Application of small-molecule inhibitor in preparation of medicine for treating / relieving depression

Abstract

The invention provides an application of a small-molecule inhibitor in preparation of a medicine for treating / relieving depression, the small-molecule inhibitor is AZD8797, and the action target of the small-molecule inhibitor is CX3CR1. Compared with the prior art, the invention has the following advantages: the small-molecule inhibitor provided by the invention is applied to preparation of drugs for treating / relieving depression, and the small-molecule inhibitor can effectively inhibit nerve synapse and dendritic spine injury caused by excessive activation of microglial cells, and has great significance in clinical treatment of depression. Meanwhile, the pharmaceutical composition also has the technical advantages of good safety, good stability, good patent medicine performance, efficient administration mode and no adverse effect.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to the use of small molecule inhibitors in the preparation of drugs for treating / alleviating depression. Background Art

[0002] Depression is a common mental disorder, known as the "cold in psychiatry". Its lifetime prevalence is as high as 10% to 20%, and there are 350 million patients worldwide. Depression is characterized by high incidence, high recurrence, and high disability. It is the leading cause of disability around the world and a major factor in the global burden of disease. The biological etiology and pathogenesis of depression are still unclear, but it is generally believed that its onset is the result of the combined effects of genetic and environmental factors. The heritability of major depression is about 40%-50%. The pathogenesis of depression involves a variety of highly complex and interrelated pathways, mainly including monoamines, HPA axis, neurotrophic factors and neurogenesis, excitatory and inhibitory neurotransmission, mitochondrial dysfunction, epigenetics, inflammation, opioid system, myelination and gut-brain axis. The unknown genetic etiology and pathological mechanism of depression and the lack of universal drug targets bring great difficulties to clinical treatment.

[0003] Since 2000, there have been a total of 12 drugs approved for the treatment of depression in the global market. In the current domestic medical market, there are more than 30 kinds of antidepressants, which cover various mechanisms of action, but their curative effects on patients are not very different. There are still quite a few patients who do not see obvious results after drug treatment, and the antidepressant effect of drug treatment is very limited. Currently, almost all antidepressants currently in clinical use improve depressive symptoms by affecting the signal transmission of monoamine neurotransmitters (including serotonin and norepinephrine), and the drug target was discovered 30 years ago. The defect of this type of drug is that it can only relieve the symptoms of a small number of patients, and it takes weeks or even months to alleviate depressive symptoms, and the side effects are serious. On March 5, 2019, the U.S. Food and Drug Administration (FDA) approved a new antidepressant drug: Spravato (esketamine) esketamine for listing, becoming the first fast-acting antidepressant on the market. This is the first drug to treat depression with a new mechanism of action in 30 years, and is used together with oral antidepressants to treat refractory depression. Unlike most antidepressants, esketamine can improve a patient's mood within 2-3 hours, but the drug requires strict dosage control and is addictive. The field of depression is in urgent need of new genetic and pathogenesis guidance and support for drug development. Just one esketamine is far from enough. With the changes in people's quality of life and environment, depression has become more and more prevalent in our lives, and the size of its drug market will continue to grow. More "safe, effective, and new" antidepressants are urgently needed in clinical practice. Summary of the invention

[0004] In view of the above-mentioned technical limitations, the present invention proposes the use of small molecule inhibitors in the preparation of drugs for treating / alleviating depression; it overcomes the deficiencies and defects mentioned in the background technology.

[0005] To achieve the above object, the present invention adopts the following technical solutions:

[0006] The invention point of the present invention is to provide an application of a small molecule inhibitor in the preparation of a drug for treating / alleviating depression, wherein the small molecule inhibitor is AZD8797, and the target of the small molecule inhibitor is CX3CR1.

[0007] Optionally, in the above application, the CX3CR1 is the CX3CR1 gene and / or the CX3CR1 protein.

[0008] Optionally, in the above application, the small molecule inhibitor can reduce or eliminate the relative expression level of CX3CR1 mRNA, and reduce or eliminate the protein expression of CX3CR1 in cells.

[0009] Optionally, in the above application, the drug for treating / alleviating depression further includes a pharmaceutically acceptable carrier and pharmaceutical excipients.

[0010] Optionally, in the above application, the drug for treating / alleviating depression is administered by continuous administration in vivo.

[0011] Optionally, in the above application, the drug for treating / alleviating depression is continuously administered in vivo by means of an implanted capsule osmotic pump.

[0012] Optionally, in the above application, in the drug for treating / alleviating depression, the administration amount of the small molecule inhibitor is 13.6 μg / kg / day-156 μg / kg / day, preferably 80 μg / kg / day.

[0013] Compared with the prior art, the present invention has the following advantages: the use of the small molecule inhibitor provided by the present invention in the preparation of drugs for treating / alleviating depression is to study and explain the genetic laws and pathogenesis of depression from a new perspective of intergenerational inheritance, and then discover a new drug target, namely CX3CR1, based on this, and then use the small molecule inhibitor AZD8797 as a CX3CR1 gene inhibitor to treat depression. This gene inhibitor can effectively inhibit the damage of synapses and dendritic spines caused by excessive activation of microglia, which is of great significance for the clinical treatment of depression. It also has the following innovations and advantages:

[0014] First, safety: it can specifically target the target gene and has low toxicity and low immunogenicity;

[0015] Second, good stability: small molecule inhibitors are easy to transport and store, have good stability, high membrane permeability, and are convenient for clinical treatment;

[0016] Third, good drugability: small molecule inhibitors have good spatial dispersion, good drugability and pharmacokinetic properties, which give them great advantages in the drug development process and other drug fields, and are increasingly favored by the market;

[0017] Fourth, an efficient and non-adverse drug delivery method: using an implantable capsule osmotic pump ( Osmotic Pumps) can enable the small molecule inhibitor (AZD8797) to be implanted into the mouse cortex and then continuously released at a certain rate in vivo using the osmotic pressure principle. This drug delivery method not only solves the blood-brain barrier problem, but also avoids the adverse effects of multiple drug administration, making it safer, more convenient and more efficient. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 Shown is a schematic diagram of the modeling, drug administration and behavioral testing of the CUMS model of mouse depression in one embodiment of the present invention.

[0019] Figure 2 Shown is the behavioral phenotype detection result (n=15) of depression CUMS model mice after administration of CX3CR1 small molecule inhibitor (AZD8797) in one embodiment of the present invention. The behavioral phenotype detection experiments are tail suspension test TST, forced swimming test FST and novel environment feeding suppression test NSFT. DETAILED DESCRIPTION

[0020] In order to make the purpose, technical solution and advantages of the present invention more clear, the present invention is further described in detail below. However, it should be understood that the description herein is only used to explain the present invention and is not used to limit the scope of the present invention.

[0021] Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as those generally understood by those skilled in the art of the present invention, and the terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The reagents and instruments used herein are all commercially available, and the characterization means involved can refer to the relevant descriptions in the prior art, which will not be repeated herein.

[0022] In order to further understand the present invention, the present invention is further described in detail below in conjunction with the best embodiment.

[0023] Example 1

[0024] A use of a small molecule inhibitor in the preparation of a drug for treating / alleviating depression, wherein the small molecule inhibitor is AZD8797, and the target of the small molecule inhibitor is CX3CR1.

[0025] CX3CR1 is CX3CR1 gene and / or CX3CR1 protein.

[0026] Small molecule inhibitors can reduce or eliminate the relative expression level of CX3CR1 mRNA and the protein expression of CX3CR1 in cells.

[0027] The drug used to treat / alleviate depression also includes a pharmaceutically acceptable carrier and pharmaceutical excipients.

[0028] The drug used to treat / alleviate depression is administered continuously in the body.

[0029] Drugs used to treat / alleviate depression are continuously delivered into the body using an implanted capsule osmotic pump.

[0030] In the drugs used to treat / relieve depression, the dosage of the small molecule inhibitor is 13.6μg / kg / day-156μg / kg / day, which can be selected as 13.6μg / kg / day, 20μg / kg / day, 40μg / kg / day, 60μg / kg / day, 80μg / kg / day, 100μg / kg / day, 120μg / kg / day, 140μg / kg / day, 156μg / kg / day, preferably 80μg / kg / day.

[0031] Example 2

[0032] 1. CUMS modeling:

[0033] Eight-week-old C57 BL / 6J male mice were subjected to chronic unpredictable stress modeling for 6 weeks, with 1-3 stimulations per day, including noise, strobe light, cage tilt, restraint, wet cage, and day and night reversal. Behavioral testing was performed after the modeling was completed.

[0034] Table 1 shows the detailed modeling process.

[0035] Table 1

[0036]

[0037] 2. Behavioral testing methods:

[0038] 1. Open field experiment: The experimental device consists of an open field reaction box and an automatic data acquisition and processing system. The mouse open field reaction box is 25-30cm high, 72cm long at the bottom, the inner wall is painted black, and the bottom is evenly divided into 64 small squares. A digital camera is set up 2m above, and its field of view can cover the entire open field. The experiment is carried out in a quiet environment. Place the animal in the center of the bottom of the box, and take pictures and time it for 10 minutes. Clean the inner wall and bottom of the box to prevent the remaining information of the animal from the last time (such as the animal's urine, feces, and odor) from affecting the results of the next test. Replace the animal and continue the experiment.

[0039] 2. Tail suspension test: Use a small clip to clamp the mouse's tail 1 cm away, suspend it for 5 minutes, and detect its struggling and immobility time.

[0040] 3. Forced swimming: The mice were taught to swim in 25°C water for 15 minutes in advance. During the test, the mice were placed in 25°C warm water and the behavioral instrument was used to record the swimming, floating, and struggling time for 5 minutes.

[0041] 4. Inhibition of eating in a new environment: The mice were fasted for 24 hours. During the test, the mice were placed from the corner into the open field, and allowed to adapt to the environment for 1 minute. The mice were then taken out and a sugar pill / mouse food was placed in the center of the open field. The instrument recorded the time taken by the mice from the time they were placed in the open field to the time they ate within five minutes.

[0042] 3. Treatment of depression with small molecule inhibitor AZD8797:

[0043] The CX3CR1 small molecule inhibitor (AZD8797) Osmotic Pumps (Yuyan Instrument, 2006) were implanted in the dorsal subcutaneous tissue of mice, and then introduced into the cerebral cortex of mice using a mouse intrathecal catheter (Model: 0007743), so that it could be continuously released at a rate of 80 μg / kg / day sc to inhibit CX3CR1. At the same time, cums modeling was performed, and three different stimuli were given every day. Behavioral tests were performed after 6 weeks. The results showed that the small molecule inhibitor of CX3CR1 (AZD8797) showed obvious therapeutic effects ( Figure 2 ).

[0044] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. Use of a small molecule inhibitor in the preparation of a drug for treating / alleviating depression, characterized in that: The small molecule inhibitor is AZD8797, and the target of the small molecule inhibitor is CX3CR1.

2. The use according to claim 1, characterized in that: The CX3CR1 is the CX3CR1 gene and / or the CX3CR1 protein.

3. The use according to any one of claims 1 or 2, characterized in that: The small molecule inhibitor can reduce or eliminate the relative expression level of CX3CR1 mRNA, and reduce or eliminate the protein expression of CX3CR1 in cells.

4. The use according to claim 3, characterized in that: The drug for treating / alleviating depression also includes a pharmaceutically acceptable carrier and pharmaceutical excipients.

5. The use according to claim 4, characterized in that: The administration method of the drug for treating / alleviating depression is continuous administration in vivo.

6. The use according to claim 5, characterized in that: The drug for treating / alleviating depression is continuously administered in vivo by means of an implanted capsule osmotic pump.

7. The use according to claim 6, characterized in that: In the drug for treating / alleviating depression, the administration amount of the small molecule inhibitor is 13.6 μg / kg / day to 156 μg / kg / day, preferably 80 μg / kg / day.

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