CN110664822A - Novel application of dutasteride in resisting inflammatory injury - Google Patents
Novel application of dutasteride in resisting inflammatory injury Download PDFInfo
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- CN110664822A CN110664822A CN201911004053.XA CN201911004053A CN110664822A CN 110664822 A CN110664822 A CN 110664822A CN 201911004053 A CN201911004053 A CN 201911004053A CN 110664822 A CN110664822 A CN 110664822A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
The invention belongs to the field of medicine research, and discloses a new application of dutasteride in resisting inflammatory injury. The application of the preparation containing the dutasteride component in resisting inflammatory injury has obvious drug effect, and the dutasteride is a drug on the market, has clear toxic and side effects, and can be quickly applied.
Description
Technical Field
The invention belongs to the field of medicine research, and relates to a new medicine application.
Background
When pathogenic microorganisms are infected, cells in vivo generate a plurality of cytokines, exert non-specific immune functions and cause inflammatory reactions. Inflammation is generated to release a large amount of inflammation-related cytokines, and some small molecules can permeate blood-brain barriers through blood, so that intracerebral nerve inflammation is caused. Neuroinflammation is an inherent immune response in the brain, primarily manifested by the activation of microglia. Transient neuroinflammatory responses recruit and activate glial cells to the target area, and the damaged cells are phagocytosed and repaired before they return to a quiescent state. If inflammation is "irritated" over a long period of time, the development of inflammation can accumulate over time, gradually aggravating central nervous system injury and turning into a chronic inflammatory response. It is mainly manifested by the activation of microglia, the destruction of the blood-brain barrier (increased permeability) and the entry of peripheral immune cells (such as macrophages, NK cells, etc.) into the brain parenchyma. Chronic inflammatory reactions can cause inflammatory damage in the brain and even ultimately lead to neuronal damage and neurodegenerative diseases (alzheimer's disease, etc.). At present, the treatment aiming at intracerebral inflammatory injury caused by neuroinflammation mostly focuses on using non-steroidal anti-inflammatory drugs, including ibuprofen, indomethacin, aspirin and the like, but no remarkable curative effect exists, and the reason may be related to the fact that the non-steroidal anti-inflammatory drugs cannot directly enter a blood brain barrier to play the efficacy of the non-steroidal anti-inflammatory drugs. Therefore, it is urgent to find a drug that can enter the brain to resist inflammatory injury.
Disclosure of Invention
In order to solve the problems, the invention provides an application of dutasteride in resisting inflammatory injury.
Lipopolysaccharide (LPS) is a complex of lipids and polysaccharides in the cell wall of gram-negative bacteria and is widely used to induce neuroinflammation. After entering into the body, the polypeptide can be combined with Toll-like receptor 4 (TLR 4) to activate the immune system, generate peripheral inflammation and cause inflammatory injury.
Dutasteride belongs to approved marketed drugs, has known safety, and can penetrate the blood brain barrier into brain tissues. The medicine can be used for treating clinical inflammatory injury, can relieve inflammatory injury in brain, and has remarkable benefit.
In a first aspect the invention provides the use of dutasteride in the manufacture of a medicament against inflammatory injury, including injury caused by any factor likely to cause inflammatory injury, such as endotoxin Lipopolysaccharide (LPS), in one embodiment of the invention the inflammatory injury factor is LPS-induced injury.
The invention also provides a medicament for resisting the inflammatory injury, which is a preparation prepared by adding pharmaceutic adjuvants into dutasteride which is the only active component. The drug administration method of the invention includes various administration methods such as injection, oral administration and the like.
The invention achieves the following beneficial effects:
the invention applies the preparation containing the dutasteride component to the application of resisting the inflammatory injury, and has obvious drug effect. And the dutasteride is a drug on the market, has clear toxic and side effects and can be quickly applied.
Drawings
Figure 1 shows that dutasteride has a significant improvement in the reduction of thymus/body weight ratio due to inflammatory injury.
Figure 2 shows that dutasteride has a significant improvement effect on learning and memory impairment of mice caused by acute inflammatory injury (test period).
Figure 3 shows that dutasteride has a significant improvement effect on learning and memory impairment of mice caused by acute inflammatory injury (daily statistics in learning phase).
Figure 4 shows the improvement of dutasteride in the prolongation of escape latency in mice caused by chronic inflammatory injury.
Figure 5 shows the improvement of dutasteride in reducing the number of ring crossings in mice caused by chronic inflammatory injury.
Figure 6 shows the improvement of dutasteride in the reduction of mouse target quadrant residence time due to chronic inflammatory injury.
Figure 7 shows that dutasteride has a remarkable improvement effect on the increase of a mouse inflammatory response marker IL-6 in plasma caused by inflammatory injury.
Figure 8 shows that dutasteride has a significant improvement effect on the increase of the mouse inflammatory response marker IL-6 in the hippocampus caused by inflammatory injury.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples were carried out under the conventional conditions, unless otherwise specified. The drug dutasteride used is a compound which can be obtained commercially.
The reagents and materials used in the following examples include:
c57 mouse, male, SPF grade, initial body weight 22 ± 2 g; all purchased from sbefu laboratory animals ltd, license: SCXK (Kyoto) 2016-.
Dutasteride (Dutasteride,164656-23-9, TargetMol)
Lipopolysaccharide (Lipopolysaccharide, O111: B4, Sigma)
TLR4 antagonists: TAK-242(243984-11-4, Shanghai Vast Bio-technology Limited)
Test example 1 Effect of Dutasteride on learning and memory impairment of LPS-induced acute inflammation model mice
And (3) environmental adaptation: within 7 days of acclimatization, mice were gently grabbed for 3 minutes each day in order to reduce the effect of irrelevant stress stimuli on subsequent experimental manipulations. In the experimental process, the relative silence of the experimental environment is ensured.
Grouping experiments: the method comprises the steps of detecting the autonomous activity of mice, screening and discarding the mice which do not meet the requirements according to a 95% confidence interval, randomly grouping the mice according to the remaining autonomous activity and body weight, dividing the mice into 4 groups, namely a control group, a model group, a positive drug group (TAK-242) and a test drug group (dutasteride), wherein each group of mice is 12 mice, and corresponding solvents and drugs are given according to a dose of 0.1 mL/kg.
And (3) behavioral detection: after the Morris water maze experiment on the first day is finished, TAK-242 and a solvent of a test drug (a mixture prepared according to the proportion of 30% PEG300+ 1% Tween80+ 69% deionized water) are given to a control group and a model group, a solvent (saline) of lipopolysaccharide is injected into the abdominal cavity of the control group after half an hour, lipopolysaccharide is injected into the abdominal cavity of the model group, the Morris water maze experiment is continuously carried out, the changes of escape latency, ring-penetrating times and target quadrant residence time of a mouse are observed, and the changes of the learning capacity of the mouse in a learning period and a testing period of four days after the Morris water maze experiment is finished (the result is shown in a figure 2 and a figure 3).
Test example 2 Effect of Dutasteride on learning and memory impairment of LPS-induced Chronic inflammation model mice
And (3) environmental adaptation: within 7 days of acclimatization, the rats were gently grabbed for 3 minutes each day, reducing the effect of irrelevant stress stimuli on the subsequent experimental manipulations. In the experimental process, the relative silence of the experimental environment is ensured.
Grouping experiments: detecting the autonomous activity of the mice, screening and discarding the mice which do not meet the requirements according to a 95% confidence interval, randomly grouping the mice according to the autonomous activity and the body weight of the rest mice into 4 groups, wherein the 4 groups are respectively a control group, a model group, a positive drug group (TAK-242) and a test drug group (dutasteride), the control group is provided with a solvent (a mixture and a salene prepared according to the proportion of 30% PEG300+ 1% Tween80+ 69% deionized water), the model group is provided with a solvent (a mixture prepared according to the proportion of 30% PEG300+ 1% Tween80+ 69% deionized water) and the abdominal cavity is injected with lipopolysaccharide; positive drug TAK-242 and intraperitoneal injection of lipopolysaccharide; the test group was given dutasteride and injected intraperitoneally with lipopolysaccharide. Each group of mice was 12 mice, and the corresponding solvent and drug were administered at a dose of 0.1mL/kg, with a frequency of 1 administration/day for two months.
And (3) behavioral detection: the mice are taken out from the rearing cage, are independently placed in another rearing cage (the mice are reared in the same size and shape as the mice on the same weekday) and are adapted for ten minutes, TAK-242 and dutasteride are respectively given 30 minutes before injecting lipopolysaccharide, then lipopolysaccharide is injected 4 hours before behavioral experiments, Morris water maze experiments are carried out, and the changes of escape latency, ring-penetrating times and target quadrant residence time of the mice are observed; the study and memory capacity of the mice during the four-day study period and the test period were summarized by treating the mice once daily before the experiment (the results are shown in FIGS. 4-6).
Test example 3 Effect of Dutasteride on inflammatory cytokines in plasma and hippocampus of lipopolysaccharide-induced model mice
The plasma and brain tissue of the mice are cracked by using a lysate and then subjected to biochemical tests, and the effect of dutasteride on the secretion of relevant factors of inflammation caused by lipopolysaccharide is observed by a Luminex multi-cytokine detection technology (the result is shown in figures 7-8).
Analysis of the results of the experimental examples was plotted using GraphPad Prism software.
Results of the experiment
Test example 1: function of dutasteride on learning and memory damage of lipopolysaccharide-induced acute inflammation model mouse
Compared with the control group, C57 mice in the second day of learning period after lipopolysaccharide injection have a significant increase in escape latency, and the positive drugs TAK-242 and dutasteride can significantly shorten the increase in escape latency of mice caused by lipopolysaccharide injection (see FIG. 3).
The results show that: dutasteride can remarkably improve learning and memory ability damage caused by an acute inflammation model caused by lipopolysaccharide injection.
Test example 2: effect of dutasteride on learning and memory damage of chronic inflammation model mice caused by lipopolysaccharide
Compared with a control group, the C57 mouse test period escape latency is obviously increased after lipopolysaccharide injection, and the ring-penetrating times and the target quadrant retention time are obviously shortened; the positive drugs TAK-242 and dutasteride can obviously shorten the escape latency of a mouse test period, and prolong the ring-through times and the target quadrant residence time of the mouse test period (see figures 4-6).
The results show that: dutasteride can remarkably improve learning and memory ability damage caused by a chronic inflammation model caused by lipopolysaccharide injection.
Test example 3: effect of Dutasteride on levels of inflammatory-related cytokines in plasma and hippocampus of lipopolysaccharide-induced inflammation model mice
Plasma and hippocampal levels of inflammatory-related cytokines were significantly increased in C57 mice after lipopolysaccharide injection compared to control; dutasteride can significantly inhibit the secretion of inflammatory-related cytokines in plasma and hippocampus (see fig. 7-8).
Although specific embodiments of the invention have been described in detail, those skilled in the art will appreciate. Various modifications and substitutions of those details may be made in light of the overall teachings of the disclosure, and such changes are intended to be within the scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.
Claims (5)
1. Use of dutasteride in preparing medicine for resisting inflammatory injury is provided.
2. The use of claim 1, wherein the medicament is a preparation prepared by adding pharmaceutical excipients with dutasteride as the only active ingredient.
3. The use according to claim 2, wherein the medicament is an injection or an oral formulation.
4. The use according to any one of claims 1 to 3, wherein the inflammatory injury comprises injury caused by any factor likely to cause inflammatory injury.
5. The use of any one of claim 4, wherein the inflammatory injury is an endotoxin lipopolysaccharide-induced injury.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090170889A1 (en) * | 2004-12-03 | 2009-07-02 | Proteosys Ag | Use of finasteride, dutasteride and related compounds for the prevention or treatment of neurologically-associated disorders |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090170889A1 (en) * | 2004-12-03 | 2009-07-02 | Proteosys Ag | Use of finasteride, dutasteride and related compounds for the prevention or treatment of neurologically-associated disorders |
Non-Patent Citations (2)
| Title |
|---|
| NADHIR LITIM 等.: "Effect of the 5α-reductase enzyme inhibitor dutasteride in the brain of intact and parkinsonian mice.", 《THE JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY》 * |
| SHINSUKE MIZOGUCHI 等: "EFFECTS OF DUTASTERIDE ON PROSTATIC INFLAMMATION MEDIATED BY ESTROGEN RECEPTOR beta IN A RAT MODEL OF NONBACTERIAL PROSTATITIS.", 《THE JOURNAL OF UROLOGY》 * |
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