CN115990174A - Application of aescin and its salt in preparing medicine for treating dyskinesia related diseases - Google Patents
Application of aescin and its salt in preparing medicine for treating dyskinesia related diseases Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention discloses application of aescine compounds and salts thereof in preparing medicines for treating diseases related to dyskinesia. A large number of experiments show that the aescine compound and the pharmaceutically acceptable salt thereof can improve the dyskinesia of SOD1-G93AALS model mice in the Rotard stick rotation experiment, gait monitoring experiment and cage experiment, and the aescine compound can be used for treating diseases related to dyskinesia including amyotrophic lateral sclerosis.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of aescine and salts thereof in preparing medicines for treating neurological diseases related to dyskinesia. More specifically, the invention relates to application of aescin and pharmaceutically acceptable salts or pharmaceutical compositions thereof in preparing medicines for treating amyotrophic lateral sclerosis diseases, wherein the aescin has the function of improving SOD1-G93AALS model mouse dyskinesia.
Research setting
Amyotrophic Lateral Sclerosis (ALS) is a fatal degenerative disease of the nervous system, also known as "progressive freezing disease," which involves mainly spinal cord, cerebral cortex and brain stem motor neurons. Amyotrophic lateral sclerosis is a chronic progressive disease affecting both the upper motor neurons (brain, brain stem, spinal cord) and the lower motor neurons (cranial nuclei, spinal cord anterior horn cells) and their innervating trunk, extremities, and head-face muscles. ALS usually occurs in the middle-aged and elderly or later, and patients develop progressive muscle atrophy and weakness after onset, and eventually die from respiratory failure. The survival time after most patients develop disease is only 2 to 4 years. About 45 ten thousand ALS patients worldwide, the prevalence is about 1/20000, and ALS was included in the first few rare diseases catalog in China in 2018. The study in 1993 found that the SOD1 gene mutation was the causative gene of ALS, and based on this, the first ALS model mouse SOD1-G93A model mouse was made in 1994, and this animal model has been widely used in ALS study. Although ALS is a rare disease, the cure rate is extremely low, and no specific therapeutic drug can be used, so that great pain is brought to ALS patients and families. There are currently only two drugs in clinical use for the treatment of ALS, of which riluzole was approved for the market as early as 1995, but was not recently approved by the FDA for use in the treatment of ALS; edaravone, another drug, was approved by the FDA for treatment of ALS in 2017. However, these two drugs only transiently extend patient survival and do not cure ALS. Thus, there is an urgent need to explore the pathogenesis of ALS, find new targets for treating the disease, and develop drugs that are effective in treating ALS.
Aescin (Escin) is a natural mixture of triterpene saponins extracted from horse chestnut seeds. Currently, escin consists mainly of EscinA, escinB, escinC and Escin d, and in vivo bidirectional conversion occurs due to temperature and pH differences. The structure is shown in figure 1.
Escin has anti-inflammatory and vascular protecting effects, and can be used for treating chronic venous insufficiency and cerebral ischemia. Chinese patent CN110585222A discloses application of aescine compound in preparing medicine, and is especially application of aescine compound in preparing medicine for treating Huntington chorea and Parkinson disease. Huntington's disease is a hereditary progressive neurodegenerative disease, the main cause of which is mutation of the Huntington gene on chromosome four of the patient, which produces mutated proteins that gradually aggregate together in cells to form large clusters that accumulate in the brain, affecting the function of nerve cells. The etiology and pathogenesis of parkinson's disease are not clear, and may be related to social factors, pharmaceutical factors, patient factors, etc. The PD pathology changes as: the substantia nigra compact part of the midbrain, the blue spot neuron pigment is deprived, the melanin becomes thin, and the lewy body appears. The PD neurobiochemical changes to: the loss of the substantia nigra compact part and the blue spot neurons leads to the reduction of Dopamine (DA) at the parts and the nerve endings thereof, (the clinical manifestation of PD is generated when the DA reduction is more than or equal to 70 percent), while the action of Acetylcholine (ACH) antagonistic to DA function in the substantia nigra striata system is relatively excessive, and the balance of DA and ACH is disturbed. The specific mechanism of the two diseases is obviously different from the pathogenesis of Amyotrophic Lateral Sclerosis (ALS) of the invention, and no therapeutic effect on amyotrophic lateral sclerosis is reported on drugs, such as dopamine drugs, sulpride hydrochloride, tetrabenazine and vitamins drugs, for treating parkinsonism, such as levodopa, pramipexole, piribedil, selegiline, rasagiline and the like, for treating huntington's chorea.
Chinese patent CN107281203A discloses application of semen aesculi extract in preparing medicine for preventing and treating senile dementia, and specifically discloses application of semen aesculi extract with beta-aescine as active ingredient to obviously improve memory disorder and learning ability of model animals, effectively improve and regulate central cholinergic nerves, regulate free radical metabolism and other functions, and has definite curative effects on various senile dementia including Alzheimer disease, vascular dementia, mixed dementia and the like.
At present, no report is made on the effect of aescine compounds in improving the motor dysfunction of mice with SOD1-G93A model, thereby preventing amyotrophic lateral sclerosis. The present invention further finds that aescine has an anti-amyotrophic lateral sclerosis effect, and thus the present invention further finds its potential for treatment of new indications.
Disclosure of Invention
The invention aims to develop a novel medical application of aescin and pharmaceutically acceptable salts thereof. Namely application of aescin compounds or pharmaceutically acceptable salts thereof in preparing medicines for treating diseases related to dyskinesia.
As another preferred scheme, the application of the aescine compound and the pharmaceutically acceptable salt thereof in preparing the medicines for improving dyskinesia such as amyotrophic lateral sclerosis and the like is provided.
Another object of the present invention is to provide an application of a pharmaceutical composition in preparing a medicament for treating amyotrophic lateral sclerosis, wherein the pharmaceutical composition comprises aescine compounds or pharmaceutically acceptable salts thereof and pharmaceutically acceptable auxiliary materials.
For the above applications, the aescin compounds include EscinA, escinB, escinC and escin d.
More preferably, the pharmaceutically acceptable salts include inorganic or organic acid salts, such as malates, citrates, sulfonates, and the like.
The beneficial effects are that: the invention discovers a new action mechanism and drug effect of aescin, has the effect of improving the dyskinesia of mice with SOD1-G93A model, and comprises the obvious improvement of the dyskinesia state of the mice with SOD1-G93A model in the Rotard stick test, the gait monitoring test and the cage test. The compounds are useful in the treatment of amyotrophic lateral sclerosis and motor dysfunction related diseases.
Drawings
FIG. 1 shows that aescin can significantly improve dyskinesia exhibited by SOD1-G93A model mice in Rotard stick rotation experiments. *** Represents p<0.001, model group vs. control group, ### represents p<0.001, administration group vs. A Ttest was used between the two sets of data for significance analysis.
FIG. 2 shows that aescin can obviously improve abnormal gait phenomenon of SOD1-G93A model mice in gait monitoring experiments. *** Represents p<0.001, model group vs. control group, ### represents p<0.001, administration group vs. A Ttest was used between the two sets of data for significance analysis.
FIG. 3 shows that aescin can obviously improve the phenomenon of reduced grip strength of limbs of SOD1-G93A model mice in a cage experiment. *** Represents p<0.001, model group vs. control group, ### represents p<0.001, administration group vs. A Ttest was used between the two sets of data for significance analysis.
FIG. 4 shows the structural formulae of aescin EscinA, escinB, escinC and EscinD.
Detailed Description
The invention is further illustrated below in connection with specific examples which should not be construed as limiting the invention.
Escin was purchased from sigma, CAS No. 6805-41-0, lot No. as described in the examples below: BCCB0323 has a purity of more than 95%.
Test implementation: aescin improves the dyskinesia state of SOD1-G93A model mice in the behavioral experiments of Rotard stick rotation experiment, gait monitoring experiment and cage experiment.
The invention detects the influence of aescin on the improvement of the movement dysfunction state of mice in SOD1-G93A model mice, and experiments show that the aescin has the function dysfunction state which is obviously improved in the Rotard stick rotation experiment, gait monitoring experiment and cage experiment of the SOD1-G93A model mice.
1. Principle of experiment
1) Rotard rod rotation experiment: motor dysfunction occurs when SOD1-G93A model mice develop, so animal forelimb and hindlimb motor coordination and balancing functions can be assessed by detecting the length of time the mice stay on the rotating stick.
2) Gait monitoring experiment: the SOD1-G93A model mice show gait instability and resting tremor at the beginning of onset, gradually develop into hind limb atrophy, and develop into complete paralysis of double hind limbs at the late stage of disease, the step length is obviously shortened, and the fore-and-aft limb movement coordination and regulation functions of the mice are evaluated through gait analysis.
3) Cage experiment: hindlimb atrophy and limb grip strength reduction occur after the SOD1-G93A model mice are ill, and the gripping force of the limbs of the mice is detected through a cage experiment.
2. Experimental materials and methods
1) Grouping animals: experimental mouse B6SJL-BTg (SOD 1-G93A) 1Gur/J (002726) was purchased from Jackson Laboratory, inc. A total of 48 SOD1-G93A mice are obtained through gene identification, and the wild mice in the littermates are used as negative controls and randomly divided into 4 groups. The method comprises the following steps of: (1) wild type solvent set (2) wild type Escin set (1 mg/kg/day) (3) model solvent set and (4) model Escin set (1 mg/kg/day). All mice were dosed starting at 84 days of age (12 weeks of age), with 12 mice per group each sacrificed from the start of dosing to 120 days of age, and tissues such as eyeball blood, muscle and spinal cord were subjected to pathological, biochemical and immunological analyses.
2) Rotard rod rotation experiment: from 84 days old, the motor function of SOD1-G93A model mice was examined using a Rotarod stick-turning machine. Mice received one week training to become familiar with the Rotarod instrument. From 90 days of age, the test was performed twice a week. At the beginning of the experiment, mice were placed individually on the rotating cylinder of a rotarod apparatus and rotated at constant speed at a rotational speed of 12 revolutions per minute. The motor coordination and balance of each mouse was assessed by measuring the total motor time of the mice on the rotating rod. Three trials were performed for each animal and the longest residence time before drop was recorded, the longest residence time being set to 180 seconds.
3) Gait monitoring experiment: to obtain the footprint, the forefoot and hind legs of the SOD1-G93A model mice were coated with red and green non-toxic pigments, respectively. The mice walk along a track 50 cm long and 10 cm wide, and the gait of the mice is recorded. All mice were tested once a week and run three times each time. The footprints of the mice were analyzed and the average of three results statistics was used in the analysis of the step sizes of the mice.
4) Cage experiment: weekly measurements were performed starting at week 13. In the experiment, soft mats are paved on the ground to protect the mice, then the mice are placed on the cage cover, and after the mice are determined to grasp the cage cover, the cage cover is quickly turned over and timing is started at the same time. The maximum time for the mice to grasp the cage cover was recorded, the maximum time being specified as 90 seconds, and the specific time was recorded below 90 seconds. Each experiment was repeated three times and the best results were taken as records.
3. Experimental results
As shown in fig. 1, compared with the model solvent group, the model Escin group mice have better overall rotating stick experiment performance, and the model Escin group mice stay longer on the rotating stick instrument in the disease period (101-115 days) than the model solvent group mice, so that the Escin has the effect of improving the movement coordination and balancing functions of the mice; there was no significant difference between the wild type Escin mice and the wild type mice. As shown in figure 2, the step length analysis result of the model Escin group mice after 15 weeks is obviously better than that of the model solvent group mice, which shows that the aescine has the function of improving gait abnormality of the model mice; there was no significant difference between the wild type Escin mice and the wild type mice. As shown in fig. 3, model Escin group mice were better in duration in the cage experiments than model solvent group mice at 15 to 17 weeks of age, indicating that Escin had the function of enhancing muscle strength in mice. There was no significant difference between the wild type Escin mice and the wild type mice.
In conclusion, experimental results show that Escin can obviously improve the movement dysfunction of mice in the model group, and does not influence the movement function of normal mice.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (6)
1. Application of aescin compound and pharmaceutically acceptable salt thereof in preparing medicine for treating dyskinesia related diseases is provided.
2. Application of aescin compound and pharmaceutically acceptable salt thereof in preparing medicament for treating amyotrophic lateral sclerosis.
3. The application of a pharmaceutical composition in preparing medicines for treating diseases related to dyskinesia, wherein the pharmaceutical composition comprises aescine compounds or pharmaceutically acceptable salts thereof and pharmaceutically acceptable auxiliary materials.
4. The use according to claim 3, wherein the aescin compound comprises Escin a, escin B, escin C and Escin D.
5. The use according to any one of claims 1 to 5, wherein the pharmaceutically acceptable salt comprises an inorganic acid salt or an organic acid salt.
6. The use according to any one of claims 1 to 5, wherein the aescin compound significantly improves the dyskinesia state exhibited by SOD1-G93A model mice in the Rotard stick test, gait monitoring test and cage test behavioural tests.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US20150250808A1 (en) * | 2012-10-15 | 2015-09-10 | Vojo P. Deretic | Treatment of autophagy-based disorders and related pharmaceutical compositions, diagnostic and screening assays and kits |
| CN110585222A (en) * | 2019-10-12 | 2019-12-20 | 西南医科大学 | Application of aescin compound in preparing medicine |
| CN113499335A (en) * | 2021-07-13 | 2021-10-15 | 中国人民解放军军事科学院军事医学研究院 | Medicine for treating neurodegenerative diseases by targeted autophagy fusion |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20150250808A1 (en) * | 2012-10-15 | 2015-09-10 | Vojo P. Deretic | Treatment of autophagy-based disorders and related pharmaceutical compositions, diagnostic and screening assays and kits |
| CN110585222A (en) * | 2019-10-12 | 2019-12-20 | 西南医科大学 | Application of aescin compound in preparing medicine |
| CN113499335A (en) * | 2021-07-13 | 2021-10-15 | 中国人民解放军军事科学院军事医学研究院 | Medicine for treating neurodegenerative diseases by targeted autophagy fusion |
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