CN110859838A

CN110859838A - Application of clopidogrel in preparation of medicine for preventing or treating non-alcoholic fatty liver disease

Info

Publication number: CN110859838A
Application number: CN201911316136.2A
Authority: CN
Inventors: 谢红光; 李逸飞; 吉金子; 邰婷; 米琼宇; 蒋立平
Original assignee: Nanjing First Hospital
Current assignee: Nanjing First Hospital
Priority date: 2019-12-19
Filing date: 2019-12-19
Publication date: 2020-03-06

Abstract

The invention discloses application of clopidogrel in preparing a medicament for preventing or treating non-alcoholic fatty liver disease. Application of clopidogrel or medicinal salt thereof in preparing a medicament for preventing non-alcoholic fatty liver disease. Prophylactic administration of clopidogrel significantly slowed the rate of fat deposition in hepatocytes in mice fed high-fat diet. Application of clopidogrel or medicinal salt thereof in preparing a medicament for treating simple fatty liver, non-alcoholic fatty liver disease or early non-alcoholic fatty liver disease. Clopidogrel treatment administration can significantly reverse the degree of fat deposition in hepatocytes fed high-fat diet mice.

Description

Application of clopidogrel in preparation of medicine for preventing or treating non-alcoholic fatty liver disease

Technical Field

The invention belongs to the field of clinical pharmacotherapeutics, and relates to application of clopidogrel in preparing a medicine for preventing or treating non-alcoholic fatty liver.

Background

Non-alcoholic fatty liver disease (NAFLD) refers to clinical syndrome with excessive deposition of lipid (mainly triglyceride) in liver cells as main pathological features due to the exclusion of drinking and other clear reasons, and includes a series of liver cell directly related pathological changes, such as early simple fatty liver, medium-term steatohepatitis (NASH) and hepatic fibrosis, and advanced cirrhosis or hepatocellular carcinoma, etc., which are in essence a common liver pathological progressive change.

Non-alcoholic fatty liver disease (NAFL or simple fatty liver) is mainly due to over-nutrition and its subsequent complications (such as obesity, type ii diabetes, metabolic syndrome, etc.), not an independent disease. Due to the general change of people's lifestyle, non-alcoholic fatty liver has rapidly developed as a major domestic public health problem. It is estimated that about 30% of the population in China currently suffer from non-alcoholic fatty liver disease. If a patient cannot be effectively treated in an early stage (mainly manifested by simple hepatocyte steatosis or lipid deposition), the direct consequence of the progression of the disease course may be fatty hepatitis, hepatic fibrosis, liver cirrhosis or hepatocellular carcinoma, etc., until the patient is life-threatening. Therefore, effective intervention in the early stage of the non-alcoholic fatty liver disease (namely in the stage of simple fatty liver) has great clinical significance.

Non-alcoholic fatty liver disease is a serious underestimated health threat compared to the heat of concern for stroke, coronary heart disease, tumors, diabetes, and the like. In view of the fact that non-alcoholic fatty liver disease has become the most global chronic liver disease (the prevalence rate is up to 25%), the international biomedical science is accelerating the research on the prevention and treatment strategy of non-alcoholic fatty liver disease. The pathogenic mechanism of non-alcoholic fatty liver disease is currently unknown. To date, only pioglitazone and vitamin E have been recommended by relevant guidelines in the european and american countries as a possibility to reduce lipid excess deposition in hepatocytes and delay their disease progression, but long-term therapeutic efficacy remains to be confirmed.

The main clinical indications of clopidogrel include prevention of reoccurrence of cardiovascular and cerebrovascular ischemia, prevention of thrombosis in coronary stents, and the like. However, related reports that clopidogrel can prevent or treat non-alcoholic fatty liver disease are not seen at home and abroad. Therefore, the clopidogrel for preventing or treating the non-alcoholic fatty liver disease is a new indication of the medicine.

Disclosure of Invention

The invention mainly aims to provide application of clopidogrel in preparing a medicine for preventing or treating non-alcoholic fatty liver disease aiming at the relative lack of the medicine for effectively preventing and treating the non-alcoholic fatty liver disease clinically.

Application of clopidogrel or medicinal salt thereof in preparing a medicament for preventing non-alcoholic fatty liver disease.

Preferably, the clopidogrel or the medicinal salt thereof is applied to the preparation of the medicament for preventing fat deposition in the liver cells.

Prophylactic administration of clopidogrel significantly slowed the rate of fat deposition in hepatocytes in mice fed high-fat diet.

Application of clopidogrel or medicinal salt thereof in preparing a medicament for treating simple fatty liver, non-alcoholic fatty liver disease or early non-alcoholic fatty liver disease.

Preferably, the clopidogrel or the medicinal salt thereof is applied to the preparation of the medicament for treating fat deposition in the liver cells.

Clopidogrel treatment administration can significantly reverse the degree of fat deposition in hepatocytes fed hyperlipidemic chow mice.

Advantageous effects

Compared with healthy subjects, the platelet aggregation inhibiting effect of most patients suffering from non-alcoholic fatty liver disease on clopidogrel is remarkably reduced; the Mean Platelet Volume (MPV) of peripheral blood and the aggregation of activated platelets in the liver of patients with steatohepatitis are both significantly increased. These evidences indirectly suggest that there is some correlation between the enhanced platelet activity and the development and progression of nonalcoholic fatty liver disease. Therefore, antiplatelet drugs can theoretically exert a beneficial effect of preventing or treating fatty liver by inhibiting platelet function (activation, aggregation). The invention discloses that clopidogrel can effectively slow down or reverse the speed or degree of fat deposition in liver cells of mice fed with high-fat foods. The result shows that the clopidogrel has potential clinical application value for preventing and treating the non-alcoholic fatty liver.

The 'prevention' effect of clopidogrel on non-alcoholic fatty liver refers to that clopidogrel can remarkably slow down the formation speed of fat deposition in liver cells of mice fed with high-fat food or delay the generation process of fatty liver; the therapeutic effect of clopidogrel on non-alcoholic fatty liver disease means that after fat deposition is formed in liver cells of mice fed with high-fat food, clopidogrel can remarkably reverse or reduce the accumulation degree of fat deposition in liver cells or delay the development process of fatty liver. The gold standard for diagnosing fatty liver is to quantify the presence or absence or degree of fat deposition in liver cells by the size of the oil red O stained area of liver tissue.

The invention discloses that clopidogrel can remarkably slow down the fatty degeneration speed of liver cells of a high-fat feed-fed mouse (see figure 1) or remarkably reverse the degree of liver cell fat accumulation of a non-alcoholic fatty liver disease mouse model (see figure 2). Based on the new findings, the invention discovers a potential clinical application value of effectively preventing or treating the non-alcoholic fatty liver by using the clopidogrel.

Drawings

Fig. 1 clopidogrel can significantly slow down the formation rate of steatosis of liver cells of mice fed with high-fat feed (preventive effect). Male C57 mice were randomly divided into 3 groups. Control group a: feeding with common feed for 4 weeks; model group B: feeding with high fat feed for 4 weeks; c preventive administration group: high-fat diet and clopidogrel (2.5mg/kg) were given at the same time for 4 weeks. Mouse liver sections were stained with oil red O after 4 weeks and the fat area size of each group of hepatocytes was compared (data expressed as mean ± SD: n ═ 3;^###P<0.001vs. control;^**P<0.01vs. high fat group).

Fig. 2. clopidogrel can significantly reverse the degree of accumulation of steatosis in hepatocytes of high-fat diet-fed mice (therapeutic effect). After 2 weeks of non-alcoholic fatty liver mice treated with different doses of clopidogrel, liver sections of 5 groups of mice were stained with oil red O, and the difference in fat area within hepatocytes was compared. A control group; b, model group; low dose group C (clopidogrel 2.5 mg/kg); d middle dose group (clopidogrel 5 mg/kg); e high dose group (clopidogrel 10 mg/kg). Wherein, group A and group B mice are given solvent control alone(i.e., clopidogrel 0 mg/kg). Panel F shows statistical analysis of fat area in hepatocytes (data expressed as mean ± SD: n ═ 6;^###P<0.001vs. control;^***P<0.001vs. high fat group).

Detailed Description

Example 1

1. Study of clopidogrel preventive medication: male C57 mice were randomly divided into 3 groups (control, model + clopidogrel group), with 3 mice per group. The control group was given normal feed; high fat diet (60% fat) was given to the model group, the model group + clopidogrel group. Administering clopidogrel group, and performing intragastric administration of 2.5 mg/kg/day of clopidogrel; the control group and model group were each simultaneously administered solvent (control) gavage for 4 weeks. The mice were then sacrificed and their liver tissues were stained with oil red O and compared for differences between groups in the size of the area of lipid droplets in hepatocytes, the results are shown in fig. 1. As can be seen from fig. 1, clopidogrel significantly slowed the rate of formation or slowed the progression of fat deposits in hepatocytes of mice fed high-fat diet. Therefore, the clopidogrel or the medicinal salt thereof can be used for preparing the medicine for preventing the non-alcoholic fatty liver disease.

2. Study of clopidogrel therapeutic medication: male C57 mice were randomly divided into 5 groups (control, model, low, medium, high) of 6 mice each. The control group was given a normal diet, and the model group, the low dose group, the medium dose group, and the high dose group were given a high fat diet (60% fat), respectively. After feeding for 4 weeks (simple fatty liver formation), mice were initially gavaged with either low, medium or high doses of clopidogrel (2.5, 5 or 10 mg/kg/day, respectively), while control and model mice were simultaneously gavaged with solvent (control), both treated for 2 weeks, and then sacrificed, their liver tissues were taken for oil red O staining, and the differences between groups in liver lipid droplet area size were compared, and the results are shown in fig. 2. As can be seen from fig. 2, clopidogrel can significantly reverse the degree of fat accumulation of hepatocytes of a mouse model of non-alcoholic fatty liver disease. Therefore, the clopidogrel or the medicinal salt thereof can be used for preparing the medicine for treating simple fatty liver, non-alcoholic fatty liver disease or early non-alcoholic fatty liver disease.

Claims

1. Application of clopidogrel or medicinal salt thereof in preparing a medicament for preventing non-alcoholic fatty liver disease.

2. Use according to claim 1, characterized in that clopidogrel or a pharmaceutically acceptable salt thereof is used for the preparation of a medicament for the prevention of fat deposition in hepatocytes.

3. Application of clopidogrel or medicinal salt thereof in preparing a medicament for treating simple fatty liver, non-alcoholic fatty liver disease or early non-alcoholic fatty liver disease.

4. Use according to claim 3, characterized in that clopidogrel or a pharmaceutically acceptable salt thereof is used for the preparation of a medicament for the treatment of fat deposits in liver cells.