CN115707458A

CN115707458A - Application of neurotransmitter dopamine in preparing medicament for treating lung allergic inflammation

Info

Publication number: CN115707458A
Application number: CN202110947754.8A
Authority: CN
Inventors: 周洁; 曹应姣
Original assignee: Tianjin Medical University
Current assignee: Tianjin Medical University
Priority date: 2021-08-18
Filing date: 2021-08-18
Publication date: 2023-02-21

Abstract

The invention discloses a new application of dopamine or pharmaceutically acceptable salts thereof. The new application comprises the following steps: (a1) The application in the preparation of products for preventing and/or treating allergic inflammation of airways; (a2) The application in preparing products for preventing and/or treating lung allergic inflammation; (a3) The application in preparing products for preventing and/or treating allergic asthma; (a4) The application in preparing products for reducing lung eosinophilic granulocyte; said lung eosinophils are caused by allergic inflammation of the lung; (a5) Application in preparing products for inhibiting inflammatory cell infiltration in lung. After the DA treatment is exogenously given, allergic inflammation of the lung of adult mice induced by allergic raw melon protease or IL-33 can be effectively relieved, and the symptoms are shown that eosinophilic granulocytes of the lung of mice in a DA treatment group are obviously reduced, pathological staining of the lung shows that inflammatory cells infiltrate less, mucus secretion is reduced, and the degree of tissue damage is reduced.

Description

Application of neurotransmitter dopamine in preparing medicament for treating lung allergic inflammation

Technical Field

The invention belongs to the field of medicines, and particularly relates to application of neurotransmitter dopamine in preparation of a medicine for treating lung allergic inflammation.

Background

Asthma is a chronic inflammatory disease of respiratory tract, the pathogenesis of the asthma is involved in natural immunity, adaptive immunity, epithelial cells and the like, and the clinical pathological manifestations of the asthma are bronchial hyperreactivity, mucus secretion increase, airway remodeling and stenosis. Asthma is very common in developed countries, with almost 1 in every 10 children suffering from asthma and 1 in every 12 adults being asthmatic. Clinically, asthma is generally divided into two main categories, one occurs mainly in allergic asthma of children and 50% of adults, and patients suffering from asthma are usually allergic sources, such as IgE-mediated diseases caused by house dust mites, animal dander, fungal spores, pollen, peanuts and the like; the other type of non-allergic asthma generally occurs later, does not have IgE directed against allergen in serum and also has no obvious TH2 participation, and mostly occurs in adult women, and the specific etiology is unknown. The first major category of allergic asthma is of major interest in the current study. Current treatment of asthma relies primarily on inhaled glucocorticoids, whose role is to suppress inflammation, and β 2 adrenoceptor agonists; β 2 adrenoceptor agonists relax bronchial smooth muscle.

The network activity of the nervous system is a physiological regulatory mechanism with anti-inflammatory action that has evolved with the body. Recent studies have shown that neuro-immunomodulation plays an important role in maintaining mucosal barriers, which often leads to allergic inflammatory responses in neuronal and immune cell rich mucosal tissues such as the lung or intestinal tract, when the interaction between the two is disturbed. Dopamine (DA) is a pleasant neurotransmitter (called 'Happy factor') and has the main function of regulating the physiological activities of the body, such as behavior, movement, heart, kidney and gastrointestinal tract, but in recent years, research shows that DA has an important immunoregulation effect ¹ 。

In 2019, researchers at Harvard university found that dopamine aggravates asthma development in young mice by inducing Th2 cells, but not in adult mice, and this study revealed a possible cause of higher asthma in children compared to adults ² . However, the pathogenesis of asthma is complex and diverse, besides Th2, type II natural immune cells ILC2 are also important participants of asthma attack, and dopamine is used for ILC 2-mediated allergic inflammation of airwaysNo symptoms are reported at present.

Reference documents:

1.Basu,S.&Dasgupta,P.S.Dopamine,a neurotransmitter,influences the immune

system.J Neuroimmunol 102,113-124(2000).

2.Wang,W.et al.Age-Related Dopaminergic Innervation Augments T Helper 2-Type

Allergic Inflammation in the Postnatal Lung.Immunity 51,1102-1118.e1107(2019).

disclosure of Invention

The invention aims to provide a new application of a dopamine medicine.

In a first aspect, the new pharmaceutical use of dopamine or a pharmaceutically acceptable salt thereof provided by the present invention is at least one of the following (a 1) to (a 5):

(a1) The application in the preparation of products for preventing and/or treating allergic inflammation of airways;

(a2) The application in preparing products for preventing and/or treating lung allergic inflammation;

(a3) The application in preparing products for preventing and/or treating allergic asthma;

(a4) The application in preparing products for reducing lung eosinophilic granulocyte; said lung eosinophils are caused by allergic inflammation of the lung;

(a5) Application in preparing products for inhibiting inflammatory cell infiltration in lung.

In a second aspect, the new pharmaceutical use of dopamine or a pharmaceutically acceptable salt thereof provided by the present invention is at least one of the following (b 1) to (b 5):

(b1) Prevention and/or treatment of allergic inflammation of the airways;

(b2) Preventing and/or treating allergic inflammation of the lung;

(b3) Prevention and/or treatment of allergic asthma;

(b4) Reducing lung eosinophils; said lung eosinophils are caused by allergic inflammation of the lung;

(b5) Inhibiting inflammatory cell infiltration in the lung.

In a third aspect, the invention also claims a product.

The invention claims a product, the active ingredient of which is dopamine or its pharmaceutically acceptable salt; the product has at least one of the following effects:

(c1) Prevention and/or treatment of allergic inflammation of the airways;

(c2) Preventing and/or treating allergic inflammation of the lung;

(c3) Prevention and/or treatment of allergic asthma;

(c4) Reducing eosinophil number in the lung;

(c5) Inhibiting inflammatory cell infiltration in the lung.

In the present invention, the product may be a medicament or a pharmaceutical preparation. When used, the medicament or the pharmaceutical preparation can be administered by injection (such as intraperitoneal injection) or local administration (such as nasal drip administration).

In the present invention, the allergic inflammation or the allergic asthma can be induced by Papain Papain or interleukin IL-33.

Besides dopamine or pharmaceutically acceptable salts thereof, the product of the invention can also contain a suitable carrier or excipient and other effective components with compatible and synergistic effects. The carrier includes diluent, excipient, filler, binder, wetting agent, disintegrating agent, absorption enhancer, surfactant, adsorption carrier, lubricant, etc. which are conventional in the pharmaceutical field. The above medicine can be made into various forms such as injection, tablet, powder, granule, capsule, oral liquid, paste, cream, etc.; the medicaments in various dosage forms can be prepared according to the conventional method in the pharmaceutical field.

The above drugs can be introduced into body such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue by injection, spray, nasal drop, eye drop, penetration, absorption, physical or chemical mediated method; or mixed or coated with other materials and introduced into body.

The invention firstly determines that the content of neurotransmitter dopamine in peripheral blood plasma of a clinical asthma patient and alveolar lavage fluid of an asthma model mouse is obviously reduced; and after exogenously (intraperitoneally injecting or nasally dropping) DA treatment, allergic inflammation of the lung of adult mice induced by allergic raw melon protease papain or interleukin IL-33 can be effectively relieved, and the symptoms are that eosinophilic granulocytes of the lung of the mice in the DA treatment group are obviously reduced, pathological staining of the lung shows that inflammatory cell infiltration is less, mucus secretion is reduced, and the degree of tissue damage is reduced.

Therefore, the neurotransmitter dopamine can be used as a medicament for treating the allergic inflammation of the airway.

Drawings

FIG. 1 is a graph of the comparison and statistical analysis of DA content in the plasma of peripheral blood of healthy controls matched to clinical asthmatics and age groups in example 1;

FIG. 2 is a graph showing the comparison and statistical analysis of DA content in alveolar lavage fluid of asthma model mice and control untreated mice in example 2;

FIG. 3 is a graph showing the results of flow analysis of Eos in different groups of alveolar lavage fluid of example 3;

FIG. 4 is a graph of the HE staining results of lung morphology in different groups of mice in example 3;

FIG. 5 is a graph of the results of scoring lung tissue pathological inflammatory lesions of mice of different groups in example 3.

FIG. 6 is the level of eosinophilic EOS (representative of the level of inflammation) in the nasally-administered alveolar lavage (BALF) of the different groups of example 4.

Detailed Description

The present invention will be further illustrated with reference to the following specific examples, but the present invention is not limited to the following examples. The method is a conventional method unless otherwise specified. The starting materials are commercially available from the open literature unless otherwise specified.

Examples 1,

Peripheral blood (10 persons, 2-3ml per person) of clinical asthma patients and age-matched healthy control peripheral blood (10 persons, 2-3ml per person) were collected, and Dopamine (DA) content in plasma was measured after centrifugation, and then the two groups were compared and statistically analyzed. The results are shown in FIG. 1.

AS can be seen from fig. 1, the DA content in the peripheral blood of clinical asthmatic patients (asthma, AS) is significantly lower than that of Healthy Controls (HC).

Examples 2,

Constructing a Papain Papain induced asthma model mouse: 20ug Papain was dissolved in 40ul PBS and the mice anesthetized with isoflurane were inhaled intranasally at the same dose for 5 consecutive days with disease phenotype and immune cell phenotype analysis on day 6.

Alveolar lavage fluid of the asthma model mice and the control untreated mice is collected, the DA content in the supernatant is measured after centrifugation, and then the two groups are compared and statistically analyzed. The results are shown in FIG. 2.

As shown in FIG. 2, the content of DA in alveolar lavage fluid of Papain Papain-induced asthma model mice was also significantly lower than that of untreated control mice.

Example 3 inhibition of Papain-induced hypersensitivity pneumonitis in mice by DA

Pneumonia animal model experimental design: 1 experimental grouping: PBS blank control group; papain + PBS pneumonia control group; papain + DA treatment group.

2, experimental operation:

(1) 18 adult mice of 6-8 weeks of the same sex and equivalent weight, C57B6L/J, were selected and randomized into 3 groups (n = 6/group).

(2) In the reference, intraperitoneal injection of DA (50 mg/kg body weight) was started the day before nasal administration of Papain, and the control group was administered PBS solvent once a day and continued until the end of Papain molding. Papain was administered by nasal drip by dissolving 20 μ g of Papain in 40 μ l of PBS, and then after anesthetizing the mice, nasal drip was administered through the nasal cavity once a day for 5 days.

(3) After 24 hours of the last administration, the mice were anesthetized, perfused with 0.3mL of pre-chilled saline, extracted and tested for DA and type ii cytokine content, then washed 2 times with 0.5mL of PBS, 3 times combined together and centrifuged to collect cells in the mouse alveolar lavage fluid, eosinophilic granulocytes (Eos) in the mouse alveolar lavage fluid were tested by flow cytometry, and lung tissue was taken for morphological HE staining and scored pathologically.

3, experimental results:

(1) The results of flow analysis of Eos in alveolar lavage fluid are shown in FIG. 3. As can be seen in FIG. 3, the level of Eos cells in the alveolar lavage fluid of mice treated with DA administration was significantly reduced, indicating that DA was effective in inhibiting lung inflammation in mice.

(2) HE staining results for lung morphology are shown in figure 4. As can be seen from fig. 4, lung tissue destruction, inflammatory cell infiltration and mucus secretion were reduced in the DA-dosed mice compared to the PBS control mice. The results of the pathological inflammatory injury scores of lung tissues in mice are shown in figure 5. As can be seen from fig. 5, the DA administration treatment was effective in relieving Papain-induced allergic inflammatory injury of lung tissue.

Example 4 inhibition of IL-33 induced pneumonia in asthmatic mice by DA

1 experimental grouping: PBS blank control group; papain + PBS pneumonia control group; papain + DA treatment group.

2, experimental operation:

(2) On the day before the IL-33 induced asthma model mouse is constructed, 40ul 5mg/mL Dopamine (namely 200 mu g/mouse) is dripped into the nasal cavity for pretreatment; then, the same dose of domine is given every day for 3 days, and after 2-3 hours, 500ng of interleukin (IL-33) is dripped into the nasal cavity; mice were tested for lung inflammation on day 4.

(3) 24 hours after the last administration, mice were anesthetized, perfused with 0.3mL of pre-chilled saline, aspirated, then washed 2 times with 0.5mL of PBS, 3 times pooled together and centrifuged to collect cells in the mouse alveolar lavage fluid, and eosinophils (Eos) in the mouse alveolar lavage fluid were detected using flow cytometry.

4, experimental results:

the results of flow analysis of eosinophilic EOS in nasally-administered alveolar lavage (BALF) are shown in figure 6, EOS levels (representing levels of inflammation). As can be seen from FIG. 6, the level of Eos cells in the mouse alveolar lavage fluid was significantly reduced after treatment with DA nasal drops, indicating that DA nasal drops can effectively inhibit lung inflammation in mice.

Claims

1. The use of dopamine or a pharmaceutically acceptable salt thereof in the manufacture of a product for the prevention and/or treatment of allergic inflammation of the airways.

2. The application of dopamine or pharmaceutically acceptable salts thereof in preparing products for preventing and/or treating lung allergic inflammation.

3. The application of dopamine or pharmaceutically acceptable salts thereof in preparing products for preventing and/or treating allergic asthma.

4. The application of dopamine or pharmaceutically acceptable salts thereof in preparing a product for reducing lung eosinophilic granulocytes; the lung eosinophils are caused by allergic inflammation of the lung.

5. Use of dopamine or a pharmaceutically acceptable salt thereof for the manufacture of a product for inhibiting inflammatory cell infiltration in the lung.

6. Use according to any one of claims 1 to 5, characterized in that: the product is a medicament or pharmaceutical formulation; the medicament or pharmaceutical formulation is administered by injection or topically;

the allergic inflammation or the allergic asthma is induced by Papain Papain or interleukin IL-33.

7. Use of dopamine or a pharmaceutically acceptable salt thereof, which is at least one of the following (b 1) to (b 5):

(b1) Prevention and/or treatment of allergic inflammation of the airways;

(b2) Preventing and/or treating allergic inflammation of the lung;

(b3) Prevention and/or treatment of allergic asthma;

(b4) Reducing lung eosinophil number; said lung eosinophils are caused by allergic inflammation of the lung;

(b5) Inhibiting inflammatory cell infiltration in the lung.

8. A product whose active ingredient is dopamine or a pharmaceutically acceptable salt thereof; the product has at least one of the following effects:

(c1) Prevention and/or treatment of allergic inflammation of the airways;

(c2) Preventing and/or treating allergic inflammation of the lung;

(c3) Prevention and/or treatment of allergic asthma;

(c4) Reducing eosinophil numbers in the lung;

(c5) Inhibiting inflammatory cell infiltration in the lung.

9. Use according to claim 8, characterized in that: the product is a medicament or pharmaceutical formulation.

10. Use according to claim 8, characterized in that: the allergic inflammation or allergic asthma is induced by Papain or interleukin IL-33.