Traditional Chinese medicine composition for treating cognitive impairment of Parkinson's disease and application thereof

Abstract

The invention relates to the field of traditional Chinese medicine, and discloses a traditional Chinese medicine composition for treating cognitive impairment of Parkinson's disease and application thereof.The traditional Chinese medicine composition is prepared from, by weight, 180-220 parts of vinegar tortoise plastron, 90-110 parts of morinda officinalis, 90-110 parts of angelica sinensis, 90-110 parts of radix curcumae, 55-65 parts of rhizoma acori graminei, 55-65 parts of polygala tenuifolia, 180-220 parts of calcined dragon bone, 180-220 parts of caulis spatholobi and 1-3 parts of borneol. When all the medicines of the traditional Chinese medicine composition are combined, the compatibility of monarch, minister, assistant and guide is performed, so that the traditional Chinese medicine composition has the effects of tonifying kidney, promoting blood circulation, dispersing blood stasis and inducing resuscitation, can relieve cognitive impairments such as space navigation, space exploration, working memory and the like of a Parkinson's disease cognitive impairment model mouse caused by chronic hypoperfusion, and realizes the treatment effect on the Parkinson's disease cognitive impairment; good application prospects are realized.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of traditional Chinese medicine, and particularly relates to a traditional Chinese medicine composition for treating cognitive impairment of Parkinson's disease and application thereof. BACKGROUND

[0002] Parkinson's disease is a common neurodegenerative disease, which not only causes motor disorders such as tremor, muscle rigidity and bradykinesia in patients, but also causes severe cognitive impairment, including memory loss, attention deficit, executive dysfunction and the like, which greatly affects the quality of life of patients. Parkinson's disease patients with cognitive impairment are old and weak, and are prone to blood stasis. Blood stasis can cause cerebral collateral stenosis or obstruction, block the circulation of qi and blood, damage the brain marrow due to the lack of cerebral collateral, and then cause the clinical symptoms of cognitive impairment of Parkinson's disease such as mind not gathering, looking around and forgetting, holding and calculating difference, and slow thinking.

[0003] The key pathogenesis of Parkinson's disease is kidney qi deficiency and blood stasis, which leads to "cloistered spirit and spirit not guiding qi" after a long time, and thus causes cognitive impairment symptoms. Therefore, patients often have blood stasis blocking the collaterals.

[0004] Modern medical research has revealed the phenomenon and pathological mechanism of "blood stasis causing qi deficiency and damaging brain marrow" of Parkinson's disease cognitive impairment. Epidemiological studies have found that the severity of factors such as chronic hypoperfusion, cerebrovascular disease, unstable blood pressure and orthostatic hypotension are closely related to the cognitive function of Parkinson's disease. Such factors are similar to blood stasis caused by kidney qi deficiency in traditional Chinese medicine, which leads to the failure of qi and blood to run.

[0005] Therefore, it is imperative to develop a safe and effective traditional Chinese medicine composition for treating cognitive impairment of Parkinson's disease in view of the main pathogenesis of qi deficiency and blood stasis of Parkinson's disease cognitive impairment. SUMMARY

[0006] The present application provides a traditional Chinese medicine composition for treating cognitive impairment of Parkinson's disease and application thereof. The traditional Chinese medicine composition can relieve cognitive dysfunction such as spatial navigation, spatial exploration and working memory of a Parkinson's disease cognitive impairment model mouse caused by chronic hypoperfusion, and achieve the therapeutic effect on cognitive impairment of Parkinson's disease.

[0007] To achieve the above-mentioned application purposes, the technical solutions of the present application are as follows:

[0008] The present application provides a traditional Chinese medicine composition for treating cognitive impairment of Parkinson's disease, which is composed of the following raw medicinal materials by weight: vinegar turtle plate 180-220 parts, radix leonuri 90-110 parts, angelica 90-110 parts, radix curcumae 90-110 parts, rhizoma alpiniae 55-65 parts, polygala 55-65 parts, calcined dragon bone 180-220 parts, caulis spatholobi 180-220 parts, and borneol 1-3 parts.

[0009] The technical scheme of the Chinese medicine composition of the first aspect of the present application is adopted, the Chinese medicine composition is used to enhance the qi and blood, activate blood and remove blood stasis by using angelica, radix curcumae and caulis spatholobi, then radix morindae officinalis is used to supplement kidney yang qi, and borneol is used to guide the medicine into the brain marrow, open the orifice and awaken the spirit, so as to achieve the purpose of supplementing yin and yang, and the Chinese medicine composition has the effects of supplementing kidney and activating blood, removing blood stasis and awakening the spirit. Pharmacodynamic experiments show that the Chinese medicine composition can relieve the cognitive dysfunction of spatial navigation, spatial exploration and working memory of a Parkinson's disease cognitive impairment model mouse caused by chronic low perfusion, and realize the treatment effect on Parkinson's disease cognitive impairment.

[0010] The second aspect of the present application provides a preparation method for preparing the above-mentioned Chinese medicine composition, comprising the following steps:

[0011] The raw materials are weighed by weight parts, vinegar turtle plate and calcined bones are decocted with water to obtain a mixed solution, radix morindae officinalis, angelica, radix curcumae, atractylodes ovata, polygala and caulis spatholobi are added to the mixed solution, and water is added for decoction and extraction twice to obtain an extract; the two times of extract are combined, and borneol is added for dissolution after being concentrated under reduced pressure to a certain crude drug concentration to prepare the Chinese medicine composition.

[0012] The technical scheme of the preparation method of the second aspect of the present application is adopted, through step-by-step decoction and extraction, vinegar turtle plate and calcined bones are first decocted with water, because the two kinds of raw materials are relatively hard in texture, long-time decoction can make the effective components fully dissolved, then radix morindae officinalis, angelica and other remaining medicinal materials are added to the mixed solution for twice decoction, and the twice decoction can ensure that various components are extracted to the maximum extent, the preparation method is simple in process, is beneficial to the preparation of the Chinese medicine composition for treating Parkinson's disease cognitive impairment, and can effectively reduce the production cost of the medicine.

[0013] The third aspect of the present application provides a Chinese medicine preparation, which contains the above-mentioned Chinese medicine composition or the Chinese medicine composition prepared according to the above-mentioned preparation method.

[0014] The technical scheme of the Chinese medicine preparation of the third aspect of the present application has the effects of supplementing kidney and activating blood, removing blood stasis and awakening the spirit, can relieve the cognitive dysfunction of spatial navigation, spatial exploration and working memory of a Parkinson's disease cognitive impairment model mouse caused by chronic low perfusion, and realize the treatment effect on Parkinson's disease cognitive impairment.

[0015] The fourth aspect of the present application provides the application of the above-mentioned Chinese medicine composition or the Chinese medicine composition prepared according to the above-mentioned preparation method or the above-mentioned Chinese medicine preparation, which is applied to the preparation of a medicine for treating Parkinson's disease cognitive impairment.

[0016] The application of the fourth aspect of the present application improves chronic hypoperfusion caused by unilateral common carotid artery ligation of mice, and relieves cognitive dysfunction of the model mice with Parkinson's disease cognitive impairment caused by the chronic hypoperfusion, and realizes the treatment effect on Parkinson's disease cognitive impairment. BRIEF DESCRIPTION OF DRAWINGS

[0017] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings needed in the embodiment description will be briefly introduced. Obviously, the drawings in the following description are some embodiments of the present application, and other drawings can also be obtained by those skilled in the art without creative labor.

[0018] Figure 1 is a flowchart of the preparation method for preparing the traditional Chinese medicine composition for treating Parkinson's disease cognitive impairment provided by the embodiments of the present application;

[0019] Figure 2 is the weight monitoring result of the mice in each group in embodiment 7 of the present application;

[0020] Figure 3 is the serum liver function index detection result of the mice in each group in embodiment 7 of the present application, wherein, Fig. A: the content of serum ALP; Fig. B: the content of serum ALT; Fig. C: the content of serum AST; Fig. D: the content of serum TBIL; Fig. E: the content of serum DBIL; Fig. F: the content of serum IBIL; Fig. G: the content of serum TBA;

[0021] Figure 4 is the serum kidney function index detection result of the mice in each group in embodiment 7 of the present application, wherein, Fig. A: the content of serum UREA; Fig. B: the content of serum Cre; Fig. C: the content of serum UA;

[0022] Figure 5 is the cerebral perfusion and maximum blood flow velocity of the middle cerebral artery detection result of the mice in each group in embodiment 7 of the present application, wherein, Fig. A: the cerebral perfusion of the mice in each group; Fig. B: the maximum blood flow velocity of the middle cerebral artery of the mice in each group; compared with the WT group, * represents P<0.05, compared with the A53T+U group, ▲ represents P<0.05;

[0023] Figure 6 is the claw grip detection result of the mice in each group in embodiment 7 of the present application, wherein, Fig. A: the claw grip of the forelimbs of the mice in each group; Fig. B: the claw grip of the limbs of the mice in each group, compared with the WT group, * represents P<0.05;

[0024] Figure 7is the behavior performance result of each group of mice in the water maze spatial navigation test in Example 7 of the present application, wherein Figure A: escape latency on days 1-5; Figure B: percentage of time spent in the peripheral area on days 1-5, Figure C: average total distance on days 1-5; wherein compared with the WT group, * represents P<0.05, compared with the A53T+U group, ▲ represents P<0.05;

[0025] Figure 8 is the behavior performance result of each group of mice in the water maze spatial navigation test in Example 7 of the present application, wherein Figure A: escape latency on days 1-5; Figure B: percentage of time spent in the peripheral area on days 1-5, Figure C: average total distance on days 1-5; wherein compared with the WT group, * represents P<0.05, compared with the A53T+U group, ▲ represents P<0.05;

[0026] Figure 9 is the behavior performance result of each group of mice in the water maze spatial navigation test in Example 7 of the present application, wherein Figure A: escape latency on days 1-5; Figure B: percentage of time spent in the peripheral area on days 1-5, Figure C: average total distance on days 1-5; wherein compared with the WT group, * represents P<0.05, compared with the A53T+U group, ▲ represents P<0.05; DETAILED DESCRIPTION

[0027] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor fall within the scope of the present application.

[0028] The flowcharts shown in the drawings are only exemplary and do not necessarily include all contents and operations / steps, nor are they necessarily executed in the described order. For example, some operations / steps can be further decomposed, combined or partially merged, so the actual execution order can be changed according to the actual situation.

[0029] It should be understood that the terms used in the present application specification herein are only for the purpose of describing specific embodiments and are not intended to limit the present application. As used in the present application specification and the appended claims, unless otherwise clearly indicated by the context, the singular forms "a", "an" and "the" are intended to include the plural forms.

[0030] It should also be understood that the term "and / or" as used herein refers to any or all possible combinations of one or more of the associated listed items, and includes all possible combinations.

[0031] Some embodiments of the present application will be described in detail with reference to the drawings, which are shown by way of illustration. The following examples and features in the examples can be combined with each other in the case of no conflict.

[0032] The present application provides a traditional Chinese medicine composition for treating Parkinson's disease cognitive impairment, which is composed of the following raw medicinal materials by weight: vinegar turtle plate 180-220 parts, Ba Ji Tian 90-110 parts, Angelica 90-110 parts, Yujin 90-110 parts, Shichangpu 55-65 parts, Yuanzhi 55-65 parts, calcined Longgu 180-220 parts, Jixueteng 180-220 parts, and 1-3 parts of borneol.

[0033] It should be noted that each of the above traditional Chinese medicine raw materials can be adjusted within the given range of parts to achieve the best therapeutic effect by taking appropriate values according to the constitution and symptoms of patients with Parkinson's disease cognitive impairment.

[0034] Pharmacological analysis of the raw medicinal materials selected by the present application:

[0035] Vinegar turtle plate: a traditional Chinese medicine prepared by vinegar processing the carapace of the turtle Chinemys reevesii, which has the effects of nourishing yin and suppressing yang, strengthening muscles and bones, and its content may be, for example, 180 parts, 183 parts, 185 parts, 190 parts, 196 parts, 200 parts, 208 parts, 210 parts, 212 parts, 217 parts or 220 parts;

[0036] Ba Ji Tian: the dried root of the plant of the genus Radix Morindae Officinalis, which is sweet and pungent in taste, slightly warm in nature, and has the effects of tonifying kidney yang, strengthening muscles and bones, and dispelling wind and dampness, and its content may be, for example, 90 parts, 91 parts, 94 parts, 96 parts, 97 parts, 98 parts, 100 parts, 102 parts, 109 parts or 110 parts;

[0037] Angelica: a perennial herb of the genus Angelica, which is sweet and pungent in taste, warm in nature, and has the effects of tonifying blood, activating blood, regulating menstruation and relieving pain, moistening the intestines and promoting defecation, and its content may be, for example, 90 parts, 91 parts, 94 parts, 96 parts, 97 parts, 98 parts, 100 parts, 102 parts, 109 parts or 110 parts;

[0038] Yujin: the dried tuber of the plant of the genus Curcuma, which is pungent and bitter in taste, cold in nature, and has the effects of promoting qi circulation, relieving depression, cooling blood and removing stasis, and clearing the heart and promoting bile secretion, and its content may be, for example, 90 parts, 91 parts, 94 parts, 96 parts, 97 parts, 98 parts, 100 parts, 102 parts, 109 parts or 110 parts;

[0039] Aconiti Lateralis Radix Praeparata: the dried rhizome of Aconitum carmichaelii of the family Ranunculaceae, with a bitter and acrid taste and a slightly warm nature, has the functions of removing dampness to stimulate appetite, opening orifice to dissipate phlegm, and refreshing and invigorating the mind, and its content may be, for example, 55 parts, 56 parts, 58 parts, 59 parts, 60 parts, 62 parts, 63 parts, or 65 parts;

[0040] Polygalae Radix: the dried root of Polygala tenuifolia of the family Polygalaceae, with a bitter and acrid taste and a warm nature, has the functions of soothing the mind, communicating between heart and kidney, eliminating phlegm, and dissipating swelling, and its content may be, for example, 55 parts, 56 parts, 58 parts, 59 parts, 60 parts, 62 parts, 63 parts, or 65 parts;

[0041] Calcined Ossis Bezoar: the fossil of the bones of ancient large mammals such as elephants, three-toed horses, rhinoceroses, deer, and cattle, has the functions of calming the nerves, soothing the mind, stopping sweating, consolidating essence, stopping bleeding, astringing the intestines, and healing and astringing sores, and its content may be, for example, 180 parts, 183 parts, 185 parts, 190 parts, 196 parts, 200 parts, 208 parts, 210 parts, 212 parts, 217 parts, or 220 parts;

[0042] Lycium Fruit: the dried fruit of Lycium barbarum of the family Solanaceae, with a bitter and sweet taste and a warm nature, has the functions of nourishing the blood, invigorating the blood, and freeing the collaterals, and its content may be, for example, 180 parts, 183 parts, 185 parts, 190 parts, 196 parts, 200 parts, 208 parts, 210 parts, 212 parts, 217 parts, or 220 parts;

[0043] Borneolum Syntheticum: a colorless transparent or white translucent flaky crisp crystal, which is a natural crystalline compound separated from the resin of the Dipterocarpus tree, has the functions of opening all orifices, dissipating stagnation, removing nebula, clearing heat and dissipating toxin, and dissipating fire and detoxifying, and its content may be, for example, 1 part, 2 parts, or 3 parts.

[0044] The traditional Chinese medicine composition of the present application is reasonably matched, and is formed by adding Ba Ji Tian, Dang Gui, Yu Jin, JI Xue Teng and Bing Pian to the Kong Sheng Zhen Dan (vinegar turtle plate, calcined dragon bone, Shichangpu and Yuanzhi) in the "Bei Ji Qian Jin Yao Fang". Among them, the vinegar turtle plate tastes sweet and salty, belongs to the liver and kidney channels, and is a pure yin product, which is an essential medicine for filling kidney essence. Ba Ji Tian tastes sweet and pungent, also belongs to the liver and kidney channels, can tonify kidney yang and benefit essence-blood, and the two medicines are used together to generate yin and yang, tonify kidney yang and fill kidney essence, and are the monarch drug. Dang Gui and JI Xue Teng benefit blood and promote blood circulation, Yu Jin promotes blood circulation, and the three drugs are used together to promote blood circulation to remove blood stasis and promote blood circulation to transport kidney essence into the brain marrow, and are the ministerial drug. Heart governs spirit, calcined dragon bone and Yuanzhi benefit heart qi, calm the mind and tranquilize the spirit, and are the auxiliary drug. Shichangpu opens the orifices, awakens the spirit, benefits intelligence, and combines the functions of Bing Pian to open the orifices and guide the medicine into the brain marrow, and is the ministerial drug. The whole prescription tonifies yin and yang, tonifies kidney and removes blood stasis, and has the effects of tonifying kidney and promoting blood circulation, removing blood stasis and awakening the spirit. Pharmacological experiments show that the traditional Chinese medicine composition can improve chronic hypoperfusion caused by unilateral common carotid artery ligation, and relieve cognitive dysfunction such as spatial navigation, spatial exploration and working memory of Parkinson's disease cognitive impairment model mice caused by chronic hypoperfusion, indicating that the traditional Chinese medicine composition has a therapeutic effect on Parkinson's disease cognitive impairment.

[0045] In some embodiments, the present application provides a traditional Chinese medicine composition for treating Parkinson's disease cognitive impairment, which is composed of the following raw materials by weight: vinegar turtle plate 200 parts, Ba Ji Tian 100 parts, Dang Gui 100 parts, Yu Jin 100 parts, Shichangpu 60 parts, Yuanzhi 60 parts, calcined dragon bone 200 parts, JI Xue Teng 200 parts and Bing Pian 2 parts.

[0046] A large number of experimental studies have shown that this specific matching ratio can maximize the efficacy of each raw material, thereby achieving a more optimal therapeutic effect.

[0047] As shown in Figure 1 , the present application provides a preparation method for preparing a traditional Chinese medicine composition for treating Parkinson's disease cognitive impairment, which comprises steps S101 to S103.

[0048] Step S101, weigh each raw material by weight, and decoct vinegar turtle plate and calcined dragon bone with water to obtain a mixed solution.

[0049] Because the vinegar turtle plate and the calcined dragon bone have a relatively hard texture, long-time decoction can make the effective ingredients fully dissolved, so in the preparation process, the vinegar turtle plate and the calcined dragon bone are first decocted with water to obtain a mixed solution.

[0050] In some embodiments, vinegar turtle shell and calcined dragon bone are decocted with water, the decocting time is 1-1.5h, for example, the decocting time can be 1h, 1.1h, 1.2h, 1.3h, 1.4h or 1.5h, and the amount of water added is 10-12 times the weight of crude drugs, and the specific amount of water added can be 10 times, 11 times or 12 times the weight of crude drugs. By controlling the decocting time and the amount of water added, the extraction efficiency of the effective ingredients in the raw materials of vinegar turtle shell and calcined dragon bone is further improved.

[0051] Step S102, add radix pseudoginseng, angelica, radix notoginseng, atractylodes rhizome, milkvetch root and caulis perillae into the mixed solution, decoct and extract twice to obtain an extract.

[0052] Because the effective ingredients in traditional Chinese medicine raw materials are complex and diverse, including alkaloids, glycosides, flavonoids, volatile oils and other chemical substances, their solubility and release characteristics in solvents are different. During the first decoction, some water-soluble ingredients will quickly enter the solution, but some tightly combined or low-solubility ingredients will not be fully dissolved. Through the second decoction, these ingredients that were not completely extracted in the first decoction can be further released and dissolved, thereby improving the integrity and effectiveness of the extraction and ensuring that the content of various effective ingredients in the extract reaches a high level.

[0053] In some embodiments, in the two-time water decoction extraction, the first decoction time is 1-1.5h, for example, the first decoction time can be 1h, 1.1h, 1.2h, 1.3h, 1.4h or 1.5h, the first water added amount is 10-12 times the weight of crude drugs, for example, the first water added amount can be 10 times, 11 times or 12 times the weight of crude drugs, the second decoction time is 1-1.5h, for example, the second decoction time can be 1h, 1.1h, 1.2h, 1.3h, 1.4h or 1.5h, and the second water added amount is 10-12 times the weight of crude drugs, for example, the second water added amount can be 10 times, 11 times or 12 times the weight of crude drugs. By controlling the two-time decoction time and the two-time water added amount, the extraction efficiency of the effective ingredients in each raw material is further improved.

[0054] Step S103, combine the two-time extract, add ice flakes to the extract after reducing pressure and concentrating to a certain crude drug concentration, and prepare a traditional Chinese medicine composition.

[0055] The two-time extracts are combined to integrate the effective ingredients of the two-time decoction, ensuring that the composition contains comprehensive active substances of each raw material; the low-temperature evaporation is used in the reduced pressure concentration (lower than atmospheric pressure environment) to avoid the decomposition and destruction of heat-sensitive ingredients, thereby maximizing the retention of drug efficacy; the ice flakes have the effect of opening the orifices and refreshing the spirit, and the compatibility of the ice flakes with other medicinal materials in the prescription can enhance the effect of guiding drugs into the brain marrow and resolving stasis to refresh the spirit; the ice flakes are added to the concentrated solution and fully mixed to form a stable and uniform system, and finally the traditional Chinese medicine composition is prepared.

[0056] In some embodiments, the crude drug concentration is 2.00-2.50 g / ml or 6.50-7.00 g / ml. The crude drug concentration of 2.00-2.50 g / ml is a low dose concentration, for example, the low dose concentration can be 2.00 g / ml, 2.24 g / ml, 2.30 g / ml, 2.40 g / ml or 2.50 g / ml, which is mainly used for preliminary exploration of the minimum effective dose range of the drug, and also provides a reference for patients with different disease severity and individual tolerance differences; the crude drug concentration of 6.50-7.00 g / ml is a high dose concentration, for example, the high dose concentration can be 6.50 g / ml, 6.73 g / ml, 6.80 g / ml, 6.90 g / ml or 7.00 g / ml, and the pharmacodynamic experiment shows that the traditional Chinese medicine composition with high dose concentration has more significant effect on treating cognitive impairment of Parkinson's disease.

[0057] The preparation method of the present application extracts by step-by-step decoction, first decocting vinegar turtle plate and calcined dragon bone with water, because the two raw materials have hard texture, long-time decoction can make the effective components fully dissolved, then adding the remaining medicinal materials such as radix morindae officinalis and angelica into the mixed solution for secondary decoction, which can ensure that various components are extracted to the maximum extent. The preparation method is simple in process and is beneficial to the preparation of traditional Chinese medicine composition for treating cognitive impairment of Parkinson's disease, which can effectively reduce the production cost of the drug.

[0058] The present application provides a traditional Chinese medicine preparation, which contains the above-mentioned traditional Chinese medicine composition or is prepared according to the above-mentioned preparation method.

[0059] For example, the traditional Chinese medicine preparation can be in the form of liquid, which has the advantages of quick effect, high bioavailability, flexible dose adjustment, etc., without limitation.

[0060] The traditional Chinese medicine preparation of the present application has the effects of tonifying kidney and activating blood, removing blood stasis and awakening spirit, and can relieve the cognitive dysfunction of spatial navigation, spatial exploration and working memory of Parkinson's disease cognitive impairment model mice caused by chronic hypoperfusion, thereby achieving the therapeutic effect on Parkinson's disease cognitive impairment.

[0061] The present application provides the application of the above-mentioned traditional Chinese medicine composition, or the traditional Chinese medicine composition prepared according to the above-mentioned preparation method, or the above-mentioned traditional Chinese medicine preparation, which is applied to the preparation of a drug for treating cognitive impairment of Parkinson's disease.

[0062] In the pharmacodynamics experiment, a chronic hypoperfusion-induced Parkinson's disease cognitive impairment model mouse is established, and the cognitive function disorders such as spatial navigation, spatial exploration and working memory are detected to evaluate the therapeutic effect of the traditional Chinese medicine composition, the traditional Chinese medicine composition prepared according to the preparation method, or the traditional Chinese medicine preparation on Parkinson's disease cognitive impairment.

[0063] The pharmacodynamics experiment shows that the application can improve the chronic hypoperfusion caused by unilateral common carotid artery ligation, alleviate the cognitive function disorders such as spatial navigation, spatial exploration and working memory of the chronic hypoperfusion-induced Parkinson's disease cognitive impairment model mouse, and achieve the therapeutic effect on Parkinson's disease cognitive impairment.

[0064] The application provides a kind of traditional Chinese medicine composition for treating Parkinson's disease cognitive impairment and its application, which will be described in detail below through specific examples and experimental data.

[0065] Example 1

[0066] Please refer to Figure 1 , the raw material is weighed according to the weight part: vinegar turtle plate 200 parts, Ba Ji Tian 100 parts, Angelica 100 parts, Yujin 100 parts, Shichangpu 60 parts, Yuanzhi 60 parts, calcined dragon bone 200 parts, Jixueteng 200 parts, and 2 parts of borneol. The vinegar turtle plate and the calcined dragon bone are decocted with water, the decoction time is 1h, and the water amount is 10 times the weight of the crude drug, to obtain a mixed solution;

[0067] The Ba Ji Tian, Angelica, Yujin, Shichangpu, Yuanzhi and Jixueteng are added to the above-mentioned mixed solution, and the extraction is carried out twice with water, the first decoction time is 1h, the water amount is 10 times the weight of the crude drug, the second decoction time is 1h, and the second water amount is 10 times the weight of the crude drug, to obtain an extract;

[0068] The two extraction solutions are combined, concentrated under reduced pressure to contain 2.24g / ml of crude drug, and then mixed with borneol to obtain a traditional Chinese medicine composition, which contains a low-dose concentration of crude drug.

[0069] Example 2

[0070] Please refer to Figure 1 , the raw material is weighed according to the weight part: vinegar turtle plate 200 parts, Ba Ji Tian 100 parts, Angelica 100 parts, Yujin 100 parts, Shichangpu 60 parts, Yuanzhi 60 parts, calcined dragon bone 200 parts, Jixueteng 200 parts, and 2 parts of borneol. The vinegar turtle plate and the calcined dragon bone are decocted with water, the decoction time is 1h, and the water amount is 10 times the weight of the crude drug, to obtain a mixed solution;

[0071] Radix Morindae Officinalis, Angelica sinensis, Radix Anemarrhena Asphodeloidis, Polygala tenuifolia and Spatholobus suberectus were added into the above mixed solution, and water was added to extract twice. The first time of extraction was 1 h, and the amount of water was 10 times of the weight of raw medicine. The second time of extraction was 1 h, and the amount of water was 10 times of the weight of raw medicine. The extract was obtained.

[0072] The twice extracted solutions were combined, and concentrated under reduced pressure to contain 6.73 g / ml of raw medicine, and then menthol was added to dissolve. The traditional Chinese medicine composition was prepared, and the content of raw medicine was high dose concentration.

[0073] Example 3

[0074] Please refer to Figure 1 , the raw medicine was weighed by weight parts: 180 parts of vinegar turtle plate, 90 parts of Radix Morindae Officinalis, 90 parts of Angelica sinensis, 90 parts of Radix Anemarrhena Asphodeloidis, 55 parts of Polygala tenuifolia, 55 parts of Spatholobus suberectus, 180 parts of calcined dragon bone, 180 parts of Spatholobus suberectus, and 1 part of menthol. The vinegar turtle plate and the calcined dragon bone were added to water to extract, and the extraction time was 1 h. The amount of water was 10 times of the weight of raw medicine. The mixed solution was obtained.

[0075] Radix Morindae Officinalis, Angelica sinensis, Radix Anemarrhena Asphodeloidis, Polygala tenuifolia and Spatholobus suberectus were added into the above mixed solution, and water was added to extract twice. The first time of extraction was 1 h, and the amount of water was 10 times of the weight of raw medicine. The second time of extraction was 1 h, and the amount of water was 10 times of the weight of raw medicine. The extract was obtained.

[0076] The twice extracted solutions were combined, and concentrated under reduced pressure to contain 2.00 g / ml of raw medicine, and then menthol was added to dissolve. The traditional Chinese medicine composition was prepared, and the content of raw medicine was low dose concentration.

[0077] Example 4

[0078] Please refer to Figure 1 , the raw medicine was weighed by weight parts: 180 parts of vinegar turtle plate, 90 parts of Radix Morindae Officinalis, 90 parts of Angelica sinensis, 90 parts of Radix Anemarrhena Asphodeloidis, 55 parts of Polygala tenuifolia, 55 parts of Spatholobus suberectus, 180 parts of calcined dragon bone, 180 parts of Spatholobus suberectus, and 1 part of menthol. The vinegar turtle plate and the calcined dragon bone were added to water to extract, and the extraction time was 1 h. The amount of water was 10 times of the weight of raw medicine. The mixed solution was obtained.

[0079] Please refer to Figure 1 , Radix Morindae Officinalis, Angelica sinensis, Radix Anemarrhena Asphodeloidis, Polygala tenuifolia and Spatholobus suberectus were added into the above mixed solution, and water was added to extract twice. The first time of extraction was 1 h, and the amount of water was 10 times of the weight of raw medicine. The second time of extraction was 1 h, and the amount of water was 10 times of the weight of raw medicine. The extract was obtained.

[0080] The twice extracted solutions were combined, and concentrated under reduced pressure to contain 2.50 g / ml of raw medicine, and then menthol was added to dissolve. The traditional Chinese medicine composition was prepared, and the content of raw medicine was low dose concentration.

[0081] Example 5

[0082] Please refer to Figure 1 , each raw material is weighed by weight parts: vinegar turtle plate 220 parts, radix morindae officinalis 110 parts, angelica 110 parts, radix curcumae 110 parts, aconiti tuber 65 parts, polygala 65 parts, calcined oyster shell 220 parts, caulis paedilini 220 parts, and borneol 3 parts, the vinegar turtle plate and the calcined oyster shell are decocted with water, the decocting time is 1.5 h, and the water amount is 12 times the weight of the raw medicine, to obtain a mixed solution;

[0083] Radix morindae officinalis, angelica, radix curcumae, aconiti tuber, polygala and caulis paedilini are added to the above-mentioned mixed solution, and are decocted with water twice, the first decocting time is 1.5 h, the water amount is 12 times the weight of the raw medicine, the second decocting time is 1.5 h, and the second water amount is 12 times the weight of the raw medicine, to obtain an extract;

[0084] The twice extracts are combined, and are concentrated under reduced pressure to contain 6.50 g / ml of raw medicine, then borneol is added to dissolve, to prepare a traditional Chinese medicine composition, which contains high-dose concentration of raw medicine.

[0085] Example 6

[0086] Please refer to Figure 1 , each raw material is weighed by weight parts: vinegar turtle plate 220 parts, radix morindae officinalis 110 parts, angelica 110 parts, radix curcumae 110 parts, aconiti tuber 65 parts, polygala 65 parts, calcined oyster shell 220 parts, caulis paedilini 220 parts, and borneol 3 parts, the vinegar turtle plate and the calcined oyster shell are decocted with water, the decocting time is 1.5 h, and the water amount is 12 times the weight of the raw medicine, to obtain a mixed solution;

[0087] Radix morindae officinalis, angelica, radix curcumae, aconiti tuber, polygala and caulis paedilini are added to the above-mentioned mixed solution, and are decocted with water twice, the first decocting time is 1.5 h, the water amount is 12 times the weight of the raw medicine, the second decocting time is 1.5 h, and the second water amount is 12 times the weight of the raw medicine, to obtain an extract;

[0088] The twice extracts are combined, and are concentrated under reduced pressure to contain 7.00 g / ml of raw medicine, then borneol is added to dissolve, to prepare a traditional Chinese medicine composition, which contains high-dose concentration of raw medicine.

[0089] Example 7

[0090] Pharmacodynamic experiment

[0091] In order to explore the efficacy of the traditional Chinese medicine composition of the application on treating Parkinson's disease cognitive impairment, the application establishes a Parkinson's disease cognitive impairment model caused by chronic low perfusion of α-Syn A53T+ / - mice, and conducts behavior detection, liver function and kidney function detection and laser speckle analysis on the traditional Chinese medicine composition of the application, to evaluate the treatment effect on Parkinson's disease cognitive impairment.

[0092] 1. Experimental animals

[0093] The α-Syn A53T+ / -mice were purchased from Changzhou Cavens Experimental Animal Co., Ltd., and the animal qualification certificate number was NO. 202134209. The animals were bred in a quiet environment with a room temperature of about 22°C, day and night, and were allowed to drink water and eat freely. The male and female α-Syn A53T+ / -mice were mated, and the genotypes were identified when the young mice were 1 month old. Forty 9-month-old mice were selected for the experiment, including 10 wild-type mice and 30 α-Syn A53T+ / -mice.

[0094] 2. Animal grouping, modeling, and drug administration

[0095] Ten wild-type mice were used as the WT group, and the 30 α-Syn A53T+ / -mice were randomly divided into 3 groups, each group of 10, namely the A53T+U group, the High JWKSZZD group, and the Low JWKSZZD group.

[0096] The modeling and drug administration methods of each group were as follows:

[0097] WT group: The wild-type mice received sham operation of unilateral common carotid artery ligation and were given distilled water by gavage at a dose of 0.1 ml / kg;

[0098] A53T+U group: The α-Syn A53T+ / -mice received sham operation of unilateral common carotid artery ligation and were given distilled water by gavage at a dose of 0.1 ml / kg;

[0099] High JWKSZZD group: The α-Syn A53T+ / -mice were first given the traditional Chinese medicine composition prepared in Example 2 by gavage once a day for 2 weeks at a dose of 0.1 ml / kg, then received sham operation of unilateral common carotid artery ligation, and were given the traditional Chinese medicine composition prepared in Example 2 by gavage once a day for 4 weeks after the operation;

[0100] Low JWKSZZD group: The α-Syn A53T+ / -mice were first given the traditional Chinese medicine composition prepared in Example 1 by gavage once a day for 2 weeks at a dose of 0.1 ml / kg, then received sham operation of unilateral common carotid artery ligation, and were given the traditional Chinese medicine composition prepared in Example 1 by gavage once a day for 4 weeks after the operation.

[0101] 3. Behavioral detection

[0102] 3.1 Animal weight monitoring: The body weights of the mice in each group were recorded on the first day of the experiment, and then the body weights were measured once a week.

[0103] 3.2 Grip strength test

[0104] When testing the forelimb and limb grip strength of mice using a mouse grip strength tester, first zero the instrument, place the mouse on the bar of the grip strength tester so that its forelimbs or limbs tightly grasp the force bar, then grasp the mouse tail and pull it straight in the horizontal direction, and when the mouse loses grip, the instrument automatically records the maximum grip value. The forelimb and limb grip strength of each mouse is measured 3 times, and the maximum value is taken as the final value.

[0105] 3.3 Morris water maze experiment

[0106] Before the experiment, a Morris water maze pool with a diameter of 120 cm is filled with an appropriate amount of water, the water temperature is maintained at 25°C or room temperature, an appropriate amount of white pigment is added and mixed to make the water uniformly milky white, the platform is placed 1-2 cm under the water so that it is not visible, and in the analysis system, the center of the pool is taken as the reference point to divide the area into 4 equal quadrants. The area from 15 cm to the pool wall is designated as the peripheral area, and 4 different patterned labels are pasted on the pool walls of the 4 quadrants.

[0107] Spatial navigation test: On days 1-5, the mice were allowed to enter the water from the 4 quadrants, and given 90s to find the platform. Once found, they were required to stay on the platform for 15s. If the mouse did not find the platform within 90s, the experimenter guided it to the platform and also stayed for 15s. The escape latency of the mouse (i.e. the time to find the platform) was recorded, as well as the time spent in the peripheral area and the total distance.

[0108] Spatial exploration test: On day 6, the platform was removed and the mice were allowed to enter the water from the opposite quadrant of the quadrant where the platform was located. The number of times the mouse crossed the platform in 90s, the time spent in the platform quadrant, the time spent in the peripheral area, the total distance, and the average speed were recorded.

[0109] Working memory test: On days 7-9, the platform was moved to the next quadrant in the clockwise direction each day, and 5 different entry points were set each day. The first time was an adaptation test, and the data from the 2nd to 5th times were used for analysis. Each observation time was 90s. If the mouse found the new platform, it stayed for 15s. If the mouse could not find the platform, it was manually guided to the new platform and stayed for 15s. Then the mouse was placed in the original cage for 1 min, and then taken out and placed in the 2nd entry point for further testing. Finally, the average escape latency and the time spent in the platform quadrant on days 7-9 were calculated.

[0110] 4. Liver function and kidney function test

[0111] Twenty-four hours after the behavioral tests were completed, mice were anesthetized with isoflurane, their skin was prepared, and blood was collected via the abdominal main vein. After centrifugation at 12000 x g for 10 min, the serum was separated, and the following indicators were detected using a fully automated biochemical analyzer: alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), total bile acid (TBA), urea (UREA), creatinine (Cre), and uric acid (UA).

[0112] 5. Laser speckle analysis

[0113] Mice were anesthetized with isoflurane, their hair was shaved, their scalps were cut open to expose the skull, and the skull was focused. The instrument parameters were set as follows: image resolution 2048×2048, duration 12s, pseudo-color threshold for low cerebral blood flow perfusion 62, pseudo-color threshold for high cerebral blood flow perfusion 650, and laser intensity 110mW. After observing and calculating the average cerebral blood flow perfusion, the mouse scalp was sutured with 3-0 sutures.

[0114] 6. Experimental Results

[0115] 6.1 Oral administration of low-dose and high-dose concentrations of the traditional Chinese medicine composition did not affect the body weight, liver function, or kidney function of mice.

[0116] like Figure 2 As shown, during the experiment, the body weight of mice in the WT group, A53T+U group, Low JWKSZZD group and High JWKSZZD group all showed a gradual increasing trend, but there was no significant difference between the groups (P>0.05). This indicates that neither low-dose nor high-dose concentration of the traditional Chinese medicine composition affected the body weight of the mice, suggesting that under the intervention of low-dose and high-dose concentration of the traditional Chinese medicine composition, the mice's food intake and defecation were normal.

[0117] like Figures 3-4As shown, compared with the WT group and the A53T+U group, the contents of ALP, ALT, AST, TBIL, DBIL, IBIL, TBA, UREA, Cre and UA in the serum of mice in the Low JWKSZZD group and the High JWKSZZD group had no significant difference (P>0.05), which indicated that taking the low-dose and high-dose concentration of the traditional Chinese medicine composition would not cause damage to the liver and kidney functions, and suggested that the low-dose and high-dose concentration of the traditional Chinese medicine composition had good safety in treating cognitive impairment of Parkinson's disease.

[0118] 6.2 The low-dose and high-dose concentration of the traditional Chinese medicine composition can improve chronic hypoperfusion caused by unilateral common carotid artery ligation.

[0119] The cerebral blood perfusion of mice in each group was evaluated by laser speckle analysis, and the results were as shown in Figure 5 As shown, compared with the WT group, the cerebral blood perfusion of mice in the A53T+U group, the Low JWKSZZD group and the High JWKSZZD group was reduced, and the difference was statistically significant (P<0.05). In addition, the cerebral blood perfusion of mice in the Low JWKSZZD group and the High JWKSZZD group was higher than that in the A53T+U group, but only the High JWKSZZD group had a statistically significant difference (P<0.05). Meanwhile, compared with the A53T+U group, the Low JWKSZZD group and the High JWKSZZD group could improve the blood flow velocity of the middle cerebral artery of mice, but only the High JWKSZZD group had a statistically significant difference (P<0.05). The above results indicated that unilateral common carotid artery ligation for 4 weeks could form stable chronic hypoperfusion, and the low-dose and high-dose concentration of the traditional Chinese medicine composition could improve the blood stasis caused by chronic hypoperfusion due to unilateral common carotid artery ligation, and the high-dose concentration of the traditional Chinese medicine composition was better than the low-dose concentration of the traditional Chinese medicine composition.

[0120] 6.3 The low-dose and high-dose concentration of the traditional Chinese medicine composition can relieve cognitive dysfunction such as spatial navigation, spatial exploration and working memory of the model mice of Parkinson's disease cognitive impairment caused by chronic hypoperfusion.

[0121] As shown in Figure 6 In the grip strength test, compared with the WT group, the forelimb grip strength of mice in the A53T+U group and the Low JWKSZZD group was significantly decreased, although the forelimb grip strength of mice in the High JWKSZZD group was significantly higher than that in the A53T+U group, but the difference was not statistically significant (P>0.05). In addition, in the aspect of four limb grip strength, there was no significant difference in the grip strength of mice in the four groups (P>0.05). The above results indicated that the low-dose and high-dose concentration of the traditional Chinese medicine composition could not effectively improve the decrease of grip strength caused by chronic hypoperfusion.

[0122] AsFigure 7 As shown in the figure, in the water maze spatial navigation test, the escape latency of WT group, High JWKSZZD group and Low JWKSZZD group mice showed a downward trend on the 1st-5th day, while the escape latency of A53T+U group mice was still longer. Statistics showed that compared with the WT group, the escape latency of A53T+U group on the 1st-5th day was significantly prolonged, and the difference was statistically significant (P<0.05). Compared with the A53T+U group, the escape latency of High JWKSZZD group and Low JWKSZZD group mice on the 3rd, 4th and 5th day was significantly shortened, and the difference was statistically significant (P<0.05).

[0123] At the same time, in the spatial navigation test on the 1st-5th day, the percentage of time spent in the peripheral area of WT group, High JWKSZZD group and Low JWKSZZD group mice showed a gradual downward trend, while A53T+U group mice still maintained a high level during the 5-day training period. Compared with the WT group, the percentage of time spent in the peripheral area of A53T+U group and Low JWKSZZD group mice on the 4th and 5th day was significantly increased, and the difference was statistically significant (P<0.05). Compared with the A53T+U group, the percentage of time spent in the peripheral area of High JWKSZZD group mice on the 2nd and 5th day was significantly reduced, and the difference was statistically significant (P<0.05). In addition, in the spatial navigation test on the 1st-5th day, the average total distance of A53T+U group mice was significantly higher than that of the WT group, and the difference was statistically significant (P<0.05).

[0124] As Figure 8 shown, in the spatial exploration test on the 6th day, the number of times crossing the platform of High JWKSZZD group mice was significantly more than that of A53T+U group, and the difference was statistically significant (P<0.05), but the low dose group (Low JWKSZZD) failed to significantly increase the number of times crossing the platform. The change trend of the percentage of time spent in the platform quadrant was consistent with the number of times crossing the platform. Although the percentage of time spent in the peripheral area of High JWKSZZD group and Low JWKSZZD group mice was lower than that of A53T+U group, the difference was not statistically significant (P>0.05). There was no significant difference in total distance and average speed among the four groups of mice (P>0.05).

[0125] As Figure 9As shown, compared with the WT group, the A53T+U group mice had significantly prolonged average escape latency and significantly reduced percentage of time spent in the platform quadrant in the working memory test on days 7-9, and the difference was statistically significant (P<0.05). Compared with the A53T+U group, the High JWKSZZD group and the Low JWKSZZD group mice had significantly shortened average escape latency and significantly increased percentage of time spent in the platform quadrant, and the difference was statistically significant (P<0.05).

[0126] The above results show that the low-dose and high-dose concentrations of the traditional Chinese medicine composition cannot improve the decrease in paw grip strength caused by chronic hypoperfusion, but can alleviate the cognitive dysfunction such as spatial navigation, spatial exploration and working memory of the model mice of Parkinson's disease caused by chronic hypoperfusion. Among them, the high-dose concentration of the traditional Chinese medicine composition is better than the low-dose concentration of the traditional Chinese medicine composition.

Claims

1. A traditional Chinese medicine composition for treating Parkinson's disease cognitive impairment, characterized in that, The traditional Chinese medicine composition is composed of the following raw medicinal materials in parts by weight: vinegar turtle plate 180-220 parts, Ba Ji Tian 90-110 parts, Dang Gui 90-110 parts, Yu Jin 90-110 parts, Shihongpu 55-65 parts, Yuanzhi 55-65 parts, calcined Longgu 180-220 parts, Jixueteng 180-220 parts, and Bingpian 1-3 parts.

2. The traditional Chinese medicine composition for treating Parkinson's disease cognitive impairment according to claim 1, characterized in that, The traditional Chinese medicine composition is composed of the following raw medicinal materials in parts by weight: vinegar turtle plate 200 parts, Ba Ji Tian 100 parts, Dang Gui 100 parts, Yu Jin 100 parts, Shihongpu 60 parts, Yuanzhi 60 parts, calcined Longgu 200 parts, Jixueteng 200 parts, and Bingpian 2 parts.

3. A preparation method of the traditional Chinese medicine composition for treating cognitive impairment of Parkinson's disease according to claim 1 or 2, characterized in that, The method comprises the following steps: The raw medicinal materials are weighed, and the vinegar turtle plate and the calcined Longgu are decocted with water to obtain a mixed solution; The Ba Ji Tian, the Dang Gui, the Yu Jin, the Shihongpu, the Yuanzhi, and the Jixueteng are added to the mixed solution, and are decocted and extracted twice with water to obtain an extract; The two extract solutions are combined, and are concentrated under reduced pressure to a certain raw medicinal material concentration, and then the Bingpian is added to dissolve, to obtain the traditional Chinese medicine composition.

4. The method for preparing the traditional Chinese medicine composition for treating cognitive impairment in Parkinson's disease according to claim 3, characterized in that, In the step of decocting the vinegar turtle plate and the calcined Longgu with water, the decocting time is 1-1.5 h, and the amount of water added is 10-12 times the weight of the raw medicinal materials.

5. The method for preparing the traditional Chinese medicine composition for treating cognitive impairment in Parkinson's disease according to claim 3, characterized in that, In the step of decocting and extracting twice with water, the first decocting time is 1-1.5 h, the amount of water added is 10-12 times the weight of the raw medicinal materials, the second decocting time is 1-1.5 h, and the amount of water added in the second time is 10-12 times the weight of the raw medicinal materials.

6. The method for preparing the traditional Chinese medicine composition for treating cognitive impairment in Parkinson's disease according to claim 3, characterized in that, The certain raw medicinal material concentration is 2.00-2.50 g / ml of raw medicinal material content or 6.50-7.00 g / ml of raw medicinal material content.

7. A traditional Chinese medicine preparation, characterized in that, The traditional Chinese medicine preparation comprises the traditional Chinese medicine composition of claim 1 or 2, or the traditional Chinese medicine composition prepared according to the preparation method of any one of claims 3-6.

8. Use of the traditional Chinese medicine composition as claimed in claim 1 or 2, or the traditional Chinese medicine composition prepared by the preparation method as claimed in any one of claims 3-6, or the traditional Chinese medicine preparation as claimed in claim 7, characterized in that, The application is applied to the preparation of a medicine for treating cognitive impairment of Parkinson's disease.

Images