Use of selective arginine vasopressin receptor 2 agonists for the preparation of a medicament for the prevention and / or treatment of depression
Patent Information
- Application Number
- CN202510420116.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-03
- Publication Date
- 2026-10-16
AI Technical Summary
但精氨酸加压素不仅可以激活AVPR2，同样可以激活AVPR1A和AVPR1B，因此无法判断导致抑郁行为的因素具体是什么
[0018] This invention provides the use of arginine vasopressin receptor 2 (V2 receptor) as a target for the prevention and/or treatment of depression. Studies have found that selective V2 receptor agonists have excellent agonistic effects on the V2 receptor. By activating the V2 receptor, they increase cyclic adenosine monophosphate (cAMP) levels, thereby activating cyclic adenosine effector element-binding protein (CREB), increasing the expression of brain-derived neurotrophic factor (BDNF), and further activating the expression of downstream pathways phosphorylated ERK and phosphorylated AKT, increasing synaptic plasticity, and thus producing an antidepressant effect. Therefore, selective V2 receptor agonists have the effect of preventing and/or treating depression and can be used to prepare antidepressant drugs, possessing positive clinical application value.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of biomedical technology, specifically relating to the use of selective arginine vasopressin receptor 2 agonists in the preparation of medicaments for the prevention and / or treatment of depression. Background Technology
[0002] Arginine vasopressin receptors (AVPRs) are a class of G protein-coupled receptors (GPCRs) that bind to arginine vasopressin (AVP). There are three main subtypes: arginine vasopressin receptor 1A (AVPR1A, also known as V1a receptor), arginine vasopressin receptor 1B (AVPR1B, also known as V1b receptor), and arginine vasopressin receptor 2 (AVPR2, also known as V2 receptor).
[0003] V1a receptors are mainly distributed in vascular smooth muscle cells, liver, kidneys, and other tissues. Activation on vascular smooth muscle cells causes vasoconstriction, thereby increasing blood pressure. In organs such as the liver and kidneys, V1a receptor activation also participates in regulating physiological processes such as plasma osmotic pressure and blood volume. V1a receptors are generally associated with cardiovascular diseases, kidney diseases, and liver diseases. V1b receptors are mainly distributed in the anterior pituitary gland, hypothalamus, and other central nervous system regions. Activation in the anterior pituitary gland promotes the secretion of adrenocorticotropic hormone (ACTH), thereby regulating stress responses. In addition, V1b receptors also play a role in hypothalamic neurons, participating in the regulation of central nervous system functions such as behavior and emotion. V1b receptors are associated with neurological diseases; for example, V1b receptor antagonists may be used to treat stress-related diseases such as depression and anxiety. Abnormalities in V1b receptors may be related to neurodevelopmental disorders or neurodegenerative diseases. V2 receptors are mainly distributed on the basolateral membrane of the chief cells of the collecting ducts of the kidneys. Upon activation, it increases intracellular cAMP levels, promotes the expression of aquaporin 2 (AQP2) on the luminal membrane, increases the permeability of collecting ducts to water, thereby promoting water reabsorption and reducing urine volume. Abnormal V2 receptor function is one of the main causes of diabetes insipidus. V2 receptor agonists (such as desmopressin) can be used to treat central diabetes insipidus and some cases of nephrogenic diabetes insipidus.
[0004] The paper "Vasopressin drives aberrant myeloid differentiation of hematopoietic stem cells, contributing to depression in mice" (Rong Mou et al., Cell Stem Cell, 2024) found that arginine vasopressin (AVP) activates AVPR2, promoting the release of IL-36G from neutrophils, which in turn activates IL-36R, leading to the differentiation of bone marrow hematopoietic stem cells (HSCs) into myeloid cells, triggering neuroinflammation and depressive behavior. This paper suggests that activating AVPR2 can induce depressive behavior. However, arginine vasopressin can activate not only AVPR2 but also AVPR1A and AVPR1B, making it impossible to determine the specific factors leading to depressive behavior.
[0005] It is said that V2 receptors are also distributed in the brain, but there is currently no research showing that V2 receptors are related to depression, and there is no research showing that selective V2 receptor agonists can be used for the prevention and treatment of depression. Summary of the Invention
[0006] The purpose of this invention is to provide the use of selective arginine vasopressin receptor 2 agonists in the preparation of medicaments for the prevention and / or treatment of depression.
[0007] This invention provides the use of selective arginine vasopressin receptor 2 agonists in the preparation of medicaments for the prevention and / or treatment of depression.
[0008] Furthermore, the drug is a drug that increases the expression level of brain-derived neurotrophic factor mRNA in the hippocampus.
[0009] Furthermore, the drug is a drug that increases the expression levels of p-CREB, p-ERK, p-AKT and / or BDNF proteins in the hippocampus.
[0010] Furthermore, the drug is a drug that increases cAMP levels.
[0011] Furthermore, the drug is a drug that activates CREB.
[0012] Furthermore, the drug is a drug that activates the expression of downstream pathways such as phosphorylated ERK and phosphorylated AKT.
[0013] Furthermore, the drug is a drug that increases synaptic plasticity in the hippocampus.
[0014] Furthermore, the selective arginine vasopressin receptor 2 agonist is desmopressin acetate.
[0015] The present invention also provides a medicament for the prevention and / or treatment of depression, which is prepared with a selective arginine vasopressin receptor 2 agonist as the active ingredient, plus pharmaceutically acceptable excipients or auxiliary ingredients.
[0016] Furthermore, the selective arginine vasopressin receptor 2 agonist is desmopressin acetate.
[0017] The present invention has achieved the following beneficial effects:
[0018] This invention provides the use of arginine vasopressin receptor 2 (V2 receptor) as a target for the prevention and / or treatment of depression. Studies have found that selective V2 receptor agonists have excellent agonistic effects on the V2 receptor. By activating the V2 receptor, they increase cyclic adenosine monophosphate (cAMP) levels, thereby activating cyclic adenosine effector element-binding protein (CREB), increasing the expression of brain-derived neurotrophic factor (BDNF), and further activating the expression of downstream pathways phosphorylated ERK and phosphorylated AKT, increasing synaptic plasticity, and thus producing an antidepressant effect. Therefore, selective V2 receptor agonists have the effect of preventing and / or treating depression and can be used to prepare antidepressant drugs, possessing positive clinical application value.
[0019] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.
[0020] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description
[0021] Figure 1 The antidepressant effects of different concentrations of desmopressin acetate (DDAVP) on a corticosterone (CORT)-induced chronic depression model in mice are shown in the figures: A represents the total distance traveled in the open field test; B represents the immobility time in the tail suspension test; C represents the immobility time in the forced swimming test. In the figures, * indicates a p-value less than 0.05 compared to the model group, ** indicates a p-value less than 0.01 compared to the model group, and *** indicates a p-value less than 0.001 compared to the model group.
[0022] Figure 2The antidepressant effects of different concentrations of desmopressin acetate (DDAVP) on a mouse model of chronic depression induced by chronic unpredictable stimuli (CUMS): A is the total distance traveled in the open field test; B is the immobility time in the tail suspension test; C is the immobility time in the forced swimming test; in the figure, * indicates a p-value less than 0.05 compared with the model group, ** indicates a p-value less than 0.01 compared with the model group, and *** indicates a p-value less than 0.001 compared with the model group.
[0023] Figure 3 The transcriptional levels of brain-derived neurotrophic factor (BDNF) in the hippocampus of depressed mice were detected by qPCR after treatment with different concentrations of desmopressin acetate (DDAVP). A represents the results of the CORT model experiment; B represents the results of the CUMS model experiment. In the figure, * indicates a p-value less than 0.05 compared with the model group, and ** indicates a p-value less than 0.01 compared with the model group.
[0024] Figure 4 Western blot analysis (WB) was performed on depressed mice after treatment with different concentrations of desmopressin acetate (DDAVP) to detect the expression of some depression-related proteins in the hippocampus of the mice: A is the WB result of the CORT model; B is the protein statistical result of each experimental group of the CORT model; C is the WB result of the CUMS model; D is the protein statistical result of each experimental group of the CUMS model; in the figure, * indicates a p-value less than 0.05 compared with the model group, ** indicates a p-value less than 0.01 compared with the model group, and *** indicates a p-value less than 0.001 compared with the model group.
[0025] Figure 5 The results of Golgi staining to detect the density of dendritic spines in the hippocampus of CUMS model depressed mice after treatment with different concentrations of desmopressin acetate (DDAVP) are as follows: A is a representative image of Golgi-stained hippocampal tissue (scale bar is 5 μm); B is the statistical results of dendritic spine density in each experimental group; * in the figure indicates a p-value less than 0.05 compared with the model group, and ** indicates a p-value less than 0.01 compared with the model group. Detailed Implementation
[0026] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products from TargetMol.
[0027] The desaminoglycan acetate used in this invention is a known selective arginine vasopressin receptor 2 agonist.
[0028] Example 1: Antidepressant activity of different concentrations of desmopressin acetate against a corticosterone-induced mouse model of chronic depression.
[0029] 1. Experimental Methods
[0030] The experiment was divided into a negative control group (Vehicle), a model group (CORT+Vehicle), and groups receiving different doses of medication.
[0031] The model group and different dose groups were used to construct a depression-like model as follows: Corticosterone (35 μg / mL) was dissolved in drinking water containing 0.45 wt% 2-hydroxypropyl-β-cyclodextrin to prepare a corticosterone (CORT) solution. C57BL / 6 male mice were given the CORT solution to drink freely for 5 weeks, and the CORT solution was changed every two days to construct a CORT-induced depression-like model.
[0032] After model establishment (5 weeks after drinking CORT solution), different dosage groups were intraperitoneally injected with 0.002 mg / kg and 0.02 mg / kg of desmopressin acetate, respectively. Desmopressin acetate was dissolved in physiological saline. The injection dose was 10 μL / g, once daily for 3 days. The model group received an equal volume of solvent using the same method. The negative control group received an equal volume of solvent from healthy mice using the same method.
[0033] One hour after daily administration, a behavioral test was performed, in the following order: open field test (OFT), tail suspension test (TST), and forced swimming test (FST) to detect the antidepressant activity of different concentrations of desmopressin acetate on a corticosterone-induced mouse model of chronic depression.
[0034] 2. Experimental Results
[0035] like Figure 1 As shown in A-1C, compared with the negative control group (Vehicle), CORT model mice (CORT+Vehicle) exhibited increased immobility in the tail suspension and forced swimming tests, and decreased total distance traveled in the open field test, with statistically significant differences, indicating successful establishment of the depression-like model. Intraperitoneal injection of different concentrations of desmopressin acetate (DDAVP) significantly reduced immobility and increased total distance traveled in mice, demonstrating antidepressant activity.
[0036] Example 2: Antidepressant activity test of different concentrations of desmopressin acetate on a mouse model of chronic depression induced by chronic unpredictable stimuli.
[0037] 1. Experimental Methods
[0038] The experiment was divided into a negative control group (Vehicle), a model group (CUMS+Vehicle), and different dose groups.
[0039] A depression-like model was constructed in the model group and different dose groups as follows: C57BL / 6 male mice were repeatedly exposed to various mild stressors in unpredictable ways. These stressors included: restraint (mice were placed in 50 ml centrifuge tubes with holes for 2 hours), forced swimming (mice were swam in 25°C water for 30 minutes), fasting (mice were not given food for 24 hours), light / dark cycle reversal (mice were placed in an environment with reversed day and night for 12 hours), prolonged light or darkness (24 hours of continuous light or 24 hours of darkness), mice were placed in moist (250 ml of water was poured into the bedding to make the cage moist) or empty cages for 12 hours, mice were placed in tilted cages (the cages were tilted at 45°) for 7 hours, exposure to noise (exposure to 90 dB white noise for 30 minutes), and electrical stimulation (mice were given 0.4 mA of electrical stimulation for 12 minutes, with 8 seconds of stimulation and 4 seconds of rest). Mice were randomly exposed to two different stressors each day, with the same stimulus not appearing for two consecutive days, for a period of 5 weeks, in order to construct a CUMS-induced depression-like model.
[0040] After model establishment (5 weeks after chronic unpredictable stimulation), mice in different dosage groups were intraperitoneally injected with 0.002 mg / kg and 0.02 mg / kg of desmopressin acetate, respectively. Desmopressin acetate was dissolved in physiological saline. Each injection was 10 μL / g, administered once daily for 3 days. The model group received an equal volume of solvent using the same method. Healthy mice in the negative control group received an equal volume of solvent using the same method.
[0041] One hour after daily administration, a behavioral test was performed, in the following order: open field test (OFT), tail suspension test (TST), and forced swimming test (FST) to detect the antidepressant activity of different concentrations of desmopressin acetate on a mouse model of chronic depression induced by chronic unpredictable stimuli.
[0042] 2. Experimental Results
[0043] like Figure 2 As shown in A-2C, compared with the negative control group (Vehicle), CUMS model mice (CUMS+Vehicle) exhibited increased immobility in the tail suspension and forced swimming tests, and decreased total distance traveled in the open field test, with statistically significant differences, indicating successful establishment of the depression-like model. Intraperitoneal injection of different concentrations of desmopressin acetate (DDAVP) significantly reduced immobility and increased total distance traveled in mice, demonstrating antidepressant activity.
[0044] Example 3: Effects of different concentrations of desmopressin acetate (DDAVP) on brain-derived neurotrophic factor (BDNF) in the hippocampus of depressed mice.
[0045] 1. Experimental Methods
[0046] Modeling and drug administration were performed according to the methods described in Examples 1 and 2. The drugs were administered continuously for 4 days. One hour after administration on day 4, the mice were sacrificed, and the hippocampus was harvested. qPCR was used to observe the effect of the drugs on the mRNA levels of brain-derived neurotrophic factor (BDNF) in the hippocampus of the two depression model mice. Decreased BDNF levels are an important pathological feature of depression.
[0047] 2. Experimental Results
[0048] like Figure 3 As shown, desmopressin acetate significantly increased brain-derived neurotrophic factor (BDNF) in the hippocampus of depressed mice, indicating that desmopressin acetate can increase BDNF transcription in the hippocampus of both depression models. This further demonstrates that desmopressin acetate has an antidepressant effect.
[0049] Experiment Example 4: Effects of different concentrations of desmopressin acetate (DDAVP) on certain depression-related proteins in the hippocampus of depressed mice.
[0050] 1. Experimental Methods
[0051] Modeling and drug administration were performed according to the methods described in Examples 1 and 2. The drugs were administered continuously for 4 days. One hour after administration on the 4th day, the mice were sacrificed, and the hippocampus of the mice was collected. The Western blot (WB) experiment was used to observe the effect of the drugs on the expression levels of some depression-related proteins in the hippocampus of the two depression model mice.
[0052] 2. Experimental Results
[0053] like Figure 4 As shown, desmopressin acetate had a dose-dependent increase in p-CREB, p-ERK, p-AKT, and BDNF proteins in the hippocampus of two depression models of mice. This indicates that desmopressin acetate can activate V2 receptors and increase cAMP levels in mice, thereby activating CREB. Activated CREB can increase BDNF expression, which in turn activates the expression of downstream pathways p-ERK and p-AKT, thus producing an antidepressant effect.
[0054] Experiment Example 5: Effects of different concentrations of desmopressin acetate (DDAVP) on synaptic plasticity in the hippocampus of depressed mice.
[0055] 1. Experimental Methods
[0056] The model was established and the drug was administered according to the method described in Example 2. The drug was administered for 4 consecutive days. One hour after administration on the 4th day, the mice were sacrificed, and the hippocampus of the mice was collected. The effect of the drug on synaptic plasticity in the mouse hippocampus was observed by the Golgi-Cox staining experiment.
[0057] 2. Experimental Results
[0058] like Figure 5 As shown, desmopressin acetate had a dose-dependent increase in the density of dendritic spines in the hippocampus of CUMS model depressed mice, indicating that desmopressin acetate can increase synaptic plasticity in mice and thus produce an antidepressant effect.
[0059] In summary, this invention provides the use of arginine vasopressin receptor 2 (V2 receptor) as a target for the prevention and / or treatment of depression. Studies have found that selective V2 receptor agonists exhibit excellent V2 receptor agonistic effects. By activating the V2 receptor, they increase cyclic adenosine monophosphate (cAMP) levels, thereby activating cyclic adenosine effector element-binding protein (CREB), increasing the expression of brain-derived neurotrophic factor (BDNF), and subsequently activating the expression of downstream pathways phosphorylated ERK and phosphorylated AKT, increasing synaptic plasticity, and thus producing an antidepressant effect. Therefore, selective V2 receptor agonists have the effect of preventing and / or treating depression and can be used to prepare antidepressant drugs, possessing positive clinical application value.
Claims
1. Use of selective arginine vasopressin receptor 2 agonists in the preparation of medicines for the prevention and / or treatment of depression.
2. The use according to claim 1, characterized in that: The drug is a drug that increases the expression level of brain-derived neurotrophic factor mRNA in the hippocampus.
3. The use according to claim 1, characterized in that: The drug is a drug that increases the expression levels of p-CREB, p-ERK, p-AKT and / or BDNF proteins in the hippocampus.
4. The use according to claim 1, characterized in that: The drug mentioned is one that increases cAMP levels.
5. The use according to claim 4, characterized in that: The drug mentioned is one that activates CREB.
6. The use according to claim 5, characterized in that: The drug is a drug that activates the expression of downstream pathways such as phosphorylated ERK and phosphorylated AKT.
7. The use according to claim 1, characterized in that: The drug is one that increases synaptic plasticity in the hippocampus.
8. The use according to any one of claims 1 to 7, characterized in that: The selective arginine vasopressin receptor 2 agonist is desaminoglycan acetate.
9. A drug for the prevention and / or treatment of depression, characterized in that: It is prepared with a selective arginine vasopressin receptor 2 agonist as the active ingredient, plus pharmaceutically acceptable excipients or auxiliary ingredients.
10. The medicament according to claim 9, characterized in that: The selective arginine vasopressin receptor 2 agonist is desaminoglycan acetate.