Application of agomelatine in preparation of medicine for treating sicca syndrome

Abstract

The invention provides application of agomelatine in preparation of a medicine for treating sicca syndrome, and relates to the technical field of biomedicine, agomelatine is a novel anti-depression medicine, and the main action mechanism of agomelatine is that anti-depression and anti-anxiety effects are achieved by activating melatonin receptors (MT1 and MT2) and antagonizing a 5-HT2c receptor. According to the application, an 8w-old NOD mouse is selected as a sicca syndrome model mouse, and meanwhile, an ICR mouse is selected as a normal mouse of the same control. NOD mice are randomly divided into a blank control group, a hydroxychloroquine (HCQ) treatment group (50 mg / kg), a melatonin (MLT) treatment group (15 mg / kg) and an agomelatine (AGO) treatment group (50 mg / kg). And observing the disease degree of the sicca syndrome mouse after 4W treatment. A specific verification experiment proves that the agomelatine in the application can be used for remarkably improving the sicca syndrome.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technology, and particularly to the use of agomelatine in the preparation of a drug for treating Sjogren's syndrome. Background Art

[0002] Sjogren's syndrome (SS) is a common autoimmune disease that often occurs in women and is usually manifested as dry mouth, dry eyes, difficulty in swallowing, and fatigue. These symptoms greatly affect the quality of life of patients. Anxiety and depression are common psychological problems. Therefore, people are paying more and more attention to mental health. It is reported that some patients with Sjogren's syndrome have anxiety and depression, and the incidence rate is significantly higher than that of the normal population.

[0003] Currently, the treatment of Sjogren's syndrome is usually symptomatic treatment, that is, relieving the symptoms of patients, monitoring the condition of patients, and delaying the progression of the disease. However, the treatment of the psychological condition of patients with Sjogren's syndrome is often neglected. Therefore, it is necessary to find new available therapeutic drugs. Summary of the Invention

[0004] The purpose of the present invention is to solve the problem that in the prior art, the treatment of Sjogren's syndrome is usually symptomatic treatment, and the curative effect on the psychological condition of patients with Sjogren's syndrome is often neglected.

[0005] In order to achieve the above purpose, the present invention adopts the following technical solutions:

[0006] The application of agomelatine in the preparation of a drug for treating Sjogren's syndrome, characterized in that: the agomelatine is an active ingredient in the drug.

[0007] Preferably, the drug can be prepared into a clinically acceptable dosage form by adding other pharmaceutically acceptable active ingredients and excipients through a conventional process.

[0008] Preferably, the drug dosage form includes tablets and capsules.

[0009] Preferably, the clinical manifestations of Sjogren's syndrome include but are not limited to dry mouth, dry eyes, difficulty in swallowing, and fatigue.

[0010] The present application also provides a drug for treating Sjogren's syndrome, and the drug contains agomelatine.

[0011] Preferably, the drug may further include at least one of hydroxychloroquine and melatonin.

[0012] The present application also provides a verification method for verifying the therapeutic effect of a drug in Sjogren's syndrome. The verification method uses NOD mice as model mice for Sjogren's syndrome, and simultaneously selects ICR mice as normal mice for allogeneic control.

[0013] Preferably, the verification method is as follows:

[0014] Group NOD mice and ICR mice according to the types of drugs to be administered.

[0015] After continuous intraperitoneal injection for 4 weeks, sacrifice the mice. During the administration period, weigh and photograph the mice daily. After sacrificing the mice, take the salivary glands of the mice, perform HE staining and record the results; take the spleens of the mice for flow cytometry analysis.

[0016] Preferably, the types of drugs to be administered include a blank control group, an HCQ treatment group, an MLT treatment group, and an AGO treatment group. Beneficial effects:

[0017] The present invention finds that agomelatine can effectively improve the symptoms of mice with Sjogren's syndrome model. Therefore, agomelatine has the prospect of being developed into a drug for treating Sjogren's syndrome. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 It is a tissue section of a mouse in an embodiment of the present invention. Figure 1 A. Representative images of hematoxylin-eosin (HE) staining of salivary glands of mice in each group. Figure 1 B. Histological scores of salivary gland inflammation in each group of mice;

[0019] Figure 2 It is the proportion of immune cells in the spleen of each group of mice in an embodiment of the present invention. Figure 2 A. Representative images of the proportion of TH1 cells in lymphocytes of mice in each group. Figure 2 B. Representative images of the proportion of TH17 cells in lymphocytes of mice in each group. Figure 2 C. Representative images of the proportion of TREG cells in lymphocytes of mice in each group. Figure 2 D. Statistical chart of A. Figure 2 E. Statistical chart of B. Figure 2 F. Statistical chart of C.

[0020] Figure 3 It is the behavioral experiment of NOD mice in an embodiment of the present invention. Figure 3 A. Behavioral trajectories of mice in each group in the open field experiment. Figure 3 B. Total moving distance of mice in the open field experiment. Figure 3 C. Time that mice stay in the center of the open field. Figure 3 D. Immobile time of mice in each group in the tail suspension experiment. DETAILED DESCRIPTION OF THE INVENTION

[0021] The present invention will be further described in detail below with reference to specific embodiments.

[0022] The present application provides the use of agomelatine in the preparation of a medicament for treating Sjogren's syndrome, wherein the agomelatine is an active ingredient in the medicament.

[0023] The medicament can be prepared into a clinically acceptable dosage form by adding other pharmaceutically acceptable active ingredients and excipients through conventional processes.

[0024] In one embodiment, the dosage forms of the medicament include tablets and capsules.

[0025] The clinical manifestations of Sjogren's syndrome include but are not limited to dry mouth, dry eyes, dysphagia, and fatigue.

[0026] In addition, the present application also provides a medicament for treating Sjogren's syndrome, which contains agomelatine.

[0027] In one embodiment, the medicament may further include at least one of hydroxychloroquine and melatonin. The treatment of Sjogren's syndrome is carried out by combination administration.

[0028] To verify the therapeutic effect of agomelatine in Sjogren's syndrome, the present application also proposes a verification method. The verification method uses NOD mice as model mice for Sjogren's syndrome, and at the same time selects ICR mice as normal mice for allogeneic control (ICR mice are a closed colony of mice with relatively stable and diverse genetic backgrounds, strong adaptability, high fertility, fast growth rate, and good experimental repeatability. NOD mice originated from ICR mice and were inbred. Therefore, ICR mice have a certain similarity with NOD mice in genetic background, but maintain normal physiological and immune functions and are suitable as a control group).

[0029] The NOD mice and ICR mice are grouped according to the types of drugs to be administered.

[0030] After continuous intraperitoneal injection for 4 weeks, the mice are sacrificed. During the administration period, the mice are weighed and photographed daily. After the mice are sacrificed, the salivary glands of the mice are taken, subjected to HE staining and the results are recorded; the spleens of the mice are taken for flow cytometry analysis.

[0031] In one embodiment, the types of drugs to be administered include a blank control group, a hydroxychloroquine (HCQ) treatment group, a melatonin (MLT) treatment group, and an agomelatine (AGO) treatment group.

[0032] The above content is verified by the following specific verification experiments:

[0033] I. Experimental materials and related sources:

[0034]

[0035]

[0036] II. Experimental procedures:

[0037] 1. Preparation of mice:

[0038] NOD mice at 8 weeks of age were purchased from Nantong Jingqi Biotechnology Co., Ltd. and fed in the animal house of the Medical Center of the School of Medicine, Nantong University. Five mice were housed in each cage, with free access to water and food, and the temperature was maintained at 22°C - 24°C. The experimental methods involved in this application have been approved by the Bioethics Committee of the School of Medicine, Nantong University.

[0039] 2. Preparation of drugs

[0040] Weigh the drugs according to the daily dosage per mouse and the administration time, dissolve them in DMSO, aliquot the drugs, and store them at -80°C.

[0041] The drugs include hydroxychloroquine (HCQ), melatonin (MLT), and agomelatine.

[0042] 3. Experimental grouping and drug administration

[0043] NOD mice at 8 weeks of age were selected as model mice for Sjogren's syndrome, and ICR mice were selected as normal mice for allogeneic control.

[0044] The NOD mice were randomly divided into a blank control group, a hydroxychloroquine (HCQ) treatment group (50 mg / kg), a melatonin (MLT) treatment group (15 mg / kg), and an agomelatine (AGO) treatment group (50 mg / kg).

[0045] After continuous intraperitoneal injection for 4 weeks, the mice were sacrificed. During the drug administration period, the mice were weighed and photographed daily. After the mice were sacrificed, the salivary glands of the mice were taken for HE staining and the results were recorded; the spleens of the mice were taken for flow cytometry analysis.

[0046] III. Experimental results:

[0047] HE staining of the salivary glands of the mice showed that in the NOD + MLT administration group, the NOD + HCQ administration group, and the NOD + AGO administration group, the salivary gland inflammation of the mice in each group was improved to varying degrees after treatment. This indicates that agomelatine may improve the salivary gland inflammation in patients with Sjogren's syndrome, thereby alleviating the condition and controlling the disease progression ( Figure 1 ).

[0048] In the pathogenesis of Sjogren's syndrome, the imbalance between Th cells and Treg cells plays an important role. Therefore, in this application, cells were extracted from the spleens of mice (after grinding treatment), and flow cytometry analysis was performed. The results showed that compared with normal ICR mice, the proportion of Th1 cells in Sjogren's syndrome model mice was significantly increased (P<0.05). After treatment with hydroxychloroquine (HCQ), melatonin (MLT), and agomelatine (AGO), the proportion of Th1 cells in each group of mice decreased (P<0.05). However, compared with normal ICR mice, there were no significant differences in the proportions of Th17 cells and Treg cells in Sjogren's syndrome model mice among the groups (P>0.05). This indicates that agomelatine may treat Sjogren's syndrome model mice by improving the proportion of Th1 cells( Figure 2 ).

[0049] In the open field test, no significant differences were observed in the total moving distance of the mice, and no significant differences were observed in the residence time of each group of mice in the central area of the open field. In the tail suspension test, the immobility time of normal ICR mice was significantly lower than that of Sjogren's syndrome model mice (P<0.05), and the immobility time of mice treated with AGO was significantly lower than that of the Sjogren's syndrome model control group, and the results were statistically significant (P<0.05)( Figure 3 ).

[0050] In summary, in this application, it was experimentally verified that agomelatine (AGO) can effectively improve the disease activity and psychological state of Sjogren's syndrome model mice. NOD mice are a recognized disease model of Sjogren's syndrome mice. AGO treatment in the dosing group significantly reduced the disease activity of NOD mice. Salivary gland HE showed that the salivary gland inflammation of mice was improved to varying degrees after treatment. Flow cytometry analysis of spleen cells showed that compared with normal ICR mice, the proportion of Th1 cells in Sjogren's syndrome model mice was significantly increased. Therefore, the present invention explores the feasibility of agomelatine (AGO) for the treatment of Sjogren's syndrome by applying the NOD mouse model. Through the experiments in the examples of the present invention, it can be summarized that the agomelatine (AGO) involved in this application is a new treatment method for the treatment of Sjogren's syndrome.

Claims

1. Use of agomelatine in the preparation of a drug for treating Sjögren's syndrome, characterized in that: The agomelatine is an active ingredient in the medicine.

2. The use of agomelatine according to claim 1 in the preparation of a drug for treating Sjögren's syndrome, characterized in that: The drug can be prepared into a clinically acceptable dosage form by adding other pharmaceutically acceptable active ingredients and excipients through conventional processes.

3. The use of agomelatine according to claim 1 in the preparation of a drug for treating Sjögren's syndrome, characterized in that: The pharmaceutical dosage forms include tablets and capsules.

4. The use of agomelatine according to claim 1 in the preparation of a drug for treating Sjögren's syndrome, characterized in that: The clinical manifestations of Sjögren's syndrome include, but are not limited to, dry mouth, dry eyes, dysphagia and fatigue.

5. A drug for treating Sjögren's syndrome, characterized in that: The medicine contains agomelatine.

6. A drug for treating Sjögren's syndrome according to claim 5, characterized in that: The medicine may also include at least one of hydroxychloroquine and melatonin.

7. A verification method for verifying the therapeutic effect of a drug on Sjögren's syndrome, characterized in that: The validation method uses NOD mice as model mice of Sjögren's syndrome, and selects ICR mice as normal mice of the same species as controls.

8. A verification method according to claim 7, characterized in that: The verification method steps are as follows: The NOD mice and ICR mice were divided into groups according to the type of drug to be administered. The mice were killed after 4 weeks of continuous administration. They were weighed and photographed daily during the administration period. The salivary glands of the mice were obtained after the mice were killed, and HE staining was performed and the results were recorded; the spleens of the mice were obtained for flow cytometry analysis.

9. A verification method according to claim 8, characterized in that: The types of administration include blank control, HCQ treatment group, MLT treatment group and AGO treatment group.

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