cariprazine, lurasidone, aripiprazole, ziprasidone, and haloperidol.

[0027] In a specific embodiment of the present invention, the antipsychotic drug is selected from one or more of olanzapine, clozapine, and risperidone.

[0028] In a specific embodiment of the present invention, the disease exhibits symptoms of metabolic dysfunction.

[0029] In a specific embodiment of the present invention, the metabolic dysfunction is manifested as one or more of the following: hypothermia, obesity, impaired glucose tolerance, impaired insulin response, hyperappetite, and sedation.

[0030] In a specific embodiment of the present invention, the metabolic dysfunction is manifested as hypothermia and / or sedation, and one or more of obesity, impaired glucose tolerance, impaired insulin response, and hyperappetite.

[0031] In a specific embodiment of the present invention, the metabolic dysfunction is manifested as hypothermia, and one or more selected from obesity, impaired glucose tolerance, impaired insulin response, hyperappetite, and sedation behavior.

[0032] To solve the above-mentioned technical problems, the present invention provides the following technical solution: a kit containing a GLP-2 receptor agonist and an antipsychotic drug.

[0033] In a specific embodiment of the present invention, the GLP-2 receptor agonist comprises an amino acid sequence as shown in SEQ ID NO:1 or 2, or comprises an amino acid sequence having at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in SEQ ID NO:1 or 2; and / or, the antipsychotic drug is capable of inhibiting VMH. Pdyn Neuron, for example, selected from one or more of olanzapine, clozapine, risperidone, zoltipine, serindole, ilopiperidone, quetiapine, palpanidone, asenapine, flupentixol, epipiperidone, amisulpride, flufenazine, cariprazine, lurasidone, aripiprazole, ziprasidone, and haloperidol.

[0034] In a specific embodiment of the present invention, the GLP-2 receptor agonist is GLP-2 or teduglutide, or an analogue of GLP-2 or teduglutide; and / or, the antipsychotic drug is selected from one or more of olanzapine, clozapine, and risperidone.

[0035] In a specific embodiment of the present invention, the kit contains teduglutide and olanzapine.

[0036] To solve the above-mentioned technical problems, the technical solution provided by the present invention is: the use of the kit described in the above technical solution of the present invention in the preparation of drugs for treating mental illnesses.

[0037] In a specific embodiment of the present invention, the mental illness is selected from one or more of depression, bipolar disorder, schizophrenia, and anxiety disorder.

[0038] To solve the above-mentioned technical problems, the technical solution provided by the present invention is: a method for activating VMH in vivo or in vitro. Pdyn A method for neuronal reactions, the method comprising administering a GLP-2 receptor agonist and the VMH Pdyn Neuronal contact. GLP-2 receptor agonists interact with neurons in the VMH. Pdyn GLP-2 receptors expressed on neurons bind to and activate VMH. Pdyn The function of neurons.

[0039] In specific embodiments of the present invention, the method is for non-diagnostic, preventive, and / or therapeutic purposes. In the present invention, the application scenarios for "non-diagnostic, preventive, and / or therapeutic purposes" include, but are not limited to, activating VMH in vivo or in vitro using GLP-2 receptor agonists for research purposes in a laboratory setting. Pdyn Neuron.

[0040] In a specific embodiment of the present invention, the VMH Pdyn Neuronal inhibition by antipsychotic drugs (GLP-2 receptor agonists themselves can cause VMH) Pdyn The activation of neurons (which, when used with antipsychotics, blocks the inhibitory effect of the antipsychotics); and / or, the GLP-2 receptor agonist comprises an amino acid sequence as shown in SEQ ID NO:1 or 2, or comprises an amino acid sequence having at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in SEQ ID NO:1 or 2.

[0041] In a specific embodiment of the present invention, the VMH Pdyn Neurons may be acutely or chronically inhibited.

[0042] In a specific embodiment of the present invention, the antipsychotic drug is selected from one or more of olanzapine, clozapine, risperidone, zotepine, serindole, ilopiperidone, quetiapine, palpanidone, asenapine, flupentixol, epipiperidone, amisulpride, flufenazine, cariprazine, lurasidone, aripiprazole, ziprasidone, and haloperidol; and / or, the GLP-2 receptor agonist is GLP-2 or teduglutide, or an analogue of GLP-2 or teduglutide.

[0043] In a specific embodiment of the present invention, the antipsychotic drug is selected from one or more of olanzapine, clozapine, and risperidone.

[0044] To solve the above-mentioned technical problems, the present invention provides the following technical solution: a method for preventing and / or treating metabolic dysfunction caused by antipsychotic drugs, the method comprising administering an effective amount of a GLP-2 receptor agonist to a subject in need.

[0045] In a specific embodiment of the present invention, the GLP-2 receptor agonist comprises an amino acid sequence as shown in SEQ ID NO:1 or 2, or comprises an amino acid sequence having at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in SEQ ID NO:1 or 2.

[0046] In a specific embodiment of the present invention, the GLP-2 receptor agonist is GLP-2 or teduglutide, or an analogue of GLP-2 or teduglutide.

[0047] In a specific embodiment of the present invention, the antipsychotic drug can inhibit VMH. Pdyn Neuron.

[0048] In a specific embodiment of the present invention, the antipsychotic drug is selected from one or more of olanzapine, clozapine, risperidone, zoltipine, serindole, ilopiperidone, quetiapine, palpanidone, asenapine, flupentixol, epipiperidone, amisulpride, flufenazine, cariprazine, lurasidone, aripiprazole, ziprasidone, and haloperidol.

[0049] In a specific embodiment of the present invention, the antipsychotic drug is selected from one or more of olanzapine, clozapine, and risperidone.

[0050] In a specific embodiment of the present invention, the metabolic dysfunction is caused by acute or chronic administration of antipsychotic drugs.

[0051] In a specific embodiment of the present invention, the metabolic dysfunction is manifested as one or more of the following: hypothermia, obesity, impaired glucose tolerance, impaired insulin response, hyperappetite, and sedation.

[0052] In a specific embodiment of the present invention, the metabolic dysfunction is manifested as hypothermia and / or sedation, and one or more of obesity, impaired glucose tolerance, impaired insulin response, and hyperappetite.

[0053] In a specific embodiment of the present invention, the metabolic dysfunction is manifested as hypothermia, and one or more selected from obesity, impaired glucose tolerance, impaired insulin response, hyperappetite, and sedation behavior.

[0054] To solve the above-mentioned technical problems, the present invention provides a GLP-2 receptor agonist for the prevention and / or treatment of metabolic dysfunction caused by antipsychotic drugs.

[0055] In a specific embodiment of the present invention, the GLP-2 receptor agonist comprises an amino acid sequence as shown in SEQ ID NO:1 or 2, or comprises an amino acid sequence having at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in SEQ ID NO:1 or 2.

[0056] In a specific embodiment of the present invention, the GLP-2 receptor agonist is GLP-2 or teduglutide, or an analogue of GLP-2 or teduglutide.

[0057] In a specific embodiment of the present invention, the antipsychotic drug can inhibit VMH. Pdyn Neuron.

[0058] In a specific embodiment of the present invention, the antipsychotic drug is selected from one or more of olanzapine, clozapine, risperidone, zoltipine, serindole, ilopiperidone, quetiapine, palpanidone, asenapine, flupentixol, epipiperidone, amisulpride, flufenazine, cariprazine, lurasidone, aripiprazole, ziprasidone, and haloperidol.

[0059] In a specific embodiment of the present invention, the antipsychotic drug is selected from one or more of olanzapine, clozapine, and risperidone.

[0060] In a specific embodiment of the present invention, the metabolic dysfunction is caused by acute or chronic administration of antipsychotic drugs.

[0061] In a specific embodiment of the present invention, the metabolic dysfunction is manifested as one or more of the following: hypothermia, obesity, impaired glucose tolerance, impaired insulin response, hyperappetite, and sedation.

[0062] In a specific embodiment of the present invention, the metabolic dysfunction is manifested as hypothermia and / or sedation, and one or more of obesity, impaired glucose tolerance, impaired insulin response, and hyperappetite.

[0063] In a specific embodiment of the present invention, the metabolic dysfunction is manifested as hypothermia, and one or more selected from obesity, impaired glucose tolerance, impaired insulin response, hyperappetite, and sedation behavior.

[0064] To solve the above-mentioned technical problems, the technical solution provided by the present invention is: a method for preventing and / or treating VMH. Pdyn A method for treating diseases caused by neuronal suppression, the method comprising administering an effective amount of a GLP-2 receptor agonist to a subject in need.

[0065] In a specific embodiment of the present invention, the GLP-2 receptor agonist comprises an amino acid sequence as shown in SEQ ID NO:1 or 2, or comprises an amino acid sequence having at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in SEQ ID NO:1 or 2.

[0066] In a specific embodiment of the present invention, the GLP-2 receptor agonist is GLP-2 or teduglutide, or an analogue of GLP-2 or teduglutide.

[0067] In a specific embodiment of the present invention, the VMH Pdyn Neurons may be acutely or chronically inhibited.

[0068] In a specific embodiment of the present invention, the VMH Pdyn Neurons are suppressed by antipsychotic drugs.

[0069] In a specific embodiment of the present invention, the antipsychotic drug is selected from one or more of olanzapine, clozapine, risperidone, zoltipine, serindole, ilopiperidone, quetiapine, palpanidone, asenapine, flupentixol, epipiperidone, amisulpride, flufenazine, cariprazine, lurasidone, aripiprazole, ziprasidone, and haloperidol.

[0070] In a specific embodiment of the present invention, the antipsychotic drug is selected from one or more of olanzapine, clozapine, and risperidone.

[0071] In a specific embodiment of the present invention, the disease exhibits symptoms of metabolic dysfunction.

[0072] In a specific embodiment of the present invention, the metabolic dysfunction is manifested as one or more of the following: hypothermia, obesity, impaired glucose tolerance, impaired insulin response, hyperappetite, and sedation.

[0073] In a specific embodiment of the present invention, the metabolic dysfunction is manifested as hypothermia and / or sedation, and one or more of obesity, impaired glucose tolerance, impaired insulin response, and hyperappetite.

[0074] In a specific embodiment of the present invention, the metabolic dysfunction is manifested as hypothermia, and one or more selected from obesity, impaired glucose tolerance, impaired insulin response, hyperappetite, and sedation behavior.

[0075] To solve the above-mentioned technical problems, the present invention provides the following technical solution: a GLP-2 receptor agonist for the prevention and / or treatment of VMH. Pdyn Diseases caused by the suppression of neurons.

[0076] In a specific embodiment of the present invention, the GLP-2 receptor agonist comprises an amino acid sequence as shown in SEQ ID NO:1 or 2, or comprises an amino acid sequence having at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in SEQ ID NO:1 or 2.

[0077] In a specific embodiment of the present invention, the GLP-2 receptor agonist is GLP-2 or teduglutide, or an analogue of GLP-2 or teduglutide.

[0078] In a specific embodiment of the present invention, the VMH Pdyn Neurons may be acutely or chronically inhibited.

[0079] In a specific embodiment of the present invention, the VMH Pdyn Neurons are suppressed by antipsychotic drugs.

[0080] In a specific embodiment of the present invention, the antipsychotic drug is selected from one or more of olanzapine, clozapine, risperidone, zoltipine, serindole, ilopiperidone, quetiapine, palpanidone, asenapine, flupentixol, epipiperidone, amisulpride, flufenazine, cariprazine, lurasidone, aripiprazole, ziprasidone, and haloperidol.

[0081] In a specific embodiment of the present invention, the antipsychotic drug is selected from one or more of olanzapine, clozapine, and risperidone.

[0082] In a specific embodiment of the present invention, the disease exhibits symptoms of metabolic dysfunction.

[0083] In a specific embodiment of the present invention, the metabolic dysfunction is manifested as one or more of the following: hypothermia, obesity, impaired glucose tolerance, impaired insulin response, hyperappetite, and sedation.

[0084] In a specific embodiment of the present invention, the metabolic dysfunction is manifested as hypothermia and / or sedation, and one or more of obesity, impaired glucose tolerance, impaired insulin response, and hyperappetite.

[0085] In a specific embodiment of the present invention, the metabolic dysfunction is manifested as hypothermia, and one or more selected from obesity, impaired glucose tolerance, impaired insulin response, hyperappetite, and sedation behavior.

[0086] To solve the above-mentioned technical problems, the present invention provides the following technical solution: a method for treating mental illness, the method comprising administering an effective amount of the kit as described in the above-described technical solution of the present invention to a subject in need.

[0087] In a specific embodiment of the present invention, the mental illness is selected from one or more of depression, bipolar disorder, schizophrenia, and anxiety disorder.

[0088] To solve the above-mentioned technical problems, the technical solution provided by the present invention is: a medicine box as described in the above technical solution of the present invention, which is used to treat mental illness.

[0089] In a specific embodiment of the present invention, the mental illness is selected from one or more of depression, bipolar disorder, schizophrenia, and anxiety disorder.

[0090] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0091] The reagents and raw materials used in this invention are all commercially available.

[0092] The positive and progressive effects of this invention are as follows:

[0093] This invention discovers that GLP-2 receptor agonists, such as teduglutide, can block the inhibitory effects of antipsychotic drugs on neurons and alleviate antipsychotic drug-induced metabolic dysfunction, thereby opening up possibilities for targeting GLP-2 receptors to treat the side effects caused by antipsychotic drugs. Attached Figure Description

[0094] Figure 1 shows the results of tiduglutide alleviating olanzapine-induced hypothermia in mice in Example 1. The left side of Figure 1 is a schematic diagram of the experiment. Figure 1 shows the mean curves of core and brown adipose tissue (BAT) temperature in C57BL / 6 mice after acute intraperitoneal injection of saline or olanzapine (Olz) solution (2.5 mg / kg) (3-4 mice per group). The shaded areas in the graphs represent time points that are statistically significant compared to the control group. Injection begins at time point 0 (dashed line and arrow). The right side of Figure 1 shows representative infrared thermograms after injection of the control or olanzapine. The p-value was determined by two-way ANOVA, followed by Dunnett's multiple comparison test.

[0095] Figure 2 shows the changes in core temperature curve (left) and area under the curve (AUC) (right) in the presence of olanzapine (ip) during treatment with the specified drugs (metformin = 200 mg / kg, tiduglutide = 1 mg / kg, and GLP-1R agonist: Exendin-4 = 2.5 μg / kg) (N = 4–6 mice per group). The p-value in the left figure was determined by two-way ANOVA followed by Dunnett's multiple comparison test; the p-value in the right figure was determined by one-way ANOVA followed by Dunnett's multiple comparison test.

[0096] Figure 3 (left) shows the experimental timeline for FOS sample collection and subsequent staining; Figure 3 (right) shows the quantification of FOS-positive cells in designated brain regions (N=3 mice per group): PAG (periaqueductal gray matter); ARC (arctic nucleus); PVN (paraventricular nucleus); BLA (basolateral amygdala); CeA (central nucleus of the amygdala). P-values ​​were determined using two-way ANOVA, followed by Sidak's multiple comparison test.

[0097] Figure 4 shows representative confocal images of in situ hybridization of Fos, Glp2r, and Pdyn mRNAs in VMH. Left: Low-power view of VMH (white dashed line), scale bar 100 μm; Right: High-power view of VMH (white box) in the left panel, scale bar 20 μm. Arrows indicate cells co-localized with Fos, Glp2r, and Pdyn. The bottom of Figure 4 shows the FOS+ cell count in VMH; a pie chart of Fos expression in Pdyn+ neurons; a pie chart of Glp2r expression in all neurons or Pdyn+ neurons; and a pie chart of Fos expression in Pdyn+ and Glp2r+ neurons. P-values ​​were determined by unpaired two-tailed Student's t-test (bottom left 1, bottom right 1) or by chi-square test (bottom left 2).

[0098] Figure 5 shows VMH. PdynA schematic diagram of the neuronal ablation strategy and an experimental timeline are shown in Figure 5. The lower part of Figure 5 shows the changes in core and BAT temperature in mCherry or caspase-3 mice (N=3 mice per group) after treatment with saline or olanzapine (2.5 mg / kg). The shaded areas in the figure represent statistically significant time points when comparing the mCherry-olz group with the caspase-olz group. P-values ​​were determined using two-way ANOVA, followed by Dunnett's multiple comparison test.

[0099] Figure 6 shows a schematic diagram (left) and a representative image (right) (green) of virus-mediated GCaMP expression in Pdyn-cre mice, scale bar, 100 μm; Figure 6 also shows VMH... Pdyn Mean GCaMP curves (left) and quantitative GCaMP fluorescence (right) of neurons during olanzapine (2.5 mg / kg) or saline treatment (N = 4 mice per group). P-values ​​were determined by two-way ANOVA followed by Sidak's multiple comparison test.

[0100] Figure 7 shows the flowchart of fiber optic recording at the top, and Figure 7 shows the VMH process at the bottom. Pdyn Mean GCaMP curves (left) and quantitative GCaMP fluorescence (right) of neurons during treatment with saline (1 mg / kg) or olanzapine (2.5 mg / kg) in the presence of teduglutide (1 mg / kg) (N = 4 mice per group). P-values ​​were determined by two-way ANOVA followed by Sidak's multiple comparison test.

[0101] Figure 8 (left) is a schematic diagram depicting the spatial arrangement of the electrodes; Figure 8 (right) shows VMH in the presence of olanzapine (50 μM). Pdyn Representative curves of neuronal firing changes; VMH in the presence of teduglutide (1 μM). Pdyn Representative curves of neuronal firing changes; representative curves of neuronal firing changes during olanzapine treatment, regardless of the presence of teduglutide (1 μM); quantitative plots of the above curves; p-values ​​were determined by two-way ANOVA followed by Sidak's multiple comparison test; representative trajectories of neuronal firing changes in the presence of AMPA receptor antagonists (NBQX, 20 μM), NMDA receptor antagonists (D-AP5, 50 μM), and GABAA receptor antagonists (PTX, 100 μM) concurrently with teduglutide (1 μM); p-values ​​were determined by unpaired two-tailed Student's t-test.

[0102] Figure 9 shows the VMH in Example 3. PdynThe effects of neuronal activation on the efficacy of olanzapine in treating schizophrenia are illustrated in Figure 9. The top left of Figure 9 shows a schematic diagram of intraperitoneal injection of the designated drug and the startle reflex system in mice. The top right of Figure 9 shows the prepulse inhibition (PPI) after intraperitoneal injection of the designated drug at three different prepulse intensities (76, 79, and 85 dB) in wild-type C57BL / 6 mice (N = 5–6 per group). The bottom left of Figure 9 shows the PPI in Pdyn-cre mice injected with AAV-DIO-mCherry after intraperitoneal injection of the designated drug at three different prepulse intensities (76, 79, and 85 dB) (N = 5–6 per group). The bottom right of Figure 9 shows the PPI in Pdyn-cre mice injected with AAV-DIO-hM3d after intraperitoneal injection of the designated drug at three different prepulse intensities (76, 79, and 85 dB) (N = 5–6 per group). P-values ​​were determined by two-way ANOVA, followed by Sidak's multiple comparison test.

[0103] Figure 10 shows the results of long-term combined administration of olanzapine and tiduglutide in Example 4. Specifically, chronic tiduglutide treatment resulted in changes in weight; changes in body composition; changes in ipGTT, mouse blood glucose (left), and area under the curve (AUC) (right); and changes in ipITT, mouse blood glucose (left), and AUC (right). Each group had N = 5 mice. The p-value for mouse blood glucose AUC was determined by an unpaired two-tailed Student's t-test, and other p-values ​​were determined by two-way ANOVA, followed by Sidak's multiple comparison test.

[0104] Figure 11 shows the results of long-term combined administration of olanzapine and tiduglutide in Example 4, specifically metabolic cage analysis of food intake, physical activity, calorie production, and respiratory entropy (RER). N = 5 mice per group. P-values ​​were determined by two-way ANOVA, followed by Sidak's multiple comparison test.

[0105] Figure 12 shows the inhibition of VMH by risperidone or clozapine in Example 5. Pdyn The results of neuronal activity are shown in the VMH diagram. Pdyn Mean GCaMP curves of neurons during treatment with risperidone (1.5 mg / kg), clozapine (10 mg / kg), or saline, and quantitative analysis of GCaMP fluorescence 30 minutes after intraperitoneal injection. P-values ​​were determined by unpaired two-tailed Student's t-test.

[0106] Data are expressed as mean ± SEM, ns = no significance, *P<0.05, **P<0.01, ***P<0.001. Detailed Implementation

[0107] Unless otherwise defined herein, the scientific and technical terms used in this application will have the meanings commonly understood by one of ordinary skill in the art. Generally, the nomenclature and techniques used herein in relation to chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry are those well-known and frequently used in the art.

[0108] All publications, patents, and published patent applications cited in this application are expressly incorporated herein by reference. In case of conflict, this specification (including its specific definitions) shall prevail.

[0109] Each embodiment of the invention described herein can be used alone or in combination with one or more other embodiments of the invention.

[0110] Unless otherwise stated, the following definitions are provided for the specific terms used in the above written description.

[0111] Throughout this specification, the terms “comprising,” “including,” or “having” shall be understood to mean including the specified whole (or component) or group of whole (or component) but not excluding any other whole (or component) or group of whole (or component). “Comprising” and “including but not limited to” are used interchangeably and include the scope of the term “consisting of.”

[0112] Nouns without classifiers include both singular and plural forms unless the context clearly indicates otherwise.

[0113] The terms “patient,” “object,” and “individual” are used interchangeably and refer to humans or non-human animals. These terms include mammals such as humans, primates, livestock (e.g., cattle, pigs), pets (e.g., dogs, cats), and rodents (e.g., mice and rats).

[0114] The terms “polypeptide,” “peptide,” “oligopeptide,” and “protein” are used interchangeably herein to refer to polymers or oligomers of consecutive amino acid residues. Amino acids are linked together by peptide bonds between the carboxyl and amino groups of adjacent amino acid residues. As used herein, the term “amino acid” refers not only to an amino acid molecule or the amino acid residue itself, but also to an abbreviation, letter, character, or word list representing amino acid residues, such as those that are part of a peptide. Amino acids may be represented by commonly known three-letter symbols or single-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Committee.

[0115] This article uses conventional single-letter amino acid codes and three-letter amino acid codes, as shown in Table 1 below.

[0116] Table 1. Single-letter amino acid codes and three-letter amino acid codes

[0117] As used in the context of this invention, the term "agonist" refers to a substance (ligand) that activates the receptor type in question. Therefore, a GLP-2 receptor agonist refers to a substance or ligand that activates the GLP-2 receptor.

[0118] As used in the context of this invention, the term "analyte" refers to a substance with a similar chemical structure and exhibiting similar functions and / or activities. Specifically, the term "GLP-2 analogue" refers to a polypeptide with a structure similar to that of wild-type GLP-2 polypeptides and exhibiting similar functions, such as exerting biological effects through the GLP-2 receptor (GLP-2R).

[0119] In one implementation, "analyte" is represented by amino acid sequence identity. "Percentage (%) amino acid sequence identity" relative to the GLP-2 polypeptide sequence is defined as the percentage of amino acid residues in the candidate sequence that are identical to those in the wild-type GLP-2 sequence after sequence alignment and the introduction of gaps (if necessary) to obtain the maximum percentage sequence identity, and without considering any conserved substitutions as part of sequence identity. Those skilled in the art can perform sequence alignment using techniques known in the art, such as publicly available software like BLAST, BLAST2, or Align software. See, for example, Altschul et al., Methods in Enzymology 266:460-480 (1996); Pearson et al., Genomics-46:24-36, 1997, and the alignment program at molbiol.soton.ac.uk / compute / align.

[0120] The percentage sequence identity according to the invention can be determined using these procedures and their default settings. More generally, those skilled in the art can readily determine suitable parameters for determining the alignment, including any algorithm required to achieve maximum alignment over the full-length sequences being compared.

[0121] In one embodiment, the "analyte" is characterized by a mutation in the amino acid sequence. In one embodiment, the mutation includes the deletion, substitution, addition, or combination thereof of one or more amino acids. In some embodiments, the GLP-2 analog comprises an amino acid sequence having a deletion, substitution, or addition of up to 1, 2, 3, 4, or 5 amino acids compared to the wild-type GLP-2 peptide.

[0122] In one embodiment, the substitution is a conserved substitution. As used herein, "conserved substitution" means that an amino acid residue belonging to a position in the wild-type human GLP-2 peptide sequence has been substituted by an amino acid residue belonging to the same group (I, II, III, IV, V, 1, 2, 3) as defined in Table 2 below:

[0123] Table 2 Conservative Substitution

[0124] As used in this article, “non-conservative substitution” means any substitution other than the conserved substitution of amino acid residues in the wild-type human GLP-2 sequence, such as substitution with non-protein, non-natural amino acids (Sar, Nle, Aib) or substitution with amino acids that do not belong to the same group.

[0125] In one embodiment, the "analyte" is characterized by modifications in the amino acid sequence. In one embodiment, the modifications include, but are not limited to, acetylation, phosphorylation, and methylation.

[0126] In one embodiment, the present invention provides the use of a GLP-2 receptor agonist in the preparation of a medicament for treating metabolic dysfunction caused by antipsychotic drugs.

[0127] In one embodiment, the GLP-2 receptor agonist is a GLP-2 peptide. Wild-type human GLP-2 (1-33) has the following amino acid sequence:

[0128] His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp (SEQ ID NO: 1).

[0129] In one embodiment, the GLP-2 receptor agonist is a GLP-2 analog. In one embodiment, the GLP-2 analog has at least 60% amino acid sequence identity compared to wild-type GLP-2 (1-33). For example, the GLP-2 analog of the present invention may have about 60% to 97% sequence identity compared to wild-type GLP-2 (1-33), for example about 70% to 91%, and in some embodiments, at least 60%, 70%, or 85% sequence identity.

[0130] In one embodiment, the GLP-2 receptor agonist is teduglutide. Teduglutide is a natural human glucagon-like peptide-2 (GLP-2) analog in which the alanine at position 2 has been replaced by glycine, making the peptide resistant to degradation by dipeptidyl peptidase-4 (DPP-4). Therefore, teduglutide has a longer half-life than GLP-2 (1.3 hours for teduglutide and 7 minutes for GLP-2).

[0131] In one embodiment, tiduglutide has the following amino acid sequence:

[0132] His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp (SEQ ID NO: 2).

[0133] In one embodiment, the GLP-2 receptor agonist is a teduglutide analog. In one embodiment, the teduglutide analog has at least 60% amino acid sequence identity with SEQ ID NO:2.

[0134] Typically, the GLP-2 receptor agonist of the present invention has activity against the GLP-2 receptor. EC can be used. 50 The value serves as a numerical measure of agonist potency for a given receptor. EC 50 The EC50 value is a measure of the concentration of a compound required to achieve half of its maximum activity in a specific assay. For a specific receptor, the EC50 value is... 50 EC compared to the reference compound in the same assay 50 The lower concentration of the compound may be considered to have higher potency to the receptor than the reference compound.

[0135] The GLP-2 receptor agonists of the present invention generally exhibit higher activity against GLP-2 receptors (e.g., human GLP-2 receptors) than wild-type human GLP-2 (hGLP-2). Therefore, in any given assay for GLP-2 activity, GLP-2 analogs will have lower EC50 values ​​than wild-type human GLP-2 or [Gly2]-hGLP-2 (i.e., teduglutide). 50 Therefore, when evaluated in GLP-2 activity assays, the EC50 of GLP-2 analogues... 50 EC with hGLP-2 or [Gly2]-hGLP-2 50 The ratio is usually less than 1. It can be, for example, less than 0.5 or less than 0.1, or less than 0.01.

[0136] In one embodiment, the GLP-2 receptor agonist of the present invention retains GLP-2 activity, but its potency toward the GLP-2 receptor need not be the same as or higher than that of hGLP-2 or [Gly2]-hGLP-2. The GLP-2 receptor agonist of the present invention may have lower potency, as long as a sufficient level of GLP-2 activity is maintained. In any given assay of GLP-2 activity, the GLP-2 analogue may have a lower or higher EC50 than wild-type GLP-2 or [Gly2]-hGLP-2. 50When evaluated in the same GLP-2 activity assay, the EC50 of GLP-2 analogs... 50 EC with hGLP-2 or [Gly2]-hGLP-2 50 The ratio can be, for example, less than 200, less than 100, less than 10, less than 5, less than 1, less than 0.1, less than 0.5, or less than 0.1.

[0137] In one embodiment, the antipsychotic drug comprises an atypical antipsychotic (AATP). In one embodiment, the antipsychotic drug includes, but is not limited to, olanzapine, clozapine, risperidone, zotepine, serindole, ilopiperidone, quetiapine, palpanidone, asenapine, flupentixol, epiprexazole, amisulpride, flufenazine, cariprazine, lurasidone, aripiprazole, ziprasidone, and haloperidol. It should be understood that any antipsychotic drug currently known or developed in the future may be used in this invention, provided that it causes the metabolic dysfunction described herein.

[0138] In one implementation, metabolic dysfunction caused by antipsychotic drugs includes, but is not limited to, hypothermia, obesity, glucose intolerance, abnormal insulin response, hyperappetite, and sedative behavior.

[0139] In one implementation, metabolic dysfunction caused by antipsychotic drugs includes symptoms of hypothermia and / or sedation, and may also include one or more symptoms selected from obesity, glucose intolerance, impaired insulin response, and hyperappetite.

[0140] In one implementation, metabolic dysfunction caused by antipsychotic drugs includes symptoms of hypothermia, and may also include one or more symptoms selected from obesity, glucose intolerance, impaired insulin response, hyperappetite, and sedative behavior.

[0141] The inventors discovered that GLP-2 receptor agonists can block the inhibitory effect of antipsychotic drugs on neurons, thereby alleviating antipsychotic drug-induced metabolic dysfunction. Therefore, GLP-2 receptor agonists can treat any metabolic dysfunction caused by the inhibitory effect of antipsychotic drugs on neurons.

[0142] In one embodiment, the metabolic dysfunction is a side effect or adverse reaction caused by antipsychotic drugs.

[0143] In one particular implementation, the metabolic dysfunction is a metabolic dysfunction caused by olanzapine, clozapine, or risperidone.

[0144] In one particular implementation, the metabolic dysfunction is hypothermia, obesity, and / or diabetes caused by olanzapine.

[0145] In one particular implementation, the antipsychotic drug is olanzapine, clozapine, or risperidone.

[0146] In one particular implementation, the GLP-2 receptor agonist is tiduglutide.

[0147] In one particular implementation, the neuron is a VMH Pdyn Neuron.

[0148] The GLP-2 receptor agonist of the present invention can be formulated into a pharmaceutical composition for storage or administration, and the composition contains a therapeutically effective amount of the GLP-2 receptor agonist in a pharmaceutically acceptable carrier.

[0149] The effective therapeutic dose will depend on the route of administration, the type of mammal being treated, and the physical characteristics of the specific mammal under consideration. These factors determining the effective therapeutic dose and their interrelationships are well known to those skilled in the art. The effective therapeutic dose and method of administration can be adjusted to achieve optimal efficacy, but this depends on factors such as body weight, diet, and concurrent medications, as well as other factors well known to those skilled in the art. Because these factors determining the effective therapeutic dose and their interrelationships are well known, determining the amount required to achieve the desired outcome of preventing and / or treating the diseases described herein will be within the capabilities of those skilled in the art.

[0150] As used herein, a “therapeutic effective amount” is an amount that reduces symptoms of a given condition or pathology and, preferably, normalizes a physiological response in an individual with the condition or pathology. The reduction of symptoms or normalization of physiological response can be determined using conventional methods in the art and can vary depending on the given condition or pathology. In one aspect, a therapeutically effective amount of one or more GLP-2 receptor agonists of the present invention or a pharmaceutical composition comprising one or more GLP-2 receptor agonists of the present invention is an amount that restores a measurable physiological parameter to substantially the same level as that in an individual without the condition or pathology (preferably within 30%, more preferably within 20%, more preferably within 10%) of the normal value of that parameter.

[0151] In one embodiment of the invention, the GLP-2 receptor agonist or therapeutic composition of the invention is administered at a low dose level and the dose level is increased until the desired effect of prevention / treatment of the relevant medical indication is achieved. This may be defined as a therapeutically effective dose. For the GLP-2 receptor agonist of the invention, whether alone or as part of a therapeutic composition, such a dose may be from about 0.01 mg / kg to 100 mg / kg body weight, for example from about 0.01 mg / kg to 10 mg / kg body weight, for example 10-100 μg / kg body weight.

[0152] For therapeutic applications, the GLP-2 receptor agonist of the present invention can be formulated together with a pharmaceutically acceptable carrier suitable for delivering the peptide via a chosen route of administration. For the purposes of this invention, peripheral non-enteric routes include intravenous, intramuscular, subcutaneous, and intraperitoneal administration. The GLP-2 receptor agonist used in this invention is also suitable for administration via oral, rectal, nasal, or lower respiratory tract routes. These are referred to as non-enteric routes. The pharmaceutical compositions of the present invention comprise the GLP-2 receptor agonist of the present invention and a pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers are those conventionally used with peptide-based drugs, such as diluents, excipients, etc. Pharmaceutically acceptable carriers for therapeutic applications are well known in the pharmaceutical industry and described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (ARGennaro, ed., 1985). For example, sterile saline and slightly acidic or physiologically pH phosphate-buffered saline can be used. Suitable pH buffers may be phosphates, citrates, acetates, tris(hydroxymethyl)aminomethane (TRIS), N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS), ammonium bicarbonate, diethanolamine, histidine, arginine, lysine, or acetates, or mixtures thereof. In some embodiments, preferred buffering ranges are pH 4-8, pH 6.5-8, and more preferably pH 7-7.5. Preservatives may be provided in the pharmaceutical composition, such as p-, o-, and m-cresols, methylparaben, propylparaben, phenol, benzyl alcohol, sodium benzoate, benzoic acid, benzyl benzoate, sorbic acid, and / or propionic acid. Stabilizers that prevent oxidation, deamidation, isomerization, racemization, cyclization, and peptide hydrolysis may be provided in the pharmaceutical composition, such as ascorbic acid, methionine, tryptophan, EDTA, aspartic acid, lysine, arginine, glutamine, and / or glycine. Stabilizers that prevent aggregation, fibrosis, and precipitation, such as sodium dodecyl sulfate, polyethylene glycol, carboxymethyl cellulose, and / or cyclodextrin, may also be provided in the pharmaceutical composition. Organic modifiers for solubilization or preventing aggregation, such as ethanol, acetic acid, and / or acetates, may be provided in the pharmaceutical composition. Isotonic agents, such as salts like sodium chloride, or sugars like glucose, mannitol, lactose, trehalose, sucrose, or mixtures thereof, may be provided in the pharmaceutical composition.

[0153] Detergents, such as Tween 20, Tween 80, SDS, or poloxamer, such as pluronic F-68 or pluronic F-127, may be provided in the pharmaceutical compositions of the present invention. Dyes and flavoring agents may also be provided in the pharmaceutical compositions. Suspending agents may also be used.

[0154] Organic modifiers for lyophilization of lyophilized products may be provided in pharmaceutical formulations, such as ethanol, tert-butanol, 2-propanol, ethanol, glycerol, and / or polyethylene glycol. Fillers and isotropic agents, such as salts (e.g., sodium chloride), sugars (e.g., glucose, mannitol, lactose, trehalose, sucrose, or mixtures thereof), amino acids (e.g., glycine and glutamic acid), or excipients (e.g., cysteine, lecithin, or human serum albumin, or mixtures thereof), may be provided in pharmaceutical compositions for lyophilization.

[0155] The pharmaceutical compositions of the present invention can be formulated into the following dosage forms and used: tablets, capsules or elixirs for oral administration; suppositories for rectal administration; sterile solutions or sterile powders or suspensions for injection administration, etc.

[0156] When administered parenterally, such as intravenously and subcutaneously, injectable pharmaceutical compositions may be prepared in conventional forms, such as aqueous solutions or suspensions; lyophilized solid forms suitable for reconstitution before use; or suspensions or emulsions in liquids prior to injection.

[0157] The diluent used for reconstitution of lyophilized products may be selected, for example, from the buffers listed above or from water, brine, glucose, mannitol, lactose, trehalose, sucrose, lecithin, albumin, monosodium glutamate, cysteine ​​hydrochloride, or water for injection, and may contain detergents such as Tween 20, Tween 80, poloxamer (e.g., Pluronic F-68 or Pluronic F-127), polyethylene glycol, and / or preservatives such as p-cresol, o-cresol and m-cresol, methylparaben, propylparaben, phenol, benzyl alcohol, sodium benzoate, benzoic acid, benzyl benzoate, sorbic acid, propionic acid, and / or organic modifiers such as ethanol, acetic acid, citric acid, lactic acid, or their salts.

[0158] Additionally, if desired, injectable pharmaceutical compositions may contain small amounts of non-toxic excipients, such as humectants or pH buffers. Absorption-enhancing preparations (e.g., liposomes, detergents, and organic acids) may also be used.

[0159] In one embodiment of the invention, the GLP-2 receptor agonist is formulated for administration by infusion, for example, as a liquid nutritional supplement for patients undergoing total parenteral nutrition (e.g., newborns or patients with cachexia or anorexia), or by injection, such as subcutaneously, intraperitoneally, or intravenously, and thus as an aqueous solution in a sterile and pyrogen-free form, optionally buffered to a physiologically tolerable pH, such as slightly acidic or physiological pH. Formulations for intramuscular administration may be solutions or suspensions based on vegetable oils such as rapeseed oil, corn oil, or soybean oil. These oil-based formulations may be stabilized by antioxidants such as BHA (tert-butylhydroxyanisole) and BHT (di-tert-butyl-p-cresol).

[0160] Therefore, the GLP-2 receptor agonist of the present invention can be administered in a carrier (e.g., distilled water) or saline, phosphate-buffered saline, 5% glucose solution, or oil. If desired, the solubility of the GLP-2 receptor agonist of the present invention can be enhanced by introducing solubility enhancers such as detergents and / or emulsifiers.

[0161] A certain amount of gel can be added to an aqueous carrier or loading agent for injection to store GLP-2 receptor agonists at or near the injection site, thereby providing slow release at the desired site of action. Alternatively, gelling agents (such as hyaluronic acid) can be used as storage agents.

[0162] The GLP-2 receptor agonist of the present invention can be used alone or in combination with compounds having anti-inflammatory effects. Unbound by conventional wisdom, such combination therapy can enhance the beneficial therapeutic effects of the GLP-2 receptor agonist of the present invention.

[0163] Of course, the most suitable treatment dosage and regimen for a patient will vary depending on the disease or condition being treated, as well as the patient's weight and other parameters. It is not intended to be limited by any particular theory; doses in the μg / kg or mg / kg range, and shorter or longer treatment durations or frequencies, are expected to produce useful therapeutic results. In some cases, the treatment regimen may include the administration of a maintenance dose suitable for preventing tissue deterioration after cessation of initial treatment. The results obtained through this invention can guide the most suitable dosage and administration regimen for human use and can be validated in appropriately designed clinical trials.

[0164] Effective doses and treatment regimens can be determined using conventional methods, starting with a low dose in laboratory animals, monitoring the effects as the dose is increased, and similarly systematically modifying the dosing regimen. When determining the optimal dose for a given subject, clinicians may consider several factors. These considerations are known to those skilled in the art.

[0165] In one embodiment, the human dose of the GLP-2 receptor agonist according to the invention may be from about 10 μg / kg body weight / day to about 10 mg / kg / day, preferably from about 50 μg / kg / day to about 5 mg / kg / day, and most preferably from about 100 μg / kg / day to 1 mg / kg / day.

[0166] In one embodiment, the present invention provides a kit for treating mental illness, wherein the kit contains a GLP-2 receptor agonist and an antipsychotic drug.

[0167] The term "pharmacy kit" typically comprises two or more kits, each containing different medications that have related or synergistic effects in the prevention and / or treatment of a particular disease. For example, in this invention, kit A may contain a GLP-2 receptor agonist, and kit B may contain an antipsychotic. This design can be used flexibly according to specific application needs; kit A can be used first, followed by kit B, or vice versa.

[0168] The term "mental illness" refers to diseases characterized by varying degrees of impairment in cognitive, emotional, volitional, and behavioral activities due to brain dysfunction caused by various biological, psychological, and social environmental factors. These include conditions such as depression, bipolar disorder, schizophrenia, and anxiety disorders. Mental illnesses primarily affect a patient's psychological state and cognitive function, resulting in extremely high rates of disability and death, and imposing a significant psychological and economic burden on patients' families and society.

[0169] In one implementation, the mental illness includes, but is not limited to, depression, bipolar disorder, schizophrenia, and anxiety disorder.

[0170] This invention is based at least in part on the discovery that GLP-2 receptor agonists, such as GLP-2 analogs or teduglutide, can block the inhibitory effects of antipsychotic drugs on neurons, alleviate antipsychotic drug-induced metabolic dysfunction, and thereby target GLP-2 receptors to treat the side effects caused by antipsychotic drugs.

[0171] In one implementation, the side effects caused by antipsychotic drugs are metabolic dysfunctions caused by antipsychotic drugs, including but not limited to hypothermia, obesity, glucose intolerance, abnormal insulin response, hyperappetite, and sedative behavior.

[0172] In one embodiment, the antipsychotic drug includes atypical antipsychotics (AATP). In one embodiment, the antipsychotic drug includes, but is not limited to, olanzapine, clozapine, risperidone, zotepine, serindole, ilopiperidone, quetiapine, palpanidone, asenapine, flupentixol, epipiperidone, amisulpride, flufenazine, cariprazine, lurasidone, aripiprazole, ziprasidone, and haloperidol.

[0173] In one particular implementation, the drug combination comprises teduglutide and olanzapine, clozapine, or risperidone.

[0174] Therefore, the present invention provides a method for treating mental illness, comprising administering to a subject a therapeutically effective amount of a GLP-2 receptor agonist and an antipsychotic drug.

[0175] The present invention also provides a method for treating metabolic dysfunction caused by antipsychotic drugs, comprising administering to a subject a therapeutically effective amount of a GLP-2 receptor agonist and an antipsychotic drug.

[0176] The present invention also provides a method for blocking the inhibitory effect of antipsychotic drugs on neurons, comprising administering a therapeutically effective amount of a GLP-2 receptor agonist and an antipsychotic drug to a subject.

[0177] This invention does not impose specific restrictions on the frequency, timing, or dosage of GLP-2 receptor agonists and antipsychotics, as long as both work simultaneously within the expected timeframe.

[0178] To make the technical means, creative features, objectives and effects of this invention easier to understand, the invention will be further described below with reference to specific embodiments.

[0179] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; the reagents or consumables involved are commercially available unless otherwise specified.

[0180] Olanzapine is widely and long-term used in patients with schizophrenia, and is used as an example of an antipsychotic drug in this embodiment. Using a mouse model that summarizes the metabolic spectrum of antipsychotic treatment, it has been shown that the GLP-2 analog teduglutide can prevent olanzapine-induced hypothermia and weight-related phenotypes. It should be understood that olanzapine, teduglutide, and schizophrenia are merely exemplary and not intended to limit the invention to specific compounds and mental illnesses.

[0181] Furthermore, the inventors discovered neurons in the ventromedial hypothalamus that express prodynorphin (VMH) Pdyn The neurons are key neuronal groups that mediate the reduction of olanzapine-induced metabolic dysfunction by tiduglutide, including hypothermia, excessive weight gain, impaired glucose tolerance and insulin responsiveness, as well as hyperappetite and sedation.

[0182] This invention demonstrates that teduglutide can alleviate olanzapine-induced hypothermia and metabolic dysfunction, and identifies the neural substrates of acute and chronic AATP metabolic side effects, thereby opening up possibilities for targeting this nucleus as a therapeutic strategy to combat AATP-induced side effects.

[0183] Example

[0184] Materials and Methods

[0185] laboratory animals

[0186] Mice were housed in individually ventilated cages with an artificial light-dark cycle of 12 hours (lights on at 7:00 AM and off at 7:00 PM) and room temperature (20-25°C). All procedures were approved by the Animal Conservation and Use Committee of the Shanghai Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences.

[0187] C57BL / 6 mice were purchased from Shanghai SLAC Laboratory Animal Co., Ltd. Pdyn-IRES-cre (JAX: 027958) and Ai9 (JAX: 007909) mice were purchased from Jackson Laboratory.

[0188] In a study of chronic olanzapine treatment, 8-9 week old mice were paired by weight and assigned to designated groups. Mice were fed a high-fat diet provided by Jiangsu Xietong Pharmaceutical Biotechnology Co., Ltd., in which 45% of the calories came from fat, 35% from carbohydrates, and 15% from protein. Olanzapine at a concentration of 50 mg / kg was added to the high-fat diet.

[0189] In the chronic teduglutide treatment study, mice were intraperitoneally injected (ip) with 200 μl of saline or teduglutide daily at a dose of 10 μg per mouse for 3 months.

[0190] Metabolic phenotype analysis

[0191] The body composition (fat mass, lean mass, and fluid volume) of mice was analyzed using a magnetic resonance whole-body composition analyzer (Bruker, Minispec mq10 NMR analyzer).

[0192] The effects on food intake, activity, energy expenditure, and respiratory entropy (RER) were measured using an indirect calorimetry system (TSE Systems, PhenoMaster). Experimental animals were housed alone in the metabolic chamber for at least 24 hours prior to data collection.

[0193] In the glucose tolerance test (GTT), mice were fasted for 16–18 hours but had free access to water. During the GTT, glucose was administered intravenously at a dose of 2 g / kg body weight, and blood glucose levels were monitored at 0, 15, 30, 60, 90, and 120 minutes. Blood was drawn from the tail vein, and blood glucose concentrations were analyzed using a Roche Accu-Chek Performa Connect glucometer.

[0194] In the insulin tolerance test (ITT), mice were fasted for 4–6 hours and given free access to water. Blood glucose levels were then monitored at 0, 15, 30, 60, 90, and 120 minutes after the test. The insulin dose was 0.75 U / kg (body weight).

[0195] Stereoscopic injection

[0196] Mice aged 8–12 weeks were anesthetized with 2% isoflurane and injected using a small animal stereotactic instrument (RWD Life Science, 68030). The virus was injected into the target area using a NanojectIII (Drummond Scientific) at a rate of 30 nanoliters per second per cycle, with 10 cycles performed at 30-second intervals. Experimental and control animals underwent the same surgical and behavioral procedures. The recovery and viral expression period in mice was at least 2 weeks.

[0197] To record the fiber optic photometric calcium signal, 200 nL of AAV2 / 8-hSyn-FLEX-GCaMP6s-WPRE-pA (Taitool Bioscience, Co, Shanghai, Cat#S0026-8) was unilaterally injected into a VMH (AP-1.55 mm, ML 0.55 mm, DV-5.65 mm), and then a 400 μm diameter optical fiber was implanted at the same coordinates as the virus injection.

[0198] To perform chemogenetic manipulation, 150 nL of AAV2 / 5-hsyn-DIO-hM3D(Gq)-mCherry-WPRE-pA (Taitool Bioscience, Co, Shanghai, Cat#S0192-5) or AAV2 / 5-hsyn-DIO-mCherry-WPRE-pA (Taitool Bioscience, Co, Shanghai, Cat#S0240-5) was bilaterally injected into the VMH.

[0199] Fiber Optic Photometric Recording

[0200] GCaMP6s signals were measured using an RZ10x (Tucker-Davis Technologies) via a unilaterally implanted fiber (diameter: 400 μm; length: 6.0 mm; NA: 0.37; Inper) above the VMH. ΔF represents fluorescence change, and F represents baseline fluorescence. Fluorescence excited at 465 nm was corrected for fluorescence excited at 405 nm. Three trials were performed on each mouse, and the data shown are the average of these trials. Data were analyzed using MATLAB.

[0201] Immunohistochemistry and fluorescence in situ hybridization (FISH)

[0202] Mice were first perfused with PBS, and then their brains were fixed with 4% paraformaldehyde. The brains were then transferred to PFA at 4°C for 12 hours for fixation, followed by dehydration and cryoprotection with 30% sucrose. After embedding and freezing, the brains were cut into 50 μm pieces (for immunohistochemistry) or 30 μm pieces (for FISH).

[0203] For immunohistochemistry, brain slices were first rinsed three times with PBS, then incubated for 2 hours at room temperature with blocking buffer (PBS containing 3% BSA (Sigma-Aldrich, A1933) and 0.4% Triton X-100). The slices were then incubated overnight at 4°C with anti-FOS antibody (Cell Singaling Technology, #2250, 1:500). The slices were rinsed with PBS for 3 × 10 minutes, then incubated with donkey anti-rabbit 488 secondary antibody (Invitrogen, A21206, 1:1000) for 2 hours. The slices were rinsed again with PBS for 3 × 10 minutes. Finally, the slices were mounted on slides. Whole-brain FOS staining was quantified using QuPath (v0.4.3).

[0204] FISH was performed according to the manufacturer's instructions for RNAscope Multiplex Fluorescent Assays V2 (Advanced Cell Diagnostics). Pdyn (318771) and FOS (506931-C2) probes were used. Fluorescence images were captured using a fluorescence microscope (VS120, Olympus) or a confocal microscope (FV3000, Olympus).

[0205] Electrophysiology

[0206] According to *Stereocoordinates of the Mouse Brain* (2nd Edition), coronal sections (300 μm thick) containing the VMH region were cut using a vibratory microtome (VT 1200S; Leica, Wetzlar, Germany). The sections were then transferred to a recording chamber, which was continuously perfused with artificial cerebrospinal fluid (aCSF) containing 124 mM NaCl, 2.5 mM KCl, 1.25 mM NaH₂PO₄, 1.3 mM MgSO₄, 26 mM NaHCO₃, 2 mM CaCl₂, and 20 mM D-glucose, and equilibrated with 95% O₂ and 5% CO₂ (flow rate 2 ml / min).

[0207] Whole-cell patch-clamp recordings were performed using borosilicate glass electrodes containing 130 mM K-gluconate, 10 mM HEPES, 5 mM KCl, 2 mM MgCl2, 2 mM NaCl, 1 mM MgSO4, 0.2 mM EGTA, 10 mM sodium phosphocreatine, 4 mM Na2-ATP, and 0.4 mM GTP-Tris. The pH was adjusted to 7.2 with 1 M KOH. The electrode resistance in the bath was maintained at 5–7 MΩ, and the series resistance was continuously monitored and stabilized below 20%. Visualized whole-cell recordings were obtained from brain slices containing VMH using an Axopatch 700B amplifier (Axon Instruments, Foster City, CA). Signals were digitized via a Digidata-1550 interface (Axon Instruments), and data acquisition and analysis were performed using a pClamp11.2 (Axon Instruments). Each recorded neuron was observed for at least 10 minutes to reach stability, and then the drug was administered in current-clamp mode via water bath perfusion.

[0208] Core body temperature and BAT body temperature analysis

[0209] To measure core body temperature, a wireless core body temperature detector (TA-F10, Data Science International) was implanted into the abdominal cavity of mice. The mice were then housed alone for at least one week to allow their body temperature to return to normal. Before testing, the cages were placed on a signal receiving plate to allow the mice to acclimatize to the environment for at least one hour. All parameters were sampled at a frequency of 1 Hz, and the data were stored and analyzed.

[0210] To measure the temperature of brown adipose tissue (BAT), a thermal imager (FLIR, T450) was used. The skin above the brown adipose tissue was shaved, and the highest temperature reading on the skin surface in the mid-scapular region was taken as the temperature of the brown adipose tissue. The BAT temperature was analyzed using FLIR Tools software (FLIR, 6.X).

[0211] Chemical genetic manipulation

[0212] Pdyn-cre mice were injected with the VMH of the cre-dependent chemogenetic virus rAAV-DIO-hM3D(Gq)-mCherry (Taitool Bioscience, Co, Shanghai, Cat#S0192-5) or rAAV-DIO-mCherry (Taitool Bioscience, Co, Shanghai, Cat#S0240-5). At least two weeks later, Pdyn-Cre mice expressing DIO-hM3D(Gq) or DIO-mCherry were intraperitoneally injected with physiological saline (0.9% NaCl) or CNO dissolved in physiological saline (N-clozapine N-Oxide, 1 mg / kg). To prolong the chemoactivation time, CNO was injected intraperitoneally into the mice during the dark cycle around 10 PM each night.

[0213] Prepulse suppression

[0214] The test was conducted using a startle reflex system (Med Associates, Vermont, USA) and consisted of three consecutive phases: an adaptation period, Zone I, and Zone II. After instrument calibration, the animal was placed in a chamber to acclimatize to background white noise (67 dB) for 5 minutes. Zone I contained 10 acoustic startle stimuli (115 dB, 20 ms) applied to the background at random intervals of 10 to 30 seconds to assess baseline startle responses. Zone II contained 30 tracks of 5 types (startle stimulus-only track, pre-pulse-only track, and three pre-pulse inhibition tracks (73dB, 79dB, and 85dB, 20 ms, immediately following the startle stimulus), randomly assigned in a pseudo-random order between 10 and 30 seconds. The startle response was measured as an increase in foot pressure induced by noise. PPI was calculated as a percentage of the startle response, using the formula %PPI = (1 - (pre-pulse - startle amplitude after pulse pair / startle amplitude after pulse only)) × 100. To simulate a schizophrenia-like state, 0.3 mg / kg MK-801 was injected intraperitoneally before the experiment. Fifteen minutes after injection, mice were injected intraperitoneally with Olz (2.5 mg / kg), CNO (1 mg / kg), or saline, and then rapidly placed into the testing apparatus.

[0215] Example 1

[0216] The experimental procedure in this embodiment is illustrated in Figure 1 (left). Following an acute intraperitoneal injection (ip) of olanzapine, brown adipose tissue and core body temperature were measured in mice. As shown in Figure 1 (middle-right), olanzapine treatment resulted in a decrease in body temperature in the rodents. As shown in Figure 2, using the temperature drop as an indicator of the acute effect of olanzapine on energy expenditure, a group of antidiabetic drugs, commonly used in combination therapy to limit AATP-induced overweight, were screened. Compared to the control group, combination therapy with metformin or the GLP-1R agonist Exendin-4 was found to have no effect on hypothermia. Surprisingly, as shown in Figure 2, tiduglutide, a synthetic analog of GLP-2, was found to eliminate olanzapine-induced hypothermia in mice.

[0217] GLP-2 is a metabolic hormone encoded by the C-terminus of the proglucagon gene, and research on GLP-2 has mainly focused on its regulation of intestinal function. After establishing the interaction between olanzapine-induced hypothermia and mouse GLP-2, the inventors then focused on the effects of olanzapine on brain regions expressing GLP-2 receptors.

[0218] To this end, mice were intraperitoneally injected with olanzapine, and the expression of the immediate early gene c-Fos in brain regions expressing GLP-2R was examined. Although the inventors found that some regions showed drug-induced increases in Fos expression, the ventromedial hypothalamus (VMH) region showed a significant decrease in Fos expression under olanzapine treatment compared to the control group given the vector (Figure 3). Interestingly, the inventors' previous research identified neurons in the VMH that express prodynorphin (Pdyn), which control the thermogenic response to cold environments; therefore, the inventors examined the VMH... Pdyn Whether neurons are affected by olanzapine. The inventors found, through cFos mRNA staining (Figure 4), that olanzapine treatment inhibited VMH. Pdyn Neurons, and for VMH Pdyn In situ hybridization of neurons also revealed that they expressed Glp2r (Figure 4). Therefore, the inventors hypothesize that olanzapine inhibits VMH. Pdyn The neurons induce hypothermia, and the same group of neurons is activated by GLP-2 analogs to counteract this effect.

[0219] Example 2

[0220] VMH was ablated by injecting AAV-DIO caspase 3 (Casp3) or AAV-DIO mCherry virus into the VMH brain region of Pdyn-Cre mice. PdynNeurons (Figure 5, top). These transgenic mice express Cre enzymes under the control of the Pdyn gene promoter. The virus expresses taCasp3-TEVp or mCherry protein in a Cre-dependent manner. In the case of taCasp3, this protein activates cysteine-aspartic protease-3 and the subsequent apoptotic program, leading to the selective ablation of VMH neurons expressing Pdyn. As shown in Figure 5, bottom, without VMH... Pdyn In the case of neurons, mice showed a diminished response to olanzapine at core and brown adipose tissue temperatures. These data suggest that VMH Pdyn Neurons play a necessary role in olanzapine-induced hypothermia.

[0221] In order to analyze VMH Pdyn Direct neuronal involvement, as shown in Figure 6, was measured by the inventors in mice treated with olanzapine or teduglutide, resulting in a VMH level. Pdyn Neuronal calcium activity. As shown in Figure 6, olanzapine treatment was found to inhibit VMH in vivo. Pdyn Neurons. As shown in Figure 7, teduglutide itself causes VMH. Pdyn Mild activation of neurons, when used in conjunction with olanzapine, blocks the inhibitory effect of olanzapine. These data provide supporting evidence that teduglutide inhibits the VMH (hypothalamic thermogenic nucleus) in the hypothalamus. Pdyn It produces an activating effect.

[0222] As shown in Figure 8, patch-clamp recording further confirmed the effects of olanzapine and tiduglutide on VMH. Pdyn Effects on neuronal activity. Similarly, the above data indicate that olanzapine and teduglutide have effects on VMH. Pdyn Neurons have the opposite effect; the inhibitory effect of olanzapine is completely neutralized by tiduglutide.

[0223] The above results of this embodiment indicate that VMH Pdyn Neuronal activation may be a therapeutic target for the metabolic side effects of olanzapine.

[0224] Example 3

[0225] This embodiment explores VMH Pdyn Does neuronal activation affect the efficacy of olanzapine in treating schizophrenia?

[0226] This invention utilizes a previously established model of schizophrenia, specifically the acute induction of schizophrenia-like behavior in mice via injection of the N-methyl-D-aspartate receptor antagonist MK-801 (i.e., dizocilpine). The schizophrenia-like behavior in mice was assessed using the prepulse inhibition (PPI) behavioral paradigm. Prepulse inhibition is a reflexive behavioral inhibition process that suppresses the response to a strong stimulus (the prepulse) when it precedes a strong stimulus (the main impulse). Following injection of MK-801, mice exhibited reduced responses to different sound waves in the PPI behavioral paradigm, mimicking sensory gating abnormalities in schizophrenic patients. Treatment of these mice with olanzapine improved prepulse inhibition (Figure 9, top).

[0227] VMH during olanzapine treatment Pdyn Neuronal chemogenetic activation (i.e., treatment with N-chlorozapine) did not affect the improvement in this task, indicating that VMH Pdyn Neurons can dissociate from the circuits that regulate the antipsychotic effects of olanzapine without affecting its antipsychotic activity (Figure 9, bottom).

[0228] Example 4

[0229] This example investigates the effects of long-term combined administration of olanzapine and tiduglutide.

[0230] Tiduglutide was well tolerated in mice, and compared with the control group, this treatment significantly reduced olanzapine-induced weight and fat gain, glucose intolerance, insulin insensitivity, hyperapplying, and lack of exercise (Figures 10-11). These data collectively suggest that GLP-2R agonism is an effective target for preventing olanzapine-induced metabolic dysfunction.

[0231] Example 5

[0232] To verify that more second-generation antipsychotics have similar effects to olanzapine, a method similar to that used in Example 2 was employed to measure the VMH in mice treated with risperidone or clozapine. Pdyn Neuronal calcium activity. As shown in Figure 12, intraperitoneal injection of risperidone or clozapine into mice significantly reduced VMH. Pdyn Neuronal activity. This indicates VMH Pdyn Neuronal activation may be a therapeutic target for the metabolic side effects of risperidone or clozapine.

[0233] In this specification, the invention has been described with reference to specific embodiments thereof. However, it will be apparent that various modifications and variations can be made without departing from the spirit and scope of the invention. Therefore, this specification should be considered illustrative rather than restrictive.

Claims

1. Use of GLP-2 receptor agonists in the preparation of medicaments for the prevention and / or treatment of metabolic dysfunction caused by antipsychotic drugs.

2. The use as described in claim 1, characterized in that, The GLP-2 receptor agonist comprises an amino acid sequence as shown in SEQ ID NO:1 or 2, or comprises an amino acid sequence having at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in SEQ ID NO:1 or 2. Preferably, the GLP-2 receptor agonist is GLP-2 or teduglutide, or an analogue of GLP-2 or teduglutide.

3. The use as described in claim 1 or 2, characterized in that, The antipsychotic drug can inhibit VMH Pdyn Neuron; Preferably, the antipsychotic drug is selected from one or more of olanzapine, clozapine, risperidone, zotepine, serindole, ilopiperidone, quetiapine, palpanidone, asenapine, flupentixol, epipiperidone, amisulpride, flufenazine, cariprazine, lurasidone, aripiprazole, ziprasidone, and haloperidol; More preferably, the antipsychotic drug is selected from one or more of olanzapine, clozapine, and risperidone.

4. The use as described in any one of claims 1 to 3, characterized in that, The metabolic dysfunction is characterized by one or more of the following: hypothermia, obesity, impaired glucose tolerance, impaired insulin response, hyperappetite, and sedation. Preferably, the metabolic dysfunction manifests as hypothermia and / or sedation, and one or more of obesity, impaired glucose tolerance, impaired insulin response, and hyperappetite.

5. GLP-2 receptor agonists in the preparation of drugs for the prevention and / or treatment of VMH Pdyn Use in drugs for diseases caused by neuronal suppression.

6. The use as described in claim 5, characterized in that, The GLP-2 receptor agonist comprises an amino acid sequence as shown in SEQ ID NO:1 or 2, or comprises an amino acid sequence having at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in SEQ ID NO:1 or 2. Preferably, the GLP-2 receptor agonist is GLP-2 or teduglutide, or an analogue of GLP-2 or teduglutide.

7. The use as described in claim 5 or 6, characterized in that, The VMH Pdyn Neurons are suppressed by antipsychotic drugs; Preferably, the antipsychotic drug is selected from one or more of olanzapine, clozapine, risperidone, zotepine, serindole, ilopiperidone, quetiapine, palpanidone, asenapine, flupentixol, epipiperidone, amisulpride, flufenazine, cariprazine, lurasidone, aripiprazole, ziprasidone, and haloperidol; More preferably, the antipsychotic drug is selected from one or more of olanzapine, clozapine, and risperidone.

8. The use as described in any one of claims 5 to 7, characterized in that, The disease presents with symptoms of metabolic dysfunction; Preferably, the metabolic dysfunction is manifested as one or more of the following: hypothermia, obesity, impaired glucose tolerance, impaired insulin response, hyperappetite, and sedation. More preferably, the metabolic dysfunction manifests as hypothermia and / or sedation, and one or more of obesity, impaired glucose tolerance, impaired insulin response, and hyperappetite.

9. A medicine box set, characterized in that, The kit contains a GLP-2 receptor agonist and an antipsychotic. Preferably, the GLP-2 receptor agonist comprises an amino acid sequence as shown in SEQ ID NO:1 or 2, or comprises an amino acid sequence having at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in SEQ ID NO:1 or 2; and / or, the antipsychotic drug is capable of inhibiting VMH. Pdyn Neuron, for example, selected from one or more of olanzapine, clozapine, risperidone, zoltipine, serindole, ilopiperidone, quetiapine, palpanidone, asenapine, flupentixol, epipiperidone, amisulpride, flufenazine, cariprazine, lurasidone, aripiprazole, ziprasidone, and haloperidol; More preferably, the GLP-2 receptor agonist is GLP-2 or teduglutide, or an analogue of GLP-2 or teduglutide; and / or, the antipsychotic drug is selected from one or more of olanzapine, clozapine, and risperidone. More preferably, the kit contains teduglutide and olanzapine.

10. Use of the pillbox as described in claim 9 in the preparation of a medicament for treating mental illness; Preferably, the mental illness is selected from one or more of depression, bipolar disorder, schizophrenia, and anxiety disorder.

11. A method for activating VMH in vivo or in vitro Pdyn The neuron method is characterized by, The method includes administering the GLP-2 receptor agonist and the VMH Pdyn Neuronal contact; optionally, the method is for non-diagnostic, preventive and / or therapeutic purposes; Preferably, the VMH Pdyn Neurons are inhibited by an antipsychotic drug; and / or, the GLP-2 receptor agonist comprises an amino acid sequence as shown in SEQ ID NO:1 or 2, or comprises an amino acid sequence having at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in SEQ ID NO:1 or 2; More preferably, the antipsychotic drug is selected from one or more of olanzapine, clozapine, risperidone, zotepine, serindole, ilopiperidone, quetiapine, palpanidone, asenapine, flupentixol, epipiperidone, amisulpride, flufenazine, cariprazine, lurasidone, aripiprazole, ziprasidone, and haloperidol; and / or, the GLP-2 receptor agonist is GLP-2 or teduglutide, or an analogue of GLP-2 or teduglutide.

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