CN102824338A - Application of s-oleylpropanolamide in preparing medicine for reducing blood fat and preventing and treating non-alcoholic fatty liver - Google Patents
Application of s-oleylpropanolamide in preparing medicine for reducing blood fat and preventing and treating non-alcoholic fatty liver Download PDFInfo
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- CN102824338A CN102824338A CN2012103472062A CN201210347206A CN102824338A CN 102824338 A CN102824338 A CN 102824338A CN 2012103472062 A CN2012103472062 A CN 2012103472062A CN 201210347206 A CN201210347206 A CN 201210347206A CN 102824338 A CN102824338 A CN 102824338A
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Abstract
The invention discloses application of s-oleylpropanolamide in preparing a medicine for reducing blood fat and preventing and treating non-alcoholic fatty liver, relating to s-oleylpropanolamide. The s-oleylpropanolamide is a natural PPAR(alpha) agonist. According to the pharmacological experiment research, s-oleylpropanolamide has obvious effects on reducing blood fat and preventing non-alcoholic fatty liver, and can be used for preventing and treating hyperlipidemia and non-alcoholic fatty liver caused by multiple factors.
Description
Technical field
The present invention relates to s-oleoyl Propanolamine, especially the purposes of s-oleoyl Propanolamine in preparation blood fat reducing, control non-alcoholic fatty liver disease medicine.
Background technology
Cardiovascular and cerebrovascular disease is present mortality rate disease with high; And its arch-criminal is an atherosclerosis; See that from Chinese dietary structure, dietary habit causing the atherosclerotic main cause of Chinese population is dyslipidemia, be mainly hyperlipemia (hyperlipidemia).Hyperlipemia is meant increasing unusually of total plasma cholesterol TC and triglyceride TG; It is atherosclerotic main hazard factor; Be the main diseases of bringing out various cardiovascular disease because of; And cardiovascular disease is human first killer, and its M & M all surpasses ND and leaps to the first.According to AHA's statistics, cardiovascular disease has endangered nearly 6,000 ten thousand Americans, spends nearly 2,590 hundred million dollars.In recent years, the various diseases that causes of hyperlipemia has the trend of obvious increase in China.Therefore the medicine of seeking the little treatment hyperlipidemia of good effect, side effect is a urgent problem.From the pathogenesis of hyperlipemia, seeking efficacious therapy albumen is the focus of Recent study.Agent for peroxisome proliferator activated receptor (peroxisome proliferator activatived receptors; PPAR) PPAR α more and more receives people's attention as the NlmR that plays an important role at hyperlipidemia formation and development process weight average.Fibrate is the pharmacological aglucon of exciting peroxisome proliferator-activated receptor α.PPAR α activates the back and regulates lipid metabolism, induces the enzyme relevant with lipid metabolism, promotes the beta oxidation and the omega oxidation of fatty acid, reduces serum triglycerides, and the effect of blood fat is transferred in performance.Because of lipid-lowering effect remarkable; The synthetic ligands of PPAR α has become a line medicine of treatment hyperlipemia; And, will make the exploitation of treatment hyperlipidemia have far reaching significance for the analog of the native ligand Oleoyl monoethanolamide (OEA) of the lower PPAR α of medium effective concentration.
S-oleoyl Propanolamine (OPA) is the synthetic voluntarily chemical compound (Jin Xin of the applicant; Sun Cuiling; Zheng Jianfeng. a kind of method of synthetic oleic amine derivant. Chinese patent: ZL200710009268.1),, structurally only differ from a methyl with the latter as the analog of OEA; The stability of OPA is strengthened; Also have relevant pharmacokinetic also to show, during through oral administration and isodose s-OPA of lumbar injection and OEA, the content of s-OPA in rat plasma and liver will be higher than OEA far away; And other transcriptional activation experiments show that also s-OPA also has activation to PPAR α, and its activation capability is apparently higher than the fenofibrate of confirming as the PPAR alfa agonists.
Summary of the invention
The purpose of this invention is to provide the purposes of a kind of s-oleoyl Propanolamine in preparation blood fat reducing, control non-alcoholic fatty liver disease medicine.
Said s-oleoyl Propanolamine is a kind of natural PPAR alfa agonists.
Find that through pharmacological experiment study s-oleoyl Propanolamine has tangible blood fat reducing, the effect of prevention non-alcoholic fatty liver disease.Said blood fat reducing is meant and reduces serum total cholesterol, triglyceride and low density lipoprotein, LDL.Said medicine is an oral administration.
The specific embodiment
One, the present invention adopts the inductive chmice acute hyperlipemia model of Triton WR1339, observes s-oleoyl Propanolamine (OPA) to the serum total cholesterol (TC) of acute hyperlipemia model mice, the influence of triglyceride (TG).
Pharmacodynamic experiment concrete grammar step provided by the invention and result are following:
1, laboratory animal and reagent
42 of Kunming mouses, male, counterpoise 18～22g is available from Shanghai Slac Experimental Animal Co., Ltd.; Credit number: SCXK (Shanghai) 2007-0005.
Triton WR1339 is available from SIGMA company.
Luxuriant and rich with fragrance nobert is available from SIGMA company.
OEA, OPA, P58, Xiamen University's medical college is synthetic.
2, animal processing method
Kunming mouse, normal illumination, temperature: 18～25 ℃; Humidity: 40%～60%, give normal diet, the adaptability of freely drinking water was raised after 7 days; Be divided into 4 groups at random, 10 every group, be respectively normal control group, acute hyperlipemia model group, fenofibrate group, OPA group.Except that the normal control group; Each group of experiment is respectively at 17 o'clock lumbar injection Triton WR1339 400mg/kg on the same day, and simultaneously to give normal group and model group normal saline, fenofibrate group concentration with the mode of irritating stomach be that to organize concentration be the OPA of 100mg/kg for fenofibrate solution, the OPA of 100mg/kg; In the next day 9 o'clock mornings (behind the 16h) all broken end get blood, measure mice serum TC, TG.
Result and analysis:
S-oleoyl Propanolamine to the influence of acute hyperlipemia mice blood lipid level referring to table 1.
Table 1 s-oleoyl Propanolamine is to the influence of acute hyperlipemia mice blood fat
Shoulder motes
###Expression is compared P with the normal control group<0.0001;
* *Expression is compared P with the hyperlipidemia model group<0.0001.
1. can find out from table 1 that hyperlipidemia model treated animal TC, TG compare equal significance and raise with the normal control group, p 0.0001, the modeling success is described.
2. the fenofibrate group is compared with the hyperlipidemia model group, and TC, TG descend 74.81%, 94.82% respectively, and significant difference is all arranged, and explains that the positive control drug fenofibrate is remarkable for acute hyperlipemia model lipid-lowering effect.
3. the OPA group is compared with the hyperlipidemia model group, and TC, TG descend 72.78%, 94.69% respectively, and significant difference is all arranged, and explain that s-oleoyl Propanolamine also has remarkable lipid-lowering effect for the acute hyperlipemia model.
Experimental result proves that OPA can obviously reduce the TC in the acute hyperlipemia mice serum, the content of TG, has certain effect for reducing blood fat.
Two, the present invention also adopts the Golden Hamster hyperlipemia model of feed high lipid food, and observation OPA is heavy to serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), HDL-C (HDL-C), body weight, the liver of hyperlipemia model Golden Hamster, the influence of liver lipid level.
Pharmacodynamic experiment concrete grammar step provided by the invention and result are following:
1, laboratory animal and reagent
56 of Golden Hamster (golden hamster), male, counterpoise 100 ~ 120 grams join the laboratory animal field available from Shanghai Songjiang district pine; Credit number: SCXK (Shanghai) 2007-0011.
Fenofibrate is available from sigma company.
S-oleoyl Propanolamine, Xiamen University's medical college is synthetic.
2, animal processing method
Golden Hamster, 23 ± 1 ℃ of temperature, humidity: 40%～60%; Natural lighting; Freely drink water, in 1 week of ad lib normal diet, be divided into 7 groups at random; Every group 8, be designated as dose groups (being designated as OPA2), OPA high dose group (being designated as OPA3) among normal control group, model group with hyperlipemia, fenofibrate group, OPA low dose group (being designated as OPA1), the OPA respectively.
Except that the normal control group gives the normal diet, all the other groups all give high lipid food.The high lipid food prescription is: normal diet 88%, Adeps Sus domestica 10%, cholesterol 2%.Fed for 5 weeks.
According to following method administration:
Normal control group and hyperlipemia group: give normal saline, mode before giving feedstuff at 14 in every day in afternoon: irritate stomach.
Fenofibrate group: be administered once dosage 20mg/kg, mode: irritate stomach before giving feedstuff at 14 in every day in afternoon.
OPA1 group: be administered once dosage 10mg/kg, mode: irritate stomach before giving feedstuff at 14 in every day in afternoon.
OPA2 group: be administered once dosage 20mg/kg, mode: irritate stomach before giving feedstuff at 14 in every day in afternoon.
OPA3 group: be administered once dosage 40mg/kg, mode: irritate stomach before giving feedstuff at 14 in every day in afternoon.
Successive administration is after 5 weeks according to the method described above, and all animal hearts are got blood, win liver organization, measures serum total cholesterol, triglyceride, low-density lipoprotein cholesterol LDL-C, HDL-C HDL-C, liver lipid.
Statistical analysis: (GraphPad Software Inc USA) carries out statistical analysis to The data Graphpad Prism 5 softwares, relatively uses one factor analysis of variance between group, and when variance analysis difference had significance, reuse t check was compared in twos.
The result with analyze as follows:
1) s-oleoyl Propanolamine is to the influence of diet property hyperlipemia Golden Hamster blood lipid level
Successive administration detects Blood Lipid (TC, TG, HDL-C/TC, LDL-C) result shown in table 2 and table 3 after 5 weeks.This result shows:
1. hyperlipidemia model treated animal TC, TG, LDL-C raise 585%, 1643%, 1368% than normal control group respectively, with compared with normal significant difference are arranged all, and the modeling success is described.
2. the fenofibrate group is compared with the hyperlipidemia model group; TC, TG, LDL-C descend 53.83%, 77.77%, 79.91% respectively; HDL-C/TC rises 138.5%, all has significant difference, explains that the positive control drug fenofibrate is remarkable for diet property hyperlipemia Golden Hamster model lipid-lowering effect.
3. each group of OPA is compared with the hyperlipidemia model group, and TC, TG, LDL-C all have decline to a certain degree, and HDL-C/TC has to a certain degree rising, and the effect of OPA2 is best, and the result all has significant difference.
Table 2 s-oleoyl Propanolamine is to the influence of diet property hyperlipemia Golden Hamster blood fat
Shoulder motes
ΔExpression is compared P with the normal control group<0.05,
The Δ ΔExpression P<0.01;
*Expression is compared P with the hyperlipidemia model group<0.05,
*Expression P<0.01.
Table 3 s-oleoyl Propanolamine is to the influence of diet property hyperlipemia Golden Hamster blood fat
Shoulder motes
ΔExpression is compared P with the normal control group<0.05,
The Δ ΔExpression P<0.01,
Δ Δ ΔExpression P<0.001;
*Expression is compared P with the hyperlipidemia model group<0.05,
*Expression P<0.01.
2) s-oleoyl Propanolamine is to the influence of diet property hyperlipemia Golden Hamster liver biochemical indexes
Successive administration is after 5 weeks, detect body weight, liver weight, liver lipid content, liver biochemical indexes (TC, TG) result as table 4～6 and shown in.This result shows:
1. the hyperlipidemia model group is compared with the normal control group, and the liver index raises 22.51%, and each group of OPA is compared with the hyperlipidemia model group has downward trend, and wherein the OPA2 group is compared with the hyperlipidemia model group and all had significant difference.(seeing table 4)
2. the hyperlipidemia model group is compared with the normal control group, and body weight, liver lipid content significantly raise.(seeing table 4～6)
3. the fenofibrate group is compared with the hyperlipidemia model group, and the horizontal significance of GSH-PX raises, and the horizontal significance of MDA reduces, and shows that fenofibrate has the liver of alleviating lipid peroxidation, but not obvious to the influence of liver lipid level.(seeing table 5)
4. in each group of OPA, the OPA2 group has significant reduction effect (table 1c) to the heavy regulating liver-QI index of liver, and the OPA3 group obviously reduces hepatic tissue MDA, and OPA2 and OPA3 have obvious rising effect to liver GSH-PX, point out the two that tangible liver protection is all arranged; For the influence of liver lipid, the OPA2 group has significant reduction effect, explains that the effect of its treatment fatty liver is the most obvious.(seeing table 5,6)
Table 4 s-oleoyl Propanolamine is to the influence of diet property hyperlipemia Golden Hamster liver
Shoulder motes
ΔExpression is compared P with the normal control group<0.05,
The Δ ΔExpression P<0.01;
*Expression is compared P with the hyperlipidemia model group<0.05,
*Expression P<0.01.
Table 5 s-oleoyl Propanolamine is to the influence of diet property hyperlipemia Golden Hamster liver
Shoulder motes
ΔExpression is compared P with the normal control group<0.05,
The Δ ΔExpression P<0.01;
*Expression is compared P with the hyperlipidemia model group<0.05,
*Expression P<0.01.
Table 6 s-oleoyl Propanolamine is to the influence of diet property hyperlipemia Golden Hamster liver lipid level
Shoulder motes
ΔExpression is compared P with the normal control group<0.05,
The Δ ΔExpression P<0.01;
*Expression is compared P with the hyperlipidemia model group<0.05,
*Expression P<0.01.
Experimental result proves that s-oleoyl Propanolamine has the effect of significant reduction serum total cholesterol, triglyceride, low density lipoprotein, LDL.Simultaneously, reduce the liver lipid, alleviate the liver level of lipid, have preventive effect for the fatty liver that hyperlipidemia model caused.Can develop s-oleoyl Propanolamine as blood fat reducing, the purposes of prevention fatty liver medicine.
Claims (3)
1.s-the purposes of oleoyl Propanolamine in preparation blood fat reducing, control non-alcoholic fatty liver disease medicine.
2. purposes as claimed in claim 1 is characterized in that said blood fat reducing is meant reduction serum total cholesterol, triglyceride and low density lipoprotein, LDL.
3. purposes as claimed in claim 1 is characterized in that said medicine is an oral administration.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1523982A (en) * | 2001-03-27 | 2004-08-25 | ���������Ǵ�ѧ���»� | Methods, compounds, and compositions for reducing body fat and modulating fatty acid metabolism |
| CN101108811A (en) * | 2007-07-24 | 2008-01-23 | 厦门大学 | Method for synthesizing amine derivant of oleic acid |
| CN102391144A (en) * | 2011-08-08 | 2012-03-28 | 厦门大学 | Synthetic method of (R)-oleoyl propanolamine |
| CN102579414A (en) * | 2012-01-29 | 2012-07-18 | 厦门大学 | Application of oleoylethanolamide being used as drug for reducing blood fat and preventing nonalcoholic fatty liver disease |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1523982A (en) * | 2001-03-27 | 2004-08-25 | ���������Ǵ�ѧ���»� | Methods, compounds, and compositions for reducing body fat and modulating fatty acid metabolism |
| CN101108811A (en) * | 2007-07-24 | 2008-01-23 | 厦门大学 | Method for synthesizing amine derivant of oleic acid |
| CN102391144A (en) * | 2011-08-08 | 2012-03-28 | 厦门大学 | Synthetic method of (R)-oleoyl propanolamine |
| CN102579414A (en) * | 2012-01-29 | 2012-07-18 | 厦门大学 | Application of oleoylethanolamide being used as drug for reducing blood fat and preventing nonalcoholic fatty liver disease |
Non-Patent Citations (1)
| Title |
|---|
| 陈彩霞等: "s-油酰丙醇胺对人脐静脉内皮细胞黏附分子表达的影响", 《中国生化药物杂志》, vol. 30, no. 2, 30 April 2009 (2009-04-30), pages 99 - 102 * |
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