Application of nervonic acid in preparing drugs for preventing and treating psoriasis

Abstract

The present invention discloses the application of nervonic acid in the preparation of a drug for preventing and treating psoriasis, which relates to the technical field of medicine. By using nervonic acid as an active ingredient in the drug for preventing and treating psoriasis, it shows good prevention and treatment effects in the psoriasis treatment model, can reduce the epidermal thickening at the psoriasis lesion site, reduce the infiltration of lymphocytes in the dermis layer at the psoriasis lesion site, reduce the parakeratosis at the psoriasis lesion site, and alleviate the erythema at the psoriasis lesion site, and can be used as a new drug for resisting the development of psoriasis.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technologies, and in particular, to an application of nervonic acid in the preparation of a drug for preventing and treating psoriasis. Background Art

[0002] Psoriasis is an immune-mediated chronic inflammatory systemic disease, characterized by keratinocyte hyperplasia, inflammatory cell infiltration, and dermal vascular hyperplasia. The incidence rate in China is about 0.5%, and there is still an increasing trend. The course of psoriasis is relatively long, with repeated attacks and protracted non-healing, bringing huge mental and psychological burdens and economic pressures to patients, and greatly affecting the quality of life of patients. In addition, some psoriasis patients may develop various complications, such as hyperlipidemia, cardiovascular diseases, diabetes, and cancer. Among them, cardiovascular and metabolic diseases are the most common comorbidities of psoriasis. Psoriasis patients usually use glucocorticoids or conventional immunosuppressants for treatment. These drugs can relieve symptoms temporarily, but can cause serious side effects, such as atherosclerosis and adrenal insufficiency. In addition, drugs such as secukinumab, although having good efficacy in the treatment of psoriasis, are expensive and not suitable for the long-term treatment of psoriasis.

[0003] In view of this, the present invention is specifically proposed. Summary of the Invention

[0004] The purpose of the present invention is to provide an application of nervonic acid in the preparation of a drug for preventing and treating psoriasis.

[0005] The present invention is implemented as follows:

[0006] In a first aspect, the present invention provides an application of nervonic acid in the preparation of a drug for preventing and treating psoriasis.

[0007] Optionally, the concentration of nervonic acid is 5% - 15%.

[0008] Optionally, the concentration of nervonic acid is 5% - 10%.

[0009] Optionally, preventing and treating psoriasis includes at least one of reducing the epidermal thickness of the psoriasis lesion, reducing lymphocyte infiltration in the dermis, and reducing epidermal cell parakeratosis.

[0010] Optionally, reducing the epidermal thickness of the psoriasis lesion is reducing the thickness of the stratum spinosum.

[0011] Optionally, the drug consists of nervonic acid and a pharmaceutically acceptable carrier.

[0012] Optionally, the drug is an external medicine.

[0013] Optionally, the dosage form of the drug includes any one of lotion, ointment, patch, film-forming agent, gel, microneedle, aerosol, or spray.

[0014] Optionally, the drug includes vaseline and nervonic acid.

[0015] Optionally, the source of nervonic acid includes Acer truncatum Bunge seed oil or other animal and plant raw materials containing nervonic acid.

[0016] Optionally, psoriasis includes any one of pustular psoriasis, psoriatic arthritis, vulgaris psoriasis or erythrodermic psoriasis.

[0017] The present invention has the following beneficial effects:

[0018] The present invention provides an application of nervonic acid in the preparation of a drug for preventing and treating psoriasis. By using nervonic acid as an active ingredient in the drug for preventing and treating psoriasis, it shows good prevention and treatment effects in a psoriasis treatment model, can reduce epidermal thickening at the psoriasis affected area, reduce lymphocyte infiltration in the dermis layer of the psoriasis affected area, reduce parakeratosis at the psoriasis affected area, and reduce erythema at the psoriasis affected area, and can be used as a new drug to resist the development of psoriasis. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the drawings required to be used in the embodiments. It should be understood that the following drawings only show some embodiments of the present invention, and therefore should not be regarded as limiting the scope. For those of ordinary skill in the art, other related drawings can also be obtained based on these drawings without creative efforts.

[0020] Figure 1 It is a diagram of the back skin state of mice in different groups on the sixth day of modeling provided in Embodiment 1 of the present invention;

[0021] Figure 2 It is a PASI erythema score diagram during the modeling process provided in Embodiment 1 of the present invention;

[0022] Figure 3 It is a PASI scale score diagram during the modeling process provided in Embodiment 1 of the present invention;

[0023] Figure 4 It is a PASI dermal cell infiltration score diagram during the modeling process provided in Embodiment 1 of the present invention;

[0024] Figure 5 It is a PASI total score diagram during the modeling process provided in Embodiment 1 of the present invention;

[0025] Figure 6 It is a diagram of the body weight change of mice during the modeling process provided in Embodiment 1 of the present invention;

[0026] Figure 7The optical microscopic image of the mouse skin tissue provided in Example 1 of the present invention after HE staining;

[0027] Figure 8 The graph showing the effects of different cell culture methods on the expression of chemokines and inflammatory factors provided in Example 2 of the present invention. Detailed implementation manners

[0028] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. For those not specified in the embodiments, the conventional conditions or the conditions recommended by the manufacturer are followed. The reagents or instruments for which the manufacturers are not specified are all conventional products that can be obtained through commercial purchase.

[0029] The features and performance of the present invention will be further described in detail below in conjunction with the embodiments.

[0030] In a first aspect, the present invention provides an application of nervonic acid in the preparation of a drug for preventing and treating psoriasis.

[0031] Nervonic acid (NA) is a special unsaturated fatty acid, which is rich in the new food resource Acer truncatum Bunge seed oil and plays an important role in human health, especially in brain development. The lack of nervonic acid will cause brain diseases such as sequelae of stroke, Alzheimer's disease, cerebral palsy, brain atrophy, memory loss, insomnia and forgetfulness. Nervonic acid has high medicinal value and unique neuroprotective effects, and can particularly promote the repair of damaged brains and improve memory. In recent years, it has attracted much attention as an important health product.

[0032] However, the inventors' research shows that nervonic acid has unexpected prevention and treatment effects in the field of psoriasis prevention and treatment. Nervonic acid mainly maintains the composition, structure and function of biological membranes through sphingomyelin and sphingolipids, thereby improving cell viability and enhancing human body functions, and thus exerting anti-inflammatory activity. Therefore, the inventors use nervonic acid as an active ingredient in the drug for preventing and treating psoriasis, thereby reducing the epidermal thickening at the psoriasis lesion, reducing the infiltration of lymphocytes in the dermis layer of the psoriasis lesion, reducing the parakeratosis of cells at the psoriasis lesion, and reducing the erythema at the psoriasis lesion. Therefore, nervonic acid can be used as a new drug to resist the development of psoriasis.

[0033] In an optional implementation manner, the concentration of nervonic acid is 5% - 15%, for example, it can be any value among 5%, 7%, 9%, 11%, 13% or 15%, or the range value between any two values.

[0034] Preferably, the concentration of nervonic acid is 5% - 10%, for example, it can be any value among 5%, 6%, 7%, 8%, 9% or 10%, or the range value between any two values.

[0035] As an active ingredient for preventing and treating psoriasis, the addition of nervonic acid can effectively relieve the specific symptoms of psoriasis, such as epidermal thickening, incomplete keratinization of epidermal cells, and lymphocyte infiltration in the dermis layer. However, controlling the concentration of nervonic acid within the above range is beneficial to improving the prevention and treatment effect of psoriasis.

[0036] In an alternative embodiment, preventing and treating psoriasis includes at least one of reducing the epidermal thickness of the psoriasis affected area, reducing lymphocyte infiltration in the dermis layer, and reducing incomplete keratinization of epidermal cells.

[0037] In an alternative embodiment, reducing the epidermal thickness of the psoriasis affected area is reducing the thickness of the stratum spinosum. Psoriasis stimulates the continuous proliferation of basal cells, resulting in an increase in spinous cells in the stratum spinosum and thickening of the stratum spinosum. More spinous cells will lead to an increase in the frequency of keratinocyte renewal and shedding, resulting in an increase in scaly shedding or semi-shed keratin. By using nervonic acid to prevent and treat psoriasis, the thickness of the stratum spinosum can be reduced, thereby alleviating the symptoms of psoriasis.

[0038] In an alternative embodiment, the drug consists of nervonic acid and a pharmaceutically acceptable carrier.

[0039] In an alternative embodiment, the drug is a topical drug.

[0040] In an alternative embodiment, the dosage form of the drug includes any one of lotion, ointment, patch, film-forming agent, gel, microneedle, aerosol or spray.

[0041] In an alternative embodiment, the drug includes vaseline and nervonic acid. As a carrier of nervonic acid, vaseline not only facilitates the storage and transportation of the drug, but also is convenient for coating and use.

[0042] In order to ensure uniform dispersion of nervonic acid, when preparing nervonic acid drugs, the addition method of adding in small amounts and multiple times should be followed and added to vaseline. After the nervonic acid added each time is uniformly dispersed, a certain amount of nervonic acid is added for dispersion.

[0043] In an alternative embodiment, the source of nervonic acid includes Acer truncatum Bunge seed oil or other animal and plant raw materials containing nervonic acid.

[0044] In an alternative embodiment, psoriasis includes any one of pustular psoriasis, psoriatic arthritis, vulgaris psoriasis or erythrodermic psoriasis.

[0045] Example 1

[0046] This example provides an application of nervonic acid in the preparation of drugs for preventing and treating psoriasis, specifically as follows:

[0047] S01. Preparation of drugs for preventing and treating psoriasis

[0048] Weigh 50 mg of nervonic acid powder and dissolve it in 1 g of petrolatum. The nervonic acid powder is added to the petrolatum in small amounts and multiple times, and sufficient stirring is maintained during the addition process until there are no powdery particles in the appearance of the ointment and the color is uniform, thus preparing an ointment with a concentration of 5% and an active ingredient of nervonic acid (hereinafter simply referred to as 5% NA ointment).

[0049] Weigh 100 mg of nervonic acid powder and dissolve it in 1 g of petrolatum. The nervonic acid powder is added to the petrolatum in small amounts and multiple times, and sufficient stirring is maintained during the addition process until there are no powdery particles in the appearance of the ointment and the color is uniform, thus preparing an ointment with a concentration of 10% and an active ingredient of nervonic acid (hereinafter simply referred to as 10% NA ointment).

[0050] Among them, the nervonic acid powder is purchased from MedChemExpress LLC, USA, and the petrolatum is purchased from Haisihai Nuo Group Co., Ltd.

[0051] S02. Induction of psoriasis model and prevention and treatment of psoriasis

[0052] The experimental mice are female Balb / c mice (SPF grade, 8 weeks old, weighing about 20 g), purchased from Beijing Speywood Co., Ltd., and the animal research has been approved by the Ethics Committee of Xinxiang Medical University.

[0053] Balb / c mice with basically the same growth status are raised under the conditions of a temperature of 24±2°C, a humidity of 40-50%, a light / dark cycle of 12 h, and no pathogenic bacteria, and are given sufficient food and water. After one week of breeding, the Balb / c mice are randomly divided into four groups (control group, petrolatum group, 5% NA group, and 10% NA group), with five mice in each group. One day before modeling, the back of the mice is depilated, and the depilated area is 2×2.5 cm.

[0054] From the day of modeling, at 9 am every day, 62.5 mg of imiquimod (IMQ) cream is applied to the depilated area on the back of the four groups of Balb / c mice. At 1 pm every day, 62.5 mg of petrolatum is applied to the depilated area on the back of the petrolatum group, 62.5 mg of 5% NA ointment is applied to the depilated area on the back of the 5% NA group, and 62.5 mg of 10% NA ointment is applied to the depilated area on the back of the 10% NA group. The control group is not treated with anything, and it is continuously applied for six days.

[0055] Among them, imiquimod (IMQ) is purchased from Sichuan Mingxin Pharmaceutical Co., Ltd.

[0056] S03. Experimental results

[0057] S031. Photographing the back skin phenotype of Balb / c mice: From the day of modeling, at the same time point every day before applying imiquimod, photograph the back skin of each group of Balb / c mice. The back skin state of Balb / c mice photographed before applying imiquimod on the day of modeling is the blank group. Compare the back skin state of Balb / c mice on the sixth day of modeling with the blank group to obtain the results as shown in Figure 1 shown below.

[0058] As can be seen from Figure 1 , the back skin of the four groups of Balb / c mice showed varying degrees of psoriasis symptoms compared with the blank group, such as increased epidermal dandruff, rough and cracked skin, etc., indicating that the psoriasis symptoms induced by imiquimod have occurred.

[0059] Among them, since no prevention and treatment measures were applied in the control group, the back skin damage was severe and the scales were the most. The vaseline group used vaseline to moisturize the skin, but it had no therapeutic effect on psoriasis. Therefore, the skin damage in the vaseline group was not alleviated, and only had a partial moisturizing effect. The 5% NA group showed a state of reduced psoriasis symptoms, with less scales, reduced erythema and reduced local infiltration compared with the control group. The 10% NA group showed a significant reduction in psoriasis symptoms compared with the control group, with significantly reduced skin scales, significantly reduced erythema and significantly reduced local infiltration in this group of mice.

[0060] Statistically analyze the changes in the back skin phenotype of Balb / c mice photographed during the six-day modeling process and perform PASI scoring to obtain the results as shown in Figures 2 to 5 shown below.

[0061] Among them, the PASI score includes erythema scoring, scale scoring and skin thickness scoring for the skin lesions of Balb / c mice, and calculates the sum of the above scores. The scoring criteria are as follows:

[0062] Erythema scoring: 0 = none; 1 = mild; 2 = obvious; 3 = severe; 4 = very severe.

[0063] Scale scoring: 0 = none; 1 = mild; 2 = obvious; 3 = severe; 4 = very severe.

[0064] Skin thickness: 0 = none; 1 = mild; 2 = obvious; 3 = severe; 4 = very severe.

[0065] As can be seen from Figures 2 to 5 , both the 5% NA group and the 10% NA group showed good effects in reducing psoriasis symptoms, and had varying degrees of improvement compared with the control group in terms of erythema scoring, scale scoring and skin thickness scoring.

[0066] S032. Balb / c mouse body weight measurement: Starting from the day of modeling, the body weight of Balb / c mice was measured and recorded at the same time point every day before applying imiquimod. After the experiment, the body weight changes of all mice were statistically analyzed, and the results were obtained as shown in Figure 3 the following.

[0067] As can be seen from Figure 6 , the degree of body weight reduction in the 5% NA group and the 10% NA group was lower than that in the control group. It is understandable that when psoriasis symptoms appear, the mice may be affected physically and psychologically to varying degrees due to the severity of the psoriasis symptoms, which may indirectly affect appetite or activity enthusiasm, etc. In this invention, nervonic acid was used to treat imiquimod-induced mice. From the effects shown in Figures 1 to 5 , the psoriasis symptoms in the 5% NA group and the 10% NA group had a significant effect of reducing the disease, so the impact on the body weight of the mice was smaller than that in the control group.

[0068] S033. After the modeling was completed, the mice were sacrificed, and about 0.5×0.5 cm of mouse skin tissue was cut and fixed in 4% paraformaldehyde solution; tissue sections (longitudinal section 5 μm) were prepared by paraffin embedding; after dewaxing, H&E staining was performed (dewaxing, gradient rehydration, hematoxylin staining of nuclei, hydrochloric acid alcohol decolorization, eosin staining of cytoplasm); after sealing with neutral resin, the pathological histological changes were observed and photographed under an optical microscope, and the results were obtained as shown in Figure 7 the following.

[0069] As can be seen from Figure 7 , psoriasis-like phenotypes such as epidermal thickening, epidermal cell parakeratosis, stratum spinosum thickening, and dermal lymphocyte infiltration appeared in the skin of the four groups of mice. However, the stratum spinosum thickness in the 5% NA group and the 10% NA group decreased compared with the control group, the parakeratotic epidermal cells decreased, and the dermal lymphocyte infiltration decreased, indicating that nervonic acid has a good effect on preventing and treating psoriasis and can be used as an active ingredient in drugs for preventing and treating psoriasis.

[0070] Example 2

[0071] This example provides an application of nervonic acid in the preparation of drugs for preventing and treating psoriasis, specifically as follows:

[0072] Blank group (control): HaCat cells (human immortalized keratinocytes) were seeded in a six-well plate and cultured in complete medium (89% DMEM medium + 10% FBS + 1% double antibody) for 5 hours. After the culture was completed, RNA was extracted, and the expression of chemokines and inflammatory factors including CXCL1, CCL20, and S100A9 was detected, and the results were obtained as shown in Figure 8 the following.

[0073] IL-17 group: HACAT cells were seeded in six-well plates and placed in complete medium containing IL-17A at a concentration of 50 μg / ml for 3 hours. RNA was extracted to detect the expression of chemokines and inflammatory factors including CXCL1, CCL20, and S100A9, and the results were obtained as shown in Figure 8 the following.

[0074] NA + IL-17 group: HACAT cells were seeded in six-well plates and pretreated in a medium containing 100 μmol / ml nervonic acid for 2 hours. Then, the medium was discarded and replaced with complete medium containing IL-17A at a concentration of 50 μg / ml for 3 hours. RNA was extracted to detect the expression of chemokines and inflammatory factors including CXCL1, CCL20, and S100A9, and the results were obtained as shown in Figure 8 the following.

[0075] As can be seen from Figure 8 the results, NA + IL-17 showed a significant inhibitory effect on the expression of CXCL1, CCL20, and S100A9, indicating that nervonic acid has obvious anti-inflammatory ability and has good application value in the prevention and treatment of psoriasis.

[0076] Comparative Example 1

[0077] Based on the application in Example 1, a 20% NA ointment was prepared. The preparation method was the same as that in Example 1, except that the mass of nervonic acid was 200 mg. The 20% NA ointment was tested according to the method in Example 1 to verify the application effect of nervonic acid in the preparation of drugs for the prevention and treatment of psoriasis, and the results were obtained as shown in Figures 1 - 7 the following.

[0078] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention can have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A use of neuraminic acid in the preparation of a drug for preventing and treating psoriasis, characterized in that: The concentration of the neuraminic acid is 5% to 10%, and the drug is for external use.

2. The use according to claim 1, characterized in that: The method for preventing and treating psoriasis comprises at least one of reducing the thickness of the epidermis in the psoriasis affected area, reducing the thickness of the stratum spinosum, reducing the lymphocyte infiltration in the dermis, and reducing the parakeratosis of epidermal cells.

3. The use according to claim 2, characterized in that: The reducing the thickness of the epidermis in the psoriasis affected area is reducing the thickness of the stratum spinosum.

4. The use according to claim 1, characterized in that: The drug consists of the neuraminic acid and a pharmaceutically acceptable carrier.

5. The use according to claim 1, characterized in that: The dosage form of the drug includes any one of lotion, ointment, patch, film coating, gel, microneedle, aerosol or spray.

6. The use according to claim 1, characterized in that: The drug includes petrolatum and the nervonic acid.

7. The use according to claim 1, characterized in that: The psoriasis includes any one of pustular psoriasis, articular psoriasis, psoriasis vulgaris or erythrodermic psoriasis.

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