Application of alkaloid in preparation of medicine for resisting neuroinflammation and improving lung injury

Abstract

The invention discloses an application of alkaloid in preparation of a medicine for resisting neuroinflammation and improving lung injury, and particularly relates to an application of Cottoquinazoline B in preparation of a medicine for preventing and / or treating neurodegenerative diseases caused by neuroinflammation, or an application of Cottoquinazoline B in preparation of a medicine for preventing and / or treating lung injury caused by lung inflammation. The invention finds that the marine derived fungus aspergillus niger source compound Cottoquinazoline B can obviously reduce the neuroinflammation reaction induced by lipopolysaccharide, can obviously relieve the lung inflammation reaction induced by lipopolysaccharide and reduce the level of serum cytokines induced by lipopolysaccharide, and has good application prospect and commercial value.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to the use of an alkaloid in the preparation of drugs for resisting neuroinflammation and improving lung injury. Background Art

[0002] Excessive inflammatory response is involved in the occurrence and development of many diseases, especially neuroinflammatory response and pulmonary inflammatory response.

[0003] Neuroinflammation is an inflammatory response of the central nervous system, which is usually associated with infection, autoimmune diseases, peripheral inflammation, mental stress and metabolic disorders. Under physiological conditions, glial cells maintain the homeostasis of the internal environment of the central nervous system by releasing neurotrophic factors, clearing synaptic glutamate and remodeling synapses. In the pathological process, glial cells in the innate immune response, especially microglia, are overactivated, releasing a large number of cytokines and inflammatory mediators such as tumor necrosis factor α, interleukin 6, nitric oxide, etc., which leads to persistent neuroinflammatory response and the occurrence and development of a series of central diseases, such as Alzheimer's disease, Parkinson's disease, depression, etc.

[0004] Lung disease is an increasingly serious global health problem and one of the causes of high morbidity and mortality worldwide. Pulmonary inflammatory response is involved in the occurrence and development of many lung diseases, especially acute lung injury, which is a serious lung disease caused by acute hypoxic respiratory insufficiency due to trauma, sepsis, surgery, drugs and infection. The main pathological features are alveolar edema, excessive infiltration of inflammatory cells and increased alveolar permeability. Its pathogenesis is very complex. It is an acute inflammatory response caused by direct or indirect injury, in which the massive release of tumor necrosis factor α and interleukin 6 activates and amplifies the inflammatory cascade reaction, leading to the occurrence and development of lung injury.

[0005] The ocean is a huge library of natural product compounds with a large number of bioactive compounds with unique structures, making it an important source for drug screening. Cottoquinazoline B compound is isolated from the marine source Aspergillus niger. It is a class of natural products with a unique skeleton, containing a pyrazinequinazolinedione molecule and an imidazoindole molecule. Its pharmacological effects have been less studied. Summary of the invention

[0006] The purpose of the present invention is to provide an application of an alkaloid in the preparation of drugs for resisting neuroinflammation and improving lung injury in view of the technical defects existing in the prior art.

[0007] The technical solution adopted to achieve the purpose of the present invention is: An application of an alkaloid in the preparation of a drug for inhibiting inflammatory response, wherein the alkaloid is Cottoquinazoline B, and the structural formula of Cottoquinazoline B is: .

[0008] In the above technical solution, the inflammatory response is an inflammatory response induced by lipopolysaccharide.

[0009] In the above technical solution, the application is the application of Cottoquinazoline B in the preparation of drugs for preventing and / or treating neurodegenerative diseases and mental illnesses caused by neuroinflammation.

[0010] In the above technical solution, the neurodegenerative disease caused by neuroinflammation is Alzheimer's disease or Parkinson's disease.

[0011] In the above technical solution, the mental illness caused by neuroinflammation is depression.

[0012] In the above technical solution, the application is the application of Cottoquinazoline B in the preparation of a drug for preventing and / or treating lung injury caused by lung inflammation.

[0013] Another aspect of the present invention also includes a drug for inhibiting inflammatory response, wherein the active ingredient includes Cottoquinazoline B, and the structural formula of Cottoquinazoline B is: .

[0014] In the above technical solution, the drug for inhibiting inflammatory response also contains pharmaceutically acceptable excipients.

[0015] In the above technical solution, the auxiliary materials include diluents, excipients, fillers, adhesives, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers or lubricants.

[0016] In the above technical solution, the dosage form of the drug is tablets, granules, pills, capsules or injections. The above various dosage forms of drugs can be prepared according to conventional methods in the pharmaceutical field.

[0017] Compared with the prior art, the present invention has the following beneficial effects: The present invention finds that Cottoquinazoline B, a compound derived from the marine fungus Aspergillus niger, can significantly reduce lipopolysaccharide-induced neuroinflammatory response, significantly alleviate lipopolysaccharide-induced lung inflammatory response, and reduce lipopolysaccharide-induced serum cytokine levels, and has good application prospects and commercial value. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 The figure shows the effect of Cottoquinazoline B on the content of tumor necrosis factor-α in mouse cortical tissue induced by lipopolysaccharide. The vertical axis represents the content of tumor necrosis factor-α per mg of mouse cortical tissue protein (pg).

[0019] Figure 2 The figure shows the effect of Cottoquinazoline B on the interleukin-6 content in mouse cortical tissue induced by lipopolysaccharide. The vertical axis represents the interleukin-6 content per mg of mouse cortical tissue protein (pg).

[0020] Figure 3 The figure shows the effect of Cottoquinazoline B on the content of tumor necrosis factor-α in the lung tissue of mice induced by lipopolysaccharide. The vertical axis represents the content of tumor necrosis factor-α per milligram of lung tissue protein (pg).

[0021] Figure 4 The figure shows the effect of Cottoquinazoline B on the interleukin-6 content in mouse lung tissue induced by lipopolysaccharide. The vertical axis represents the interleukin-6 content per milligram of mouse lung tissue protein (pg).

[0022] Figure 5 The figure shows the effect of Cottoquinazoline B on the level of tumor necrosis factor-α in mouse serum induced by lipopolysaccharide. The vertical axis represents the content of tumor necrosis factor-α per milliliter of mouse serum (pg).

[0023] Figure 6 The figure shows the effect of Cottoquinazoline B on the level of interleukin-6 in the serum of mice induced by lipopolysaccharide. The vertical axis represents the content of interleukin-6 per milliliter of mouse serum (pg).

[0024] Note: Figure 1-Figure 6 In the table, # indicates that there is a significant difference between the lipopolysaccharide model group and the control group (P < 0.05), ## indicates that there is an extremely significant difference between the lipopolysaccharide model group and the control group (P < 0.01); * indicates that there is a significant difference between the cottoquinazoline B group and the lipopolysaccharide model group (P < 0.05), ** indicates that there is an extremely significant difference between the cottoquinazoline B group and the lipopolysaccharide model group (P < 0.01); P is an important parameter used in statistics to determine the results of hypothesis testing, which is used to determine whether the observed results are significantly different. DETAILED DESCRIPTION

[0025] The present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0026] Step 1, mouse model establishment and drug administration: C57BL / 6 mice were acclimated to the environment at a constant temperature of 25℃ and a humidity of 50%-70% for 7 days, and then randomly divided into four groups, namely the control group, the lipopolysaccharide model group, and two Cottoquinazoline B groups. The two Cottoquinazoline B groups were high-dose group (20 mg / kg) and low-dose group (10 mg / kg), respectively. In these two groups, the compound CottoquinazolineB was intraperitoneally injected once a day at a dose of 10 mg / kg and 20 mg / kg (dissolved in 5% propylene glycol saline solution) for 3 days, and the mice in the control group and the lipopolysaccharide model group were given the same volume of control solution (5% propylene glycol saline solution). One hour after the third day of administration, the mice in the lipopolysaccharide model group and the Cottoguimazolime B group were intraperitoneally injected with lipopolysaccharide (dissolved in saline) at a dose of 2 mg / kg, and the control group was given the same volume of saline, and tissue samples were collected 10 hours later.

[0027] Step 2: Detect tumor necrosis factor α and interleukin 6 in tissue homogenate and serum according to the enzyme-linked immunosorbent assay kit: (1) Add standard substances and establish a standard curve; (2) Add sample (100 μL / well) and incubate in a 37°C incubator in the dark for 90 minutes; (3) Wash the plate 5 times, add biotinylated antibody working solution (100 μL / well), and incubate in a 37°C incubator in the dark for 60 min; (4) Wash the plate 5 times, add enzyme conjugate working solution (100 μL / well), and incubate in a 37°C incubator in the dark for 30 min; (5) Wash the plate five times, add chromogenic substrate (100 μL / well), and incubate in a 37°C incubator in the dark for 15 min. Add reaction stop solution (100 μL / well), mix well and measure OD 450 Value. According to OD 450 Calculate the sample concentration.

[0028] like Figure 1 and Figure 2 As shown in the figure, compared with the control group, the levels of tumor necrosis factor α and interleukin 6 in the cortical tissue of mice in the lipopolysaccharide model group were significantly increased. Compared with the mice in the lipopolysaccharide model group, the cottoquinazoline B group can significantly reduce the levels of tumor necrosis factor α and interleukin 6 in the cortical tissue of mice, and can play a role in improving neuroinflammation.

[0029] like Figure 3 and 4 As shown in the figure, compared with the control group, the levels of tumor necrosis factor α and interleukin 6 in the lung tissue of the mice in the lipopolysaccharide model group were significantly increased. Compared with the mice in the lipopolysaccharide model group, the Cottoquinazoline B group showed that Cottoquinazoline B could significantly inhibit the increase of tumor necrosis factor α and interleukin 6 levels, and play an anti-pulmonary inflammation role.

[0030] like Figure 5 and 6 The results showed that compared with the lipopolysaccharide model group, Cottoquinazoline B group could significantly reduce the levels of tumor necrosis factor-α and interleukin-6 in mouse serum, indicating that Cottoquinazoline B may inhibit the inflammatory response of multiple organs and tissues in mice.

[0031] In summary, Cottoquinazoline B can significantly reduce the neuroinflammatory response in the brain of mice induced by lipopolysaccharide. Specifically, Cottoquinazoline B significantly reduces the levels of tumor necrosis factor-α and interleukin-6 in the cortical tissue of mice induced by lipopolysaccharide.

[0032] Cottoquinazoline B can significantly inhibit the lipopolysaccharide-induced inflammatory response in the lung tissue of mice. Specifically, Cottoquinazoline B can significantly reduce the levels of tumor necrosis factor α and interleukin 6 in the lung tissue of mice induced by lipopolysaccharide, and significantly inhibit the inflammatory response in the lung.

[0033] Cottoquinazoline B can significantly inhibit the levels of tumor necrosis factor-α and interleukin-6 in the serum of mice induced by lipopolysaccharide, indicating that Cottoquinazoline B can improve the inflammatory response of multiple tissues.

[0034] Cottoquinazoline B has great value for promotion and application, and is expected to be further developed in the treatment of inflammatory-related diseases, anti-neuroinflammation, and anti-lung injury.

[0035] The above is only a preferred embodiment of the present invention. It should be pointed out that, for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. An application of an alkaloid in the preparation of a drug for inhibiting inflammatory response, characterized in that: The alkaloid is Cottoquinazoline B, and the structural formula of Cottoquinazoline B is: 。 2. The use according to claim 1, characterized in that The inflammatory response is an inflammatory response induced by lipopolysaccharide.

3. The use according to claim 1, characterized in that The application is the application of Cottoquinazoline B in the preparation of drugs for preventing and / or treating neurodegenerative diseases and mental illnesses caused by neuroinflammation.

4. The use according to claim 3, characterized in that The neurodegenerative disease caused by neuroinflammation is Alzheimer's disease or Parkinson's disease.

5. The use according to claim 3, characterized in that The mental illness caused by neuroinflammation is depression.

6. The use according to claim 1, characterized in that The application is the application of Cottoquinazoline B in the preparation of a drug for preventing and / or treating lung damage caused by lung inflammation.

7. A drug for inhibiting inflammatory response, characterized in that: The active ingredient includes Cottoquinazoline B, and the structural formula of Cottoquinazoline B is: 。 8. The drug according to claim 7, characterized in that The drug for inhibiting inflammatory response also contains pharmaceutically acceptable excipients.

9. The drug according to claim 8, characterized in that The auxiliary materials include diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers or lubricants.

10. The drug according to claim 7, characterized in that The dosage form of the medicine is tablet, granule, pill, capsule or injection.

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