CN117298098A - Application of decursin in preparation of medicines for treating vascular dementia - Google Patents
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- CN117298098A CN117298098A CN202311521026.6A CN202311521026A CN117298098A CN 117298098 A CN117298098 A CN 117298098A CN 202311521026 A CN202311521026 A CN 202311521026A CN 117298098 A CN117298098 A CN 117298098A
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- decursin
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- JXZWWIMXTVJNSF-UHFFFAOYSA-N decursin Natural products CC(=CC(=O)OC1Oc2cc3OC(=O)C=Cc3cc2CC1(C)C)C JXZWWIMXTVJNSF-UHFFFAOYSA-N 0.000 title claims abstract description 26
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
- A61K31/37—Coumarins, e.g. psoralen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Vascular Medicine (AREA)
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Abstract
The invention discloses an application of decursin in preparation of a medicine for treating vascular dementia, and belongs to the technical field of medicines. The inventor adopts the oxypeucedanum as the only active ingredient to prepare the medicine for treating vascular dementia, the single administration dosage after molding is 20mg/kg in a rat bilateral common carotid artery ligation model, once daily administration is carried out, and continuous administration is carried out for 28 days, so that the medicine can effectively relieve the situational memory defect caused by chronic cerebral hypoperfusion and the spatial learning memory disorder dependent on hippocampus, can improve the loss of neurons of the hippocampus and basically does not cause adverse reaction, and can use the oxypeucedanum as the only active ingredient to prepare the medicine for treating vascular dementia, thereby providing a new way for treating vascular dementia.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of decursin in preparation of a medicine for treating vascular dementia.
Background
Vascular dementia (vascular dementia) is a serious cognitive dysfunction syndrome (Tian Jinzhou et al, "vascular dementia diagnosis, diagnosis and efficacy assessment criteria (for research)," journal of geriatrics in China 22.5 (2002): 3.), which is a type of dementia next to Alzheimer's disease, and which causes about 15% of cases of dementia, caused by ischemic stroke, hemorrhagic stroke, and cerebrovascular diseases that cause hypoperfusion in brain regions such as memory, cognition, and behavior. Due to the non-uniform disease classification and diagnostic criteria, the lack of exact relationships between cerebrovascular pathology and cognitive impairment and the lack of a clear therapeutic target, vascular dementia is difficult to treat (O' Brien, john T, andAllan thomas. "Vascular de-mentia." Lancet (London, england) vol.386,10004 (2015): 1698-706.Doi:10.1016/S0140-6736 (15) 00463-8).
As the population ages, the number of vascular dementia patients increases year by year, and the burden on the home and society increases greatly while their quality of life decreases greatly. The current drugs used clinically for treating vascular dementia are mainly cholinesterase inhibitors and NMDA receptor antagonists for treating alzheimer's disease, and these drugs are used based on overlap of neuropathology and neurochemistry between two dementias, but their improving effect on vascular dementia is small and further clinical evaluation is required (Kavirajan, harrsh, and l.s. schneider. "Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled three." 6.9 (2007): 782-792). In addition, acetylcholinesterase inhibitors can irritate the gastrointestinal tract, causing nausea, vomiting, diarrhea, and other side effects, and NDMA receptor antagonists can cause muscle cramps. Therefore, the search for novel effective medicaments with small adverse reactions has important social and economic significance.
Oxypeucedanin (molecular formula: C) 16 H 14 O 5 CAS number: 737-52-0, chemical name 5- ((3, 3-dimethyloxiran-2-yl) method) -7H-furo [3,2-g]chromen-7-one), which is a linear furocoumarin compound, is a main effective component extracted from the open sea of the Umbelliferae plant method, is one of main effective components of traditional Chinese medicine radix angelicae, has a relative molecular mass of 286.28, and has a molecular structure shown in a formula (I):
in the prior art, very little research has been done on the pharmacological activity of oxypeucedanin. Studies have shown that oxidized peucedanin has pharmacological actions such as anti-inflammatory, antioxidant and inhibitory activities of acetylcholinesterase, BACE1 (beta-secretase) and the like (Mottaghipishah, javad. Oxypeerdine: chemoxomy, isolation, andgioactivites. Plant 10.8 (2021): 1577.), and oxidized peucedanin can inhibit NO production, TNF-alpha, IL-1 beta, IL-4 and other inflammatory factor release under lipopolysaccharide stimulation. The nerve inflammation and oxidative stress are involved in the pathological process after chronic cerebral hypoperfusion, BACE1 is an effective target point for AD treatment, and the acetylcholinesterase reversible inhibitor is widely used for treating neurodegenerative diseases. However, it has not been reported that oxidized decursin can improve cognitive defects caused by chronic cerebral hypoperfusion, and there is no report in the prior art that oxidized decursin can be used for treating vascular dementia.
Disclosure of Invention
The invention aims to solve the problems of low effectiveness, large adverse reaction and the like of vascular dementia treatment medicines in the prior art, and provides application of decursin in preparation of the vascular dementia treatment medicines.
The inventor adopts the oxypeucedanin as the only active ingredient to prepare the medicine for treating vascular dementia, the single administration dosage after molding is 20mg/kg in a rat bilateral common carotid artery ligation model, once daily administration is carried out for 28 continuous days, and the medicine can effectively relieve the situational memory defect caused by chronic cerebral hypoperfusion and the spatial learning memory disorder of hippocampal dependence and can improve the loss of hippocampal neurons to a certain extent. The rat bilateral common carotid artery ligation animal model employed in the present invention has been generally accepted internationally as a model of representative vascular dementia (Venkat, poornima, michael Chopp, and Jieli chen. "Models andmechanisms ofvascular dementia." Experimental neurology (2015): 97-108.).
The technical scheme of the invention is as follows:
use of decursin in the manufacture of a medicament for the treatment of vascular dementia, wherein decursin is the sole active ingredient. The inventor researches find that the decursin can effectively relieve the situational memory defect and the space learning memory disorder of the sea horse dependence caused by chronic cerebral hypoperfusion, and can improve the loss of sea horse neurons to a certain extent.
The decursin can be obtained in a commercial mode.
Vascular dementia described in the present invention includes chronic cerebral hypoperfusion-induced situational memory defects and hippocampal-dependent spatial learning memory disorders.
The medicine comprises the decursin and a pharmaceutically acceptable carrier.
In the medicine, the content of the decursin is 0.1-99wt%.
The medicament formulation of the invention is decoction, granules, tablets, pills, injection or the like, and is preferably injection.
When liquid formulations are used, they are generally used by intraperitoneal injection: the dosage of single administration after molding is 20mg/kg, once daily for 28 days.
The invention has the beneficial effects that: the invention discloses application of oxypeucedanin as the only active ingredient in preparing a medicament for treating vascular dementia, and the inventor researches and discovers that the oxypeucedanin can effectively relieve the situational memory defect caused by chronic cerebral hypoperfusion and the spatial learning memory disorder dependent on hippocampus, and can improve the loss of neurons of the hippocampus without causing adverse reaction basically, so the oxypeucedanin can be used as the only active ingredient for preparing the medicament for treating vascular dementia, and provides a new way for treating vascular dementia.
Drawings
FIG. 1 is a test result of the effect of chronic (repeated) administration of decursin oxide (20 mg/kg) on episodic memory deficit in chronic cerebral hypoperfusion rats;
FIG. 2 is a representative swim trace plot of groups of rats in a hidden platform test and a probe test;
FIG. 3 is escape latency test results for groups of rats in a hidden platform test;
FIG. 4 is the average swimming speed test results for each group of rats in the hidden platform test;
fig. 5 shows the results of the time spent, percent of travel, and number of passes across the platform in the target quadrant for each group of rats in the probe experiment.
FIG. 6 is a representative image of Nile staining of the CA1, CA2, CA3 regions of the hippocampus of each group of rats;
FIG. 7 is a statistical plot of the number of neurons in three regions of the hippocampus.
Detailed Description
The technical solution of the present invention will be clearly and completely described below with reference to the accompanying drawings and specific examples, and the following examples are given as detailed embodiments on the premise of the technical solution of the present invention, but the scope of protection of the present invention is not limited to the following examples.
In the following examples, the decursin used was, but not limited to, purity >98% as measured by HPLC, and was purchased from Shanghai Mo Ji Biotechnology Co., ltd.
Example 1: effect of chronic administration of oxidized peucedanum root 20mg/kg on episodic memory defect of chronic cerebral hypoperfusion rats
Grouping animals: male SD rats 32 (purchased from university of south through laboratory animal center); randomly dividing into 4 groups, namely a false operation group, a model building group, a decursin 20mg/kg dosage group and a positive medicine nimodipine 8mg/kg dosage group, wherein 8 decursin is used in each group. The sham operation group and the modeling group are given with 0.5% of sodium carboxymethyl cellulose (CMC-Na), the oxidized decursin and nimodipine are given by intraperitoneal injection, and the suspension injection is prepared by 0.5% of CMC-Na, and the administration volume is 10mL/kg.
Firstly, rats are adapted to laboratory environment for 3 days, and are alternately illuminated in 12 hours at the temperature of 24+/-1 ℃ and the humidity of 50-70%, so that diet and water are freely obtained.
The chronic cerebral hypoperfusion model or sham surgery was then established by bilateral carotid artery ligation in groups, as described in reference to (Liu, dan-Dan, et al, "CZ-7,a new derivative ofClaulansine F,ameliorates 2VO-induced vascular dementia in rats through a Nrf2-mediated antioxidant responses." Acta Pharmacologica Sinica 40.4 (2019): 425-440), i.e., one day of preoperative fasted, 100% oxygen mixed with 5% isoflurane at a flow rate of 5L/min in an animal induction chamber for anesthetizing rats, followed by maintenance of anesthesia using 3% isoflurane concentration, supine fixation. The cervical hair is shaved, the shaved area is disinfected with 75% medical alcohol, a 1.5-2cm midline incision is cut, a bilateral common carotid artery is exposed, carefully separated from the vagus nerve, two surgical knots spaced 0.5cm apart are made on each side of the common carotid artery with 4-0 silk threads, and a small incision is cut at the space to ensure that the vessel ligation is intact. The midline incision was sutured with a 6 nylon thread, sterilized with iodophor, and the rats were returned to the squirrel cage after awakening. The body temperature of the rat is maintained at 37.5+/-0.5 ℃ by using an animal heat preservation pad in the whole operation process and after operation until the rat wakes up, and the operation of the sham operation group is the same except that the blood vessel is not ligated. After the common carotid artery on both sides is completely blocked, the rat first shows transient convulsion, the body temperature is reduced, the respiration is slowed down, and the eversion and the reflection disappear; the early motion is reduced after operation, the hind limbs are splayed, and the hind limbs are ataxia, or crawl and turn; the operation is basically recovered after 7 days, and no obvious dyskinesia exists.
The administration was started the next day after the operation, once daily, and for 28 consecutive days. The number of active avoidance, latency and number of errors for each experimental group of rats was then tested using the shuttle box test method. Shuttle box experimental methods reference (mansource, mohammad Taghi, et al, "Neuroprotective effects oforal gallic acid against oxidative stress induced by 6-hydroxydopamine in rates," Food chemistry 138.2-3 (2013): 1028-1033.), specifically: rats were stroked for 1-5min daily 1-2 days prior to the experiment using a dark-avoidance shuttle tester (SA 222, jiangsu Sago Biotechnology limited, china) to eliminate their fear of experimenters. Training period of first day: rats were allowed to freely move in the test box for 5min to eliminate exploratory reflections. It was placed in the shuttle box shock zone, and light and beep were given for 20s and then 10s of electrical stimulation (current intensity 1 mA) was given. If the rat escapes to the safe area within the lighting lamp and sound 20s as an active avoidance response, the rat escapes to the safe area after the electric shock as a passive avoidance response. After several training, the rats develop an active avoidance condition response, thereby obtaining memory. Training was performed 30 times in total. The following day of formal test period: the rats were placed in the shuttle box electric shock zone, and the number of active avoidance, latency and error times were recorded during the same training period.
The statistical method adopts single factor analysis of variance, the comparison between groups adopts Turkey's multiple comparison test, and the test result is shown in figure 1. As can be seen from FIG. 1, the dose of 20mg/kg of decursin can significantly increase the shuttle times of the chronic cerebral hypoperfusion rats, reduce the error times and alleviate the situational memory defects to a certain extent.
Example 2: action of chronic administration of oxidized peucedanum 20mg/kg on hippocampal-dependent spatial learning memory disorder in chronic cerebral hypoperfusion rats
Grouping animals: male SD rats 40; the patients were randomly divided into 4 groups, namely a sham operation group, a model group, a dose group of 20mg/kg of decursinol and a dose group of 8mg/kg of nimodipine as a positive drug, 10 patients each. The sham operation group and the modeling group are given with 0.5 percent of sodium carboxymethyl cellulose (CMC-Na), the oxidized decursin and nimodipine are given by intraperitoneal injection, and the suspension injection is prepared by 0.5 percent of CMC-Na, and the administration volume is 10mL/kg.
Firstly, rats are adapted to laboratory environment for 3 days, and are alternately illuminated in 12 hours at the temperature of 24+/-1 ℃ and the humidity of 50-70%, so that diet and water are freely obtained. Then, according to the grouping, the bilateral common carotid artery ligation is performed to establish a rat chronic cerebral hypoperfusion model or a false operation, and the operation method is the same as the previous one. The administration was started the next day after the operation, once daily, and for 28 consecutive days. Morris water maze test was then performed.
Morris water maze test reference (Vorhees, charles V., and Michael T.Williams. "Morris water maze: procedures for assessing spatial and related forms of learning and memory." Nature protocols 1.2 (2006): 848-858.): in the hidden platform test, 4 quadrants each 1 time per day, rats were trained to find the hidden platform (10 cm diameter, submerged 1.5cm below the water surface, placed in the middle of a quadrant) for 5 consecutive days. In each trial, rats were given up to 120s to find the underwater platform, and if not found within 120s, the training was terminated and the time each rat reached the hidden platform was recorded as the escape latency of its spatial learning. On day 6 probe test, the platform was removed and spatial memory was assessed. Each rat was placed in the middle of the opposite quadrant of the quadrant in which the platform was located, allowed to swim freely for 120s, and the time spent, the percentage of the journey, and the number of passes through the platform were recorded in the target quadrant in which the platform was located.
The results are shown in FIGS. 2-5:
FIG. 2 is a representative swim trace plot of groups of rats in a hidden platform test and a probe test; fig. 3 shows escape latency test results of rats in each group in the hidden platform test, fig. 4 shows average swimming speed test results of rats in each group in the hidden platform test, analysis of variance is repeatedly measured by adopting two factors, multiple comparison tests of Dunnett's are adopted in comparison among groups, and it can be seen that the escape latency of chronic cerebral hypoperfusion rats can be obviously reduced by using the dose of 20mg/kg of decursin on days 2, 4 and 5. All square data points filled with black represent statistical significance (P < 0.05) compared to sham surgery groups; the other data points filled in black represent statistical significance (P < 0.05) compared to the model set. There was no significant difference in average swimming speed for each group of rats, indicating that modeling did not have an effect on athletic ability.
FIG. 5 shows the results of the test of time spent, percent of travel, and number of passes across the platform in the target quadrant for each group of rats in the probe trial using one-way anova for statistical methods, turkey's multiple comparison test for group-to-group comparisons, kraskal-Wallis test for number of passes across the platform, dunn's multiple comparison test for group-to-group comparisons. It can be found that the dose of 20mg/kg of decursin can significantly increase the time spent by the chronic cerebral hypoperfusion rats in the target quadrant, the percentage of the journey and the number of times of crossing the platform, and in conclusion, decursin improves the spatial learning and memory disorder of the chronic cerebral hypoperfusion rats depending on the hippocampus to a certain extent.
Example 3: effect of chronic administration of oxidized peucedanum element 20mg/kg on loss of neurons in chronically cerebral hypoperfusion rats
Animals were grouped and dosed as in example 2, after the end of the behavioural test, all rats were deeply anesthetized with pentobarbital sodium, and perfused with 200ml ice-cold physiological saline and 4% paraformaldehyde via the heart, the brains were removed and placed overnight in 4% paraformaldehyde, and frozen sections of 25 μm thickness were prepared after gradient dehydration with 20%, 30% sucrose solution.
Nile stain reference (Pilati, nadia et al, "A rapid method combining Golgi and Nissl staining to study neuronal morphology and cytoarchimect." Journal ofHistochemistry)&Cytochemistry 56.6 (2008): 539-550.), specifically 0.05%Triton 15min*3, picking, etc. dry; nib dye liquor for 10min; ddH 2 O5 sec 2;90% ethanol 10min x 2;100% ethanol 10min x 2; xylene 10min x 2; and (5) sealing the piece. Observations and scans were made using a nikon microscope.
The statistical method adopts single factor analysis of variance, the comparison among groups adopts Turkey's multiple comparison test, the results are shown in fig. 6-7, fig. 6 is a Nib staining representative image of CA1, CA2 and CA3 areas of the rat hippocampus of each group, fig. 7 is a statistical chart of the number of neurons in three areas of the hippocampus, and it can be seen that the loss of neurons in CA1, CA2 and CA3 areas of the chronic cerebral hypoperfusion rat can be obviously reduced by the use of the oxidized peucedanin with the dosage of 20 mg/kg.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples. Any other modifications which do not depart from the spirit and principles of the invention should be construed as being included within the scope of the invention.
Claims (7)
1. The use of decursin in the manufacture of a medicament for the treatment of vascular dementia, characterized in that decursin is the only active ingredient in the medicament.
2. The use according to claim 1, wherein said vascular dementia comprises chronic cerebral hypoperfusion-induced situational memory defects and hippocampal-dependent spatial learning memory disorders.
3. The use of claim 1, wherein the medicament comprises oxidized peucedanum element and a pharmaceutically acceptable carrier.
4. The use according to claim 1, wherein the content of decursin in the medicament is 0.1-99wt%.
5. The use according to claim 1 or 2 or 3 or 4, wherein the medicament is in the form of a decoction, a granule, a tablet, a pill or an injection.
6. The use according to claim 5, wherein the medicament is in the form of an injection.
7. The use according to claim 6, wherein the medicament is administered intraperitoneally, and wherein the single dose after molding is 20mg/kg, once daily, for 28 consecutive days.
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