CN109364050B

CN109364050B - Application of idebenone in preparation of medicine for treating pulmonary hypertension

Info

Publication number: CN109364050B
Application number: CN201811221637.8A
Authority: CN
Inventors: 沈婷婷; 刘丕旭
Original assignee: Dalian Medical University
Current assignee: Dalian Medical University
Priority date: 2018-10-19
Filing date: 2018-10-19
Publication date: 2021-02-02
Anticipated expiration: 2038-10-19
Also published as: CN109364050A

Abstract

The invention discloses idebenoneThe application in preparing the medicine for treating pulmonary hypertension. The invention belongs to the technical field of biological medicines. The invention constructs a rat model of pulmonary hypertension disease through Monocrotaline (Monocrotaline) induction. After the idebenone is injected into the abdominal cavity, the conditions of fur, diet, activity, death and the like of the pulmonary hypertension rat model are observed. The result shows that idebenone (shown in formula I) has the effects of remarkably improving pulmonary vascular remodeling of the pulmonary hypertension animal, relieving right ventricular hypertrophy and right heart failure, improving the living quality (improving food intake and water intake) of the pulmonary hypertension animal and improving the survival rate of the pulmonary hypertension animal. Therefore, the invention provides a wide application prospect of idebenone in the aspect of preventing and treating pulmonary hypertension diseases.

Description

Application of idebenone in preparation of medicine for treating pulmonary hypertension

Technical Field

The invention relates to a new application of Idebenone (Idebenone, 6- (10-hydroxyindenyl) -2, 3-dimethy-5-methyl-1, 4-benzoquinone), in particular to an application of Idebenone in preparing a medicine for treating pulmonary hypertension. The invention belongs to the technical field of biological medicines.

Background

Pulmonary Arterial Hypertension (PAH), a pathological condition in which Pulmonary circulation pressure is higher than normal, is second only to coronary heart disease and Hypertension. Most patients die from right heart failure within 2-3 years, and are known as cancer in cardiovascular diseases by the medical community. Over the last 20 years, researchers have developed several drugs that improve the prognosis and survival of patients, but until now there has been no effective cure for pulmonary hypertension, which only temporarily delays or prevents the progression of the disease.

Hypoxia is an important cause of pulmonary hypertension, and the basic pathological processes are hypoxia pulmonary vasoconstriction, remodeling and adventitial fibrosis. Pulmonary vascular remodeling comprises pulmonary angiogenesis and pulmonary artery medial smooth muscle thickening, wherein the pulmonary angiogenesis is caused by pulmonary artery injury, pulmonary artery endothelial cell proliferation and migration, the pulmonary artery medial thickening is caused by pulmonary artery smooth muscle cell hyperproliferation and apoptosis inhibition, vascular occlusive lesion is caused, pulmonary artery pressure and pulmonary vascular resistance are increased, right ventricular afterload is increased, and therefore right ventricular failure and even death are caused. Pulmonary vascular remodeling is the pathological basis of the continuous development of PAH diseases and is also the main reason for poor curative effect of the medicine.

Mitochondria (mitochondria) are the main sites for cells to carry out biological oxidation and energy conversion, providing 80% of the energy required for cell life activities, and play an important role in cell metabolism and physiological functions. In almost all pathological processes of PAH, mitochondria are involved. Under hypoxic conditions, the mitochondrial electron transport chain of pulmonary artery smooth muscle cells (papmcs) experiences a decrease in oxygen partial pressure and a decrease in mitochondrial-derived reactive oxygen production, resulting in the opening of voltage-gated potassium channels on the regulatory plasma membrane, and finally, intracytoplasmic calcium ions shrink the papmcs and thus cause pulmonary vasoconstriction. Meanwhile, the mitochondrial morphology of the papmc in PAH patients is abnormal and mitochondrial function is inhibited. These suggest that the pathological process of PAH may be reversed by correcting mitochondrial abnormalities or reactivating mitochondria.

Since the 90 s of the last century, drug therapy has been greatly advanced with the understanding and understanding of the pathological process of pulmonary hypertension and the action pathways of various drugs. In the process of preventing and treating the occurrence and development of PAH, the following medicines are already clinically applied: calcium channel blockers, nifedipine, diltiazem and amlodipine; (xiv) prostacyclin and its analogs, intravenous epoprostenol, subcutaneous treprostinil, oral beraprost, inhalation epoprostinil; ③ the endothelin receptor antagonist bosentan; fourthly, inhaling Nitric Oxide (NO) or sublingual buccal isosorbide dinitrate; phosphodiesterase inhibitor dipyridamole, sildenafil, etc. The invention and application of these drugs play an important role in the current treatment of PAH. However, the clinical use of these therapeutic agents is greatly limited due to the insurmountable side effects and the high cost of treatment. For example, calcium channel blockers can cause hypotension, ventilation-perfusion mismatch, cardiac arrest, and also can cause headache, flushing, palpitation, and other adverse reactions in patients; the prostaglandin medicines have unstable pharmacological properties, and can generate local red rash after subcutaneous injection, and occasionally have headache, nausea and diarrhea; endothelial receptor antagonists can cause male reproductive atrophy or infertility, or have potential side effects such as hepatotoxicity, anemia and edema; the action time of inhaled NO is short, only a few minutes is needed, the device for continuous inhalation can be clinically popularized, and the inhalation has potential toxicity; side effects of phosphodiesterase inhibitors include headache, nosebleed, redness of the cheeks, dyspepsia, etc. Therefore, the current drug treatment prospects are not optimistic, and the search for new therapeutic drugs is a problem to be solved urgently at present.

Idebenone (Idebenone, 6- [ 10-hydroxydecyl ] -2,3-dimethoxy-5-methyl-1,4-benzoquinone, 6- [10-hydroxyindenyl ] -2,3-dimethoxy-5-methyl-1,4-benzoquinone) is a mitochondrial activator, is mainly used for treating central nervous system degeneration diseases related to oxidative stress in clinic, such as Parkinson's disease, Alzheimer's disease, multi-infarct dementia, cerebral ischemia, cerebral failure and the like, can improve the utilization rate of glucose in brain, promotes ATP generation, and has stronger effects of resisting oxidation and scavenging free radicals. And can be used in cosmetic formula for scavenging free radicals, inhibiting lipid peroxidation, inhibiting inflammation, inhibiting DNA damage, protecting against light, and relieving pigmentation. In addition, idebenone has an anti-tumor effect, but no research report on the application of idebenone to Pulmonary Arterial Hypertension (PAH) is found at present.

The invention researches the effect of idebenone on pulmonary hypertension, and the result shows that the compound can effectively improve pulmonary vascular remodeling of pulmonary hypertension animals, relieve right ventricular hypertrophy and right heart failure, improve the living quality (improve food intake and water intake) of the pulmonary hypertension animals and improve the survival rate of the pulmonary hypertension animals, so the idebenone can be used as a novel medicament for preventing and treating the pulmonary hypertension and is used for preventing and treating the pulmonary hypertension.

Disclosure of Invention

The invention aims to provide application of Idebenone (Idebenone, 6- [ 10-hydroxydecyl ] -2,3-dimethoxy-5-methyl-1,4-benzoquinone, 6- [10-hydroxyindenyl ] -2,3-dimethoxy-5-methyl-1,4-benzoquinone) in preventing and treating pulmonary hypertension diseases.

In order to achieve the above purpose, the invention adopts the following technical means:

the invention constructs a rat model of pulmonary hypertension disease through Monocrotaline (Monocrotaline) induction. After idebenone was administered by gavage, the conditions of fur, diet, activity, death, etc. were observed in the pulmonary hypertension rat model. The result shows that Idebenone can remarkably improve the pulmonary vascular remodeling of the rat with pulmonary hypertension induced by monocrotaline, relieve right ventricular hypertrophy and right heart failure, improve the living quality (improve the food intake and water intake) of the animal with pulmonary hypertension and improve the survival rate of the animal with pulmonary hypertension, namely the Idebenone (Idebenone) has the effect of preventing and treating the pulmonary hypertension disease through research.

Therefore, on the basis of the research, the invention provides the application of Idebenone in preparing the medicine for treating pulmonary hypertension, wherein the chemical structural formula of the Idebenone (Idebenone) is shown as a formula I:

preferably, idebenone achieves the purpose of treating pulmonary hypertension by relieving pulmonary vascular remodeling of patients with pulmonary hypertension and relieving right ventricular hypertrophy and right heart failure of patients with pulmonary hypertension.

Drawings

FIG. 1 is a graph of the survival rates of the blank group, idebenone group, monocrotaline model group, and monocrotaline + idebenone treatment group on different days, illustrating that idebenone can increase the survival rate of animals with pulmonary hypertension;

FIG. 2 shows the right ventricular hypertrophy of rats in different days in the blank group, idebenone group, monocrotaline model group and monocrotaline + idebenone treatment group, which illustrates that idebenone can significantly improve right ventricular hypertrophy of rats with pulmonary hypertension;

FIG. 3 is a graph showing the food intake, water intake and weight change of rats on different days in the blank group, the idebenone group, the monocrotaline model group and the monocrotaline and idebenone treatment group, which illustrates that the monocrotaline causes the gradual decrease of the food intake and the water intake of the rats, and the idebenone treatment can remarkably inhibit the weight decrease of the pulmonary hypertension rats and increase the food intake and the water intake of the pulmonary hypertension rats;

FIG. 4 is a comparison of right ventricular pressure in pulmonary hypertension rats in the blank group, idebenone group, wilderne model group, and wilderne + idebenone treatment group, demonstrating that idebenone can lower right ventricular pressure in pulmonary hypertension rats;

p <0.01vs blank group; # P <0.01 vs. monocrotaline model group;

fig. 5 is a cross-sectional photograph of lung small vessels typical of blank group, idebenone group, monocrotaline model group and monocrotaline + idebenone treatment group, which shows that idebenone can significantly improve pulmonary hypertension rat pulmonary vessel remodeling.

Detailed Description

The present invention is further described below in conjunction with specific examples, and the advantages and features of the present invention will become more apparent as the description proceeds. These examples are merely illustrative and do not limit the scope of the invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.

Example 1 use of idebenone in the treatment of pulmonary hypertension

1. Animal and experimental reagents:

rats (strain: Wistar, purchased from Experimental animals technology, Inc., Weitongli, Beijing), Monocrotaline (bioscience, Shanghai, Yuanmu).

2. Establishing a monocrotaline-induced pulmonary hypertension model:

60 healthy Wistar male rats (weight 160-200 g) were randomly divided into two groups, namely an experimental group and a control group, according to the weight balance principle, and both were raised in a standard sterile raising environment. The rats in the control group were randomly divided into two groups according to the weight balance principle, namely a blank group (physiological saline with the same volume as that of idebenone group, intragastric method) and an idebenone group (idebenone 200 mg/kg/day, intragastric method). Experimental group rats were injected with monocrotaline 60mg/kg in the abdominal cavity once, and after 21 days, they were randomly divided into 2 groups according to the weight balance principle, namely monocrotaline model group (normal saline with the same volume as monocrotaline + idebenone treatment group, gavage method) and monocrotaline + idebenone treatment group (idebenone 200 mg/kg/day, gavage method). The skin, hair, diet, activity, death, etc. were observed.

The heart and the left lung were taken for 4% fixation of paraformaldehyde, and the remaining lung lobes were frozen. Fixed hearts and lungs were pathologically stained.

3. Results

3.1 idebenone increases survival rates in animals with pulmonary hypertension

Idebenone administration treatment was carried out 24 days after the monocrotaline injection, and the Log-rank (Mantel-Cox) test showed the survival rate (P ═ 0.005) of pulmonary hypertension animals at different days after idebenone administration, with this time point taken as 0 day for each group.

Through researches, the felbinane-induced pulmonary hypertension animals die continuously along with the increase of the feeding time, the mortality rate of a felbinane model group reaches 73% after the felbinane is injected for 60 days, and the mortality rate of a felbinane + idebenone treatment group (30 mg/kg/day and intraperitoneal injection) is only 33%, which shows that the idebenone can improve the survival rate of the pulmonary hypertension animals, and the results are shown in fig. 1.

3.2 idebenone can remarkably reduce the hypertrophy of the right ventricle of the rat with pulmonary hypertension

The study finds that the monocrotaline-induced pulmonary hypertension rats gradually die, the dead rats are obtained, and the results show that the phenotype of the obtained animals is remarkable in right ventricular hypertrophy, the right ventricular hypertrophy index (right ventricular weight/left ventricular weight + ventricular septum) is remarkably increased, and the increased right ventricular hypertrophy index after the idebenone is treated by the drug is remarkably inhibited, and the results are shown in fig. 2. The idebenone can remarkably reduce the right ventricular hypertrophy of the pulmonary hypertension rat and correct right heart failure.

3.3 idebenone can significantly improve the quality of life of the pulmonary hypertension rats

The research shows that the monocrotaline induces the pulmonary hypertension of the rats, the rats die in sequence along with the increase of the feeding time, the weight of the rats is gradually reduced in the feeding process, and the feeding and water inflow are also gradually reduced. Idebenone treatment significantly inhibited weight loss and significantly increased food intake and water intake in rats, the results are shown in figure 3.

3.4 idebenone is effective in reducing the right ventricular pressure of pulmonary hypertension rats

The monocrotaline induced pulmonary hypertension model showed a significant increase in right ventricular pressure. The condition of elevated right ventricular pressure was significantly reduced in the monocrotaline + idebenone treatment group compared to the monocrotaline model group, and the results are shown in fig. 4.

3.5 idebenone can remarkably improve pulmonary arterial hypertension rat pulmonary vascular remodeling

The monocrotaline-induced pulmonary hypertension model can lead to pulmonary vascular remodeling. Compared with the monocrotaline model group, the monocrotaline and idebenone treatment group has the advantages that the pulmonary vascular remodeling condition of the pulmonary hypertension rats is obviously improved, and the result is shown in fig. 5.

Claims

1. The application of Idebenone in preparing a medicine for treating pulmonary hypertension is characterized in that the chemical structural formula of the Idebenone (Idebenone, 6- [ 10-hydroxydecyl ] -2,3-dimethoxy-5-methyl-1,4-benzoquinone, 6- (10-hydroxyindenyl) -2,3-dimethoxy-5-methyl-1,4-benzoquinone) is shown as a formula I:

2. the use of claim 1, wherein: the idebenone achieves the purpose of treating the pulmonary hypertension by relieving the pulmonary vascular remodeling of the patient with the pulmonary hypertension and relieving the right ventricular hypertrophy and the right heart failure of the patient with the pulmonary hypertension.