Application of an alkaloid in the preparation of drugs for anti-neuroinflammation and improving lung injury

Abstract

The present invention discloses the use of an alkaloid in the preparation of a drug for anti-neuroinflammation and improving lung injury. The use is the use of Cottoquinazoline B in the preparation of a drug for preventing and / or treating neurodegenerative diseases caused by neuroinflammation, or the use is the use of Cottoquinazoline B in the preparation of a drug for preventing and / or treating lung injury caused by pulmonary inflammation. The present invention discovers that the compound Cottoquinazoline B derived from the marine-derived fungus Aspergillus niger can significantly reduce the lipopolysaccharide-induced neuroinflammatory response, can significantly alleviate the lipopolysaccharide-induced pulmonary inflammatory response, and can reduce the lipopolysaccharide-induced serum cytokine level, and has good application prospects and commercial value.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to the use of an alkaloid in the preparation of a drug for anti-neuroinflammation and improving lung injury. Background Art

[0002] Excessive inflammatory responses are involved in the occurrence and development of various diseases, especially neuroinflammatory responses and pulmonary inflammatory responses.

[0003] Neuroinflammation is an inflammatory response in the central nervous system, which is usually associated with factors such as infection, autoimmune diseases, peripheral inflammation, mental stress, and metabolic disorders. Under physiological conditions, glial cells maintain the homeostasis of the central nervous system by releasing neurotrophic factors, clearing synaptic glutamate, and remodeling synapses. In pathological processes, 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, and nitric oxide, which in turn lead to persistent neuroinflammatory responses, resulting in the occurrence and development of a series of central diseases, such as Alzheimer's disease, Parkinson's disease, and depression.

[0004] Lung diseases are an increasingly serious global health problem and one of the leading causes of high morbidity and mortality worldwide. Pulmonary inflammatory responses are involved in the occurrence and development of various lung diseases, especially acute lung injury. Acute lung injury is a severe lung disease caused by factors such as trauma, sepsis, surgery, drugs, and infection, leading to acute hypoxic respiratory insufficiency. The main pathological features are alveolar edema, excessive infiltration of inflammatory cells, and increased alveolar permeability. Its pathogenesis is very complex, being 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, resulting in the occurrence and development of lung injury.

[0005] The ocean, as a vast library of natural product compounds, contains a large number of bioactive compounds with unique structures, becoming an important source for drug screening. The compound Cottoquinazoline B is isolated from Aspergillus niger of marine origin and is a natural product with a unique skeleton, containing a pyrazinoquinazolinone molecule and an imidazolidinone molecule, and its pharmacological effects have been less studied. Summary of the Invention

[0006] The object of the present invention is to provide a use of an alkaloid in the preparation of a drug for anti-neuroinflammation and improving lung injury in view of the technical defects existing in the prior art.

[0007] The technical solution adopted to achieve the object of the present invention is as follows:

[0008] Use 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:

[0009] .

[0010] In the above technical solution, the inflammatory response is a lipopolysaccharide-induced inflammatory response.

[0011] In the above technical solution, the application is the use of Cottoquinazoline B in the preparation of a drug for preventing and / or treating neurodegenerative diseases and mental diseases caused by neuroinflammation.

[0012] In the above technical solution, the neurodegenerative disease caused by neuroinflammation is Alzheimer's disease or Parkinson's disease.

[0013] In the above technical solution, the mental disease caused by neuroinflammation is depression.

[0014] In the above technical solution, the application is the use of Cottoquinazoline B in the preparation of a drug for preventing and / or treating lung injury caused by lung inflammation.

[0015] On the other hand, 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:

[0016] .

[0017] In the above technical solution, the drug for inhibiting inflammatory response further contains pharmaceutically acceptable excipients.

[0018] In the above technical solution, the excipients include diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers or lubricants.

[0019] In the above technical solution, the dosage form of the drug is tablets, granules, pills, capsules or injections. The drugs in the above various dosage forms can all be prepared according to the conventional methods in the pharmaceutical field.

[0020] Compared with the prior art, the beneficial effects of the present invention are:

[0021] The present invention discovers that the compound Cottoquinazoline B derived from the marine-derived fungus Aspergillus niger can significantly reduce the lipopolysaccharide-induced neuroinflammatory response, can significantly alleviate the lipopolysaccharide-induced pulmonary inflammatory response, and can reduce the lipopolysaccharide-induced serum cytokine levels, having good application prospects and commercial value. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Shows the effect of Cottoquinazoline B on the content of tumor necrosis factor α in the cerebral cortex tissue of lipopolysaccharide-induced mice. The vertical axis represents the content of tumor necrosis factor α (pg) in every milligram of cerebral cortex tissue protein of mice.

[0023] Figure 2 Shows the effect of Cottoquinazoline B on the content of interleukin 6 in the cerebral cortex tissue of lipopolysaccharide-induced mice. The vertical axis represents the content of interleukin 6 (pg) in every milligram of cerebral cortex tissue protein of mice.

[0024] Figure 3 Shows the effect of Cottoquinazoline B on the content of tumor necrosis factor α in the lung tissue of lipopolysaccharide-induced mice. The vertical axis represents the content of tumor necrosis factor α (pg) in every milligram of lung tissue protein.

[0025] Figure 4 Shows the effect of Cottoquinazoline B on the content of interleukin 6 in the lung tissue of lipopolysaccharide-induced mice. The vertical axis represents the content of interleukin 6 (pg) in every milligram of lung tissue protein of mice.

[0026] Figure 5 Shows the effect of Cottoquinazoline B on the level of tumor necrosis factor α in the serum of lipopolysaccharide-induced mice. The vertical axis represents the content of tumor necrosis factor α (pg) in every milliliter of mouse serum.

[0027] Figure 6 Shows the effect of Cottoquinazoline B on the level of interleukin 6 in the serum of lipopolysaccharide-induced mice. The vertical axis represents the content of interleukin 6 (pg) in every milliliter of mouse serum.

[0028] Note: In Figures 1 - 6In this case, # indicates a significant difference between the lipopolysaccharide model group and the control group (P < 0.05), and ## indicates a highly significant difference between the lipopolysaccharide model group and the control group (P < 0.01); * indicates a significant difference between the Cottoquinazoline B group and the lipopolysaccharide model group (P < 0.05), and ** indicates a highly significant difference between the Cottoquinazoline B group and the lipopolysaccharide model group (P < 0.01); where P is an important parameter in statistics for determining the results of hypothesis testing and is used to judge whether the observed results have significant differences. Detailed implementation manners

[0029] The present invention will be 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.

[0030] Step 1, establishment of a mouse model and administration of drugs:

[0031] C57BL / 6 mice were adaptively raised in an environment with a constant temperature of 25°C and a humidity of 50% - 70% for 7 days. The mice were randomly divided into four groups, namely a control group, a lipopolysaccharide model group, and two Cottoquinazoline B groups. The two Cottoquinazoline B groups were a high-dose group (20 mg / kg) and a low-dose group (10 mg / kg). In these two groups, the compound Cottoquinazoline B 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. The mice in the control group and the lipopolysaccharide model group were given the same volume of a control solution (5% propylene glycol saline solution). One hour after the administration on the third day, the mice in the lipopolysaccharide model group and the Cottoquinazoline 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. Tissue samples were collected 10 hours later.

[0032] Step 2, detection of tumor necrosis factor α and interleukin 6 in tissue homogenates and sera, and the operation was carried out according to an enzyme-linked immunosorbent assay kit:

[0033] (1) Add standard products to establish a standard curve;

[0034] (2) Add samples (100 μL / well) and incubate in a constant temperature incubator at 37°C in the dark for 90 minutes;

[0035] (3) Wash the plate 5 times, add the biotinylated antibody working solution (100 μL / well), and incubate in a constant temperature incubator at 37°C in the dark for 60 minutes;

[0036] Wash the plate 5 times, add the enzyme conjugate working solution (100 μL / well), and incubate in the 37 °C incubator in the dark for 30 minutes;

[0037] Wash the plate 5 times, add the chromogenic substrate (100 μL / well), and incubate in the 37 °C incubator in the dark for 15 minutes;

[0038] Add the reaction stop solution (100 μL / well), mix well and measure the OD 450 value. Calculate the sample concentration according to the OD 450 value.

[0039] As Figure 1 and Figure 2 shown, compared with the control group of mice, the levels of tumor necrosis factor α and interleukin 6 in the cortical tissue of the lipopolysaccharide model group of mice were significantly increased. Compared with the lipopolysaccharide model group of mice, it can be seen that Cottoquinazoline B 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.

[0040] As Figure 3 and 4 shown, compared with the control group of mice, the levels of tumor necrosis factor α and interleukin 6 in the lung tissue of the lipopolysaccharide model group of mice were significantly increased. Compared with the lipopolysaccharide model group of mice, it can be seen that Cottoquinazoline B can significantly inhibit the increase in the levels of tumor necrosis factor α and interleukin 6, and play an anti-lung inflammation role.

[0041] As Figure 5 and 6 the results show that compared with the lipopolysaccharide model group, it can be seen that Cottoquinazoline B can significantly reduce the levels of tumor necrosis factor α and interleukin 6 in the serum of mice, indicating that Cottoquinazoline B may inhibit the inflammatory responses in multiple organs and tissues of mice.

[0042] In summary, Cottoquinazoline B can significantly reduce the neuroinflammatory response in the brains of lipopolysaccharide-induced mice. Specifically, it is manifested that Cottoquinazoline B significantly reduces the levels of tumor necrosis factor α and interleukin 6 in the cortical tissue of lipopolysaccharide-induced mice.

[0043] Cottoquinazoline B can significantly inhibit the inflammatory response in the lung tissues of mice induced by lipopolysaccharide. Specifically, it is manifested that Cottoquinazoline B can significantly reduce the levels of tumor necrosis factor-α and interleukin-6 in the lung tissues of mice induced by lipopolysaccharide, and significantly inhibit the inflammatory response in the lungs.

[0044] Cottoquinazoline B can significantly inhibit the levels of tumor necrosis factor-α and interleukin-6 in the serum of mice induced by lipopolysaccharide. The above indicates that Cottoquinazoline B can improve the inflammatory responses in multiple tissues.

[0045] Cottoquinazoline B has great value in popularization and application, and is also expected to be further developed in the treatment of inflammation-related diseases, anti-neuroinflammation, and anti-lung injury.

[0046] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope 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 preparing a drug for preventing and / or treating neuroinflammation.

4. 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.

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