Use of isoliensoline in the preparation of a medicament for treating atopic dermatitis

Abstract

The application discloses application of isonor-laudanosine in preparation of a medicine for preventing or treating atopic dermatitis. Atopic dermatitis is a chronic allergic disease, a mouse ear is coated with MC903 to construct an atopic dermatitis model, and isonor-laudanosine is coated on the surface of the skin for treatment. The treatment effect is not only superior to a positive medicine dexamethasone cream on the market, and no side effect of weight loss caused by dexamethasone is generated; in addition, the effect of isonor-laudanosine is also superior to that of two other alkaloids derived from laudanosine, including methyllaudanosine and laudanosine.

Description

Technical Field

[0001] This invention relates to the use of a compound, specifically to the use of isolidinine in the preparation of drugs for the prevention or treatment of atopic dermatitis. Background Technology

[0002] Atopic dermatitis (AD) is a chronic allergic disease characterized by prominent symptoms of skin lesions and chronic itching. Cell [2021 Jan 21;184(2):422-440.e17.]. Atopic dermatitis has a complex pathogenesis, heterogeneous clinical phenotypes, and a long course with frequent relapses, thus causing serious negative impacts on patients' health and quality of life. Currently, no studies have confirmed that lotus seed alkaloids and other active ingredients in lotus seeds have an inhibitory effect on atopic dermatitis, which is a chronic allergic disease. Summary of the Invention

[0003] Purpose of the invention: The purpose of this invention is to provide the application of isolidinine in the preparation of drugs for the prevention or treatment of atopic dermatitis.

[0004] Technical solution: Application of lotus seed heart alkaloids in the preparation of drugs for the prevention or treatment of atopic dermatitis.

[0005] In the aforementioned applications, the lotus seed heart alkaloids include isoliensine, methyloliensine, and lotusine.

[0006] The structural formula of the described application, namely isoliensine, is shown below:

[0007]

[0008] The application described herein, the prevention or treatment of atopic dermatitis, includes the reduction of one or more of the following: skin surface erythema, papules / edema, exudation / crusting, epidermal shedding, skin thickening, and dry skin.

[0009] The aforementioned application involves the addition of pharmaceutically acceptable excipients to lotus seed heart alkaloids to prepare a drug.

[0010] In the aforementioned applications, the pharmaceutically acceptable excipients include diluents, binders, disintegrants, glidants, lubricants, flavoring agents, inclusion materials, and adsorbents.

[0011] The application described herein refers to a drug formulation for topical skin use.

[0012] The aforementioned applications include topical skin preparations such as sprays, creams, patches, and gels.

[0013] The aforementioned application refers to atopic dermatitis, a chronic allergic disease.

[0014] In the aforementioned application, the lotus seed heart alkaloids are derived from lotus seed hearts or other plants or chemically synthesized.

[0015] This study established an atopic dermatitis model in mice by applying the industry-recognized MC903 to the ear skin and used it to verify the therapeutic effects of isolidinine, limonine, and methyllimonine.

[0016] This study established an atopic dermatitis model in mice by applying MC903 to the ear and used lotus seed alkaloids, methyl lotus seed alkaloids, and isolivine seed alkaloids for topical treatment to explore the potential applications of drugs for treating atopic dermatitis.

[0017] Beneficial effects: Isodonine is not only more effective than dexamethasone cream, a positive drug on the market, in treating atopic dermatitis, but also does not produce the side effect of weight loss caused by dexamethasone. In addition, isodonine is also more effective than two other alkaloids derived from lotus seeds, including methylnedonine and nedonine. Attached Figure Description

[0018] Figure 1 The appearance of the ear margin skin of mice in each group in Example 1;

[0019] Figure 2 This refers to the level of epidermal damage to the ear margin skin of mice in each group in Example 1;

[0020] Figure 3 These are biomarkers for atopic dermatitis of the ear margins in each group of mice in Example 1. Il4 mRNA expression level;

[0021] Figure 4 These are biomarkers for atopic dermatitis of the ear margins in each group of mice in Example 1. Tslp mRNA expression level;

[0022] Figure 5 This is a staining image of pathological tissue. Detailed Implementation

[0023] The structural formula of isoliensinine (IsoL) described in this invention is shown below:

[0024]

[0025] Example 1

[0026] 1. Experimental Materials

[0027] 1.1 Drugs: Isoliensinine (IsoL), neferine (Nef), and liensinine (Lien) were provided by Nanjing University of Chinese Medicine. The powders of the three compounds were suspended in 1,3-propanediol (purchased from Bid Pharmaceuticals, catalog number #BD54300) and sonicated to obtain a clear, transparent solution of 80 mg / mL. MC903 (purchased from MedChemExpress, catalog number #HY-10001) was prepared as a stock solution with DMSO and diluted to the appropriate concentration with 95% ethanol before use. Compound dexamethasone acetate cream was purchased from Anhui Xinhecheng Wannan Pharmaceutical Co., Ltd.

[0028] 1.2 Animals: ICR Mice (male, 6-8 weeks old, 21-23 g) were purchased from Qinglongshan Animal Breeding Farm, Jiangning District, Nanjing City. Husbandry conditions: Laboratory animals were fed pelleted feed and housed in a clean-grade laboratory animal facility with free access to food and water. Animal license number: SYXK (Su) 2018-0049.

[0029] 2. Experimental Methods

[0030] 2.1 Construction of an atopic dermatitis model: ICR The ears of mice were smeared with 10 μL of ethanol solution containing 5 nmol MC903 daily for 10 days.

[0031] 2.2 Grouping and administration: Mice were randomly divided into the following 6 groups (n=4): blank group, model group, isolidinine group (0.8 mg / ear / day), methylolidinine group (0.8 mg / ear / day), olidinine group (0.8 mg / ear / day) and dexamethasone group (appropriate amount, cream evenly covering the ear skin). The drugs were administered once daily starting from the day of modeling.

[0032] 2.3 Lesion Assessment: ① After the modeling and drug administration cycle, the morphology of the mouse ear skin was photographed and recorded; ② Level of epidermal damage to the ear margin: The area and total area of ​​damaged skin on the mouse ear were measured using Photoshop software, and the percentage of damaged skin was calculated (%); ③ Skin severity scoring: Based on the skin lesion types shown in the table, the severity of the skin lesions was judged and scored (none: 0; mild: 1; moderate: 2; severe: 3). ④ The expression level of classical factors of atopic dermatitis was detected by RT-qPCR, including... Il4 and Tslp mRNA expression levels. ⑤ HE staining was used to assess lesions in the marginal ear tissue.

[0033] 2.4 Statistical Analysis: Results are expressed as mean ± standard deviation. One-way ANOVA was performed using Graphpad 8.0 for significance analysis. ####<0.0001, ****<0.0001.

[0034] like Figure 1 As shown, after the modeling and drug administration cycle, compared with the control group mice, the model mice exhibited significant pathological features on the skin surface, including erythema, papules / edema, exudation / scab formation, epidermal shedding, skin thickening, and dryness. Treatment with isolidin significantly improved the symptoms of atopic dermatitis; methylolidin, isolidinine, and dexamethasone cream slightly improved the symptoms of atopic dermatitis, but their effects were not as good as those of isolidinine. The scores are shown in Table 1.

[0035] Table 1. Severity of skin lesions.

[0036]

[0037]

[0038] Note: None: 0; Mild: 1; Moderate: 2; Severe: 3

[0039] By analyzing the level of epidermal damage in the ear margin skin of mice ( Figure 2 It can be seen that isolidin significantly reduced the level of skin damage in the atopic dermatitis model, and its effect was superior to that of methylolidin, olidin, and dexamethasone cream.

[0040] Furthermore, markers of atopic dermatitis in the ear margins of mice were detected. Il4 mRNA and Tslp mRNA expression level ( Figure 3-4 Isolidinine and methylolidinine can reduce Il4 mRNA and Tslp mRNA expression levels; while lotus seed alkaloids can only reduce mRNA expression levels; Tslp mRNA expression levels; dexamethasone cream can only reduce mRNA expression levels; Il4 mRNA expression levels. This indicates that isopyrendin and methylopyrendin are superior to isopyrendin and dexamethasone cream in inhibiting inflammatory factors.

[0041] Furthermore, the pathological ameliorative effects of isolidinyl, methylolidinyl, olidinyl groups, and dexamethasone on the marginal ear tissue of atopic dermatitis were analyzed through histopathological staining. The results are as follows: Figure 5As shown, in the blank group, the epidermis, dermis, and subcutaneous tissue structures were clearly visible, the epidermis was intact, and no obvious lesions were observed. In the model group, the epidermis, dermis, and subcutaneous tissue structures were distinguishable, the epidermis was thickened, and the stratum corneum of the epidermis was significantly increased (blue arrow); a large number of inflammatory cells were infiltrated in the dermis, which was severe, and the inflammatory cells included neutrophils, lymphocytes, and macrophages (yellow arrows), and vasodilation was observed. In the isolidinine group, the skin structure was distinguishable, the stratum corneum of the epidermis was significantly increased (blue arrow), and no other obvious lesions were observed. In the methylolidinine group, the skin structure was distinguishable, the stratum corneum of the epidermis was significantly increased (blue arrow); a small amount of inflammatory cell infiltration was observed in the dermis (yellow arrow), which was mild; mild edema of the subcutaneous tissue (green arrow); and vascular congestion and edema. In the limonene group, the skin structure was distinguishable, the stratum corneum of the epidermis was significantly increased (blue arrow); inflammatory cell infiltration was observed in the dermis (yellow arrow), which was mild; and mild edema of the subcutaneous tissue (green arrow). In the dexamethasone group, the skin structure was discernible, with a significant increase in the stratum corneum of the epidermis (blue arrow); mild inflammatory cell infiltration was observed in the dermis (yellow arrow); and mild subcutaneous edema was present (green arrow). This indicates that isopyrendin has a good effect on improving inflammation in the ear margin tissue of mice with atopic dermatitis, and is superior to methylopyrendin, isopyrendin, and dexamethasone.

[0042] Finally, by measuring the mouse weight, the results showed that, with the same initial average weight after initial separation, the final average weights of each group were as follows: control group (23.4 g), model group (18.7 g), isolidinine group (22.9 g), methylolidinine group (21.8 g), isolidinine group (23.1 g), and dexamethasone group (15.4 g). Mice in the dexamethasone group exhibited significant emaciation and weakness. These results indicate that isolidinine, while treating atopic dermatitis, does not have the same significant impact on mouse weight as glucocorticoids, and thus provides good protection for the mice's well-being.

[0043] In conclusion, isolidinine is not only more effective than dexamethasone cream, a commercially available positive drug, in treating atopic dermatitis, but also does not produce the weight loss side effect caused by dexamethasone. Furthermore, isolidinine is more effective than two other alkaloids derived from lotus seeds, including methylolidinine and olidinine, and is an effective compound that can be used to prepare for the treatment and prevention of atopic dermatitis.

Claims

1. The use of isolidinine in the preparation of drugs for the prevention or treatment of atopic dermatitis, wherein the structural formula of isolidinine is shown below: 。 2. The application according to claim 1, characterized in that, The prevention or treatment of atopic dermatitis is characterized by the reduction of one or more of the following: erythema, papules / edema, exudation / crusting, epidermal shedding, thickening of the skin, and dryness of the skin surface.

3. The application according to claim 1, characterized in that, Isohesinine is formulated into a drug by adding pharmaceutically acceptable excipients.

4. The application according to claim 3, characterized in that, The pharmaceutically acceptable excipients are selected from diluents, binders, flow aids, lubricants, flavoring agents, encapsulation materials, and adsorbent materials.

5. The application according to claim 1, characterized in that, The drug is a topical preparation for skin use.

6. The application according to claim 5, characterized in that, The topical skin preparations are selected from sprays, creams, patches, and gels.

7. The application according to claim 1, characterized in that, The aforementioned atopic dermatitis is a chronic allergic disease.

8. The application according to claim 1, characterized in that, The isolithoalkaloid is derived from lotus seed hearts or other plants or through chemical synthesis.

Images