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

Abstract

This invention relates to the field of traditional Chinese medicine and discloses a traditional Chinese medicine composition for treating cognitive impairment in Parkinson's disease and its application. The traditional Chinese medicine composition consists of the following raw materials in parts by weight: 180-220 parts of vinegar-processed tortoise shell, 90-110 parts of Morinda officinalis, 90-110 parts of Angelica sinensis, 90-110 parts of Curcuma longa, 55-65 parts of Acorus tatarinowii, 55-65 parts of Polygala tenuifolia, 180-220 parts of calcined dragon bone, 180-220 parts of Spatholobus suberectus, and 1-3 parts of borneol. When the various herbs in this traditional Chinese medicine composition are used together, they are combined in a principal-assistant-adjuvant-guide manner, which has the effects of tonifying the kidney, activating blood circulation, removing blood stasis, and refreshing the mind. It can alleviate cognitive impairments such as spatial navigation, spatial exploration, and working memory in Parkinson's disease cognitive impairment model mice caused by chronic hypoperfusion, and achieve a therapeutic effect on Parkinson's disease cognitive impairment, showing good application prospects.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine, specifically relating to a traditional Chinese medicine composition for treating cognitive impairment in Parkinson's disease and its application. Background Technology

[0002] Parkinson's disease, a common neurodegenerative disorder, not only causes motor disorders such as tremor, rigidity, and bradykinesia, but also leads to severe cognitive impairment, including memory loss, poor concentration, and executive dysfunction, significantly impacting patients' quality of life. Many Parkinson's patients with cognitive impairment are elderly and frail, making them prone to blood stasis. This blood stasis can lead to narrowing or blockage of the brain's blood vessels, obstructing the flow of qi and blood, resulting in insufficient blood supply to the brain and damage to the brain marrow. Clinically, this manifests as symptoms of Parkinson's cognitive impairment such as difficulty concentrating, forgetfulness, poor calculation skills, and slowed thinking.

[0003] Ren Jixue, Zhou Zhongying, and Wang Yongyan, all masters of traditional Chinese medicine, also believe that the key pathogenesis of Parkinson's disease is kidney qi deficiency and blood stasis, which over time leads to "the orifices being blocked and the spirit being hidden, and the spirit not guiding the qi," thus resulting in cognitive impairment symptoms. Therefore, patients often have symptoms of blood stasis obstructing the collaterals.

[0004] Modern medical research has, to some extent, revealed the phenomenon and pathological mechanism of "blood stasis leading to qi deficiency and damage to the brain and marrow" in 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 is closely related to cognitive function in Parkinson's disease. These factors are similar to the blood stasis caused by kidney qi deficiency in traditional Chinese medicine, which fails to promote the circulation of qi, blood, and body fluids.

[0005] Therefore, it is imperative and urgent to develop safe and effective traditional Chinese medicine compositions for treating cognitive impairment in Parkinson's disease, targeting the main pathogenesis of qi deficiency and blood stasis. Summary of the Invention

[0006] This invention provides a traditional Chinese medicine composition for treating cognitive impairment in Parkinson's disease and its application. This traditional Chinese medicine composition can alleviate cognitive impairments such as spatial navigation, spatial exploration, and working memory in a mouse model of Parkinson's disease cognitive impairment caused by chronic hypoperfusion, thereby achieving a therapeutic effect on cognitive impairment in Parkinson's disease.

[0007] To achieve the above-mentioned objectives, the technical solution of the present invention is as follows:

[0008] The first aspect of this invention provides a traditional Chinese medicine composition for treating cognitive impairment in Parkinson's disease, the composition comprising the following raw materials in parts by weight: 180-220 parts of vinegar-processed tortoise shell, 90-110 parts of Morinda officinalis, 90-110 parts of Angelica sinensis, 90-110 parts of Curcuma longa, 55-65 parts of Acorus tatarinowii, 55-65 parts of Polygala tenuifolia, 180-220 parts of calcined dragon bone, 180-220 parts of Spatholobus suberectus, and 1-3 parts of borneol.

[0009] The technical solution of the traditional Chinese medicine composition adopted in the first aspect of the present invention uses Angelica sinensis, Curcuma longa, and Spatholobus suberectus to enhance the effects of promoting qi circulation, nourishing blood, and removing blood stasis. Then, Morinda officinalis is added to tonify the yang qi of the kidney, and borneol is added to guide the medicine into the brain marrow, open the orifices and refresh the mind, thereby achieving the purpose of tonifying yin and yang. It has the effects of tonifying the kidney, promoting blood circulation, removing blood stasis and refreshing the mind. Pharmacological experiments show that the traditional Chinese medicine composition can alleviate the cognitive impairment of spatial navigation, spatial exploration and working memory in Parkinson's disease cognitive impairment model mice caused by chronic hypoperfusion, and achieve the therapeutic effect on Parkinson's disease cognitive impairment.

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

[0011] Weigh each raw material according to the weight proportions. Add vinegar-processed tortoise shell and calcined dragon bone to water and decoct to obtain a mixed solution. Add Morinda officinalis, Angelica sinensis, Curcuma longa, Acorus tatarinowii, Polygala tenuifolia and Spatholobus suberectus to the mixed solution, decoct with water twice to obtain an extract. Combine the two extracts, concentrate under reduced pressure to a certain concentration of raw herbs, and then add borneol to mix and obtain a traditional Chinese medicine composition.

[0012] The preparation method of the second aspect of this invention involves a step-by-step decoction extraction. First, vinegar-processed tortoise shell and calcined dragon bone are decocted with water. Since these two raw materials are relatively hard, prolonged decoction allows the effective components to dissolve fully. Then, other medicinal materials such as Morinda officinalis and Angelica sinensis are added to the mixed solution for a second decoction. This second decoction ensures that all components are extracted to the maximum extent. This preparation method is simple and beneficial for preparing traditional Chinese medicine compositions for treating cognitive impairment in Parkinson's disease, effectively reducing the production cost of the drug.

[0013] A third aspect of the present invention provides a traditional Chinese medicine preparation containing the above-mentioned traditional Chinese medicine composition, or a traditional Chinese medicine composition prepared according to the above-mentioned preparation method.

[0014] The traditional Chinese medicine preparation of the third aspect of the present invention has the effects of tonifying the kidney and promoting blood circulation, removing blood stasis and refreshing the mind. It can alleviate the cognitive impairments such as spatial navigation, spatial exploration and working memory in mice with Parkinson's disease cognitive impairment caused by chronic hypoperfusion, and achieve the therapeutic effect on Parkinson's disease cognitive impairment.

[0015] The fourth aspect of this invention provides for 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, in the preparation of a drug for treating cognitive impairment in Parkinson's disease.

[0016] Using the technical solution of the fourth aspect of the present invention, pharmacodynamic experiments show that the application can improve chronic hypoperfusion caused by unilateral common carotid artery ligation in mice, and alleviate cognitive impairments such as spatial navigation, spatial exploration and working memory in Parkinson's disease cognitive impairment model mice caused by chronic hypoperfusion, thereby achieving a therapeutic effect on Parkinson's disease cognitive impairment. Attached Figure Description

[0017] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the following description of the embodiments will be briefly introduced. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0018] Figure 1 This is a schematic flowchart of a method for preparing a traditional Chinese medicine composition for treating cognitive impairment in Parkinson's disease, provided in an embodiment of the present invention.

[0019] Figure 2 These are the weight monitoring results of each group of mice in Example 7 of this invention;

[0020] Figure 3 These are the serum liver function index detection results of mice in each group in Example 7 of the present invention, wherein, Figure A: serum ALP content; Figure B: serum ALT content; Figure C: serum AST content; Figure D: serum TBIL content; Figure E: serum DBIL content; Figure F: serum IBIL content; Figure G: serum TBA content;

[0021] Figure 4 These are the serum renal function index detection results of mice in each group in Example 7 of the present invention, wherein Figure A: serum UREA content; Figure B: serum Cre content; Figure C: serum UA content;

[0022] Figure 5 The figures show the results of cerebral blood perfusion and maximum blood flow velocity in the middle cerebral artery of mice in each group in Example 7 of this invention. Figure A shows the cerebral blood perfusion of each group of mice; Figure B shows the maximum blood flow velocity in the middle cerebral artery of each group of mice. * indicates P < 0.05 compared to the WT group, and * indicates P < 0.05 compared to the A53T+U group. ▲ This indicates that P < 0.05;

[0023] Figure 6 Figure A shows the claw gripping force of each group of mice in Example 7 of this invention. Figure B shows the claw gripping force of the forelimbs of each group of mice. Compared with the WT group, * indicates P < 0.05.

[0024] Figure 7The figures show the behavioral performance of mice in each group during the water maze spatial navigation test in Example 7 of this invention. Figure A shows the escape latency from day 1 to day 5; Figure B shows the percentage of time spent in the peripheral region from day 1 to day 5; and Figure C shows the average total distance from day 1 to day 5. * indicates P < 0.05 compared to the WT group, and * indicates P < 0.05 compared to the A53T+U group. ▲ This indicates that P < 0.05;

[0025] Figure 8 The figures show the behavioral results of each group of mice in the water maze spatial exploration test in Example 7 of this invention. Figure A shows the number of times the mice traversed the platforms; Figure B shows the percentage of time spent in the platform quadrants; Figure C shows the percentage of time spent in the peripheral areas; Figure D shows the total distance; and Figure E shows the average speed. * indicates P < 0.05 compared to the WT group, and * indicates P < 0.05 compared to the A53T+U group. ▲ This indicates that P < 0.05;

[0026] Figure 9 The figures show the behavioral performance of mice in each group during the water maze working memory test in Example 7 of this invention. Figure A shows the average escape latency; Figure B shows the percentage of time spent in the platform quadrant. * indicates P < 0.05 compared to the WT group, and * indicates P < 0.05 compared to the A53T+U group. ▲ This indicates that P < 0.05; Detailed Implementation

[0027] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0028] The flowchart shown in the attached diagram is for illustrative purposes only and does not necessarily include all content and operations / steps, nor does it necessarily have to be performed in the order described. For example, some operations / steps can be broken down, combined, or partially merged, so the actual execution order may change depending on the actual situation.

[0029] It should be understood that the terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the invention. As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” are intended to include the plural forms unless the context clearly indicates otherwise.

[0030] It should also be understood that the term “and / or” as used in this specification and the appended claims refers to any combination of one or more of the associated listed items and all possible combinations, and includes such combinations.

[0031] The following detailed description of some embodiments of the present invention is provided in conjunction with the accompanying drawings. Unless otherwise specified, the following embodiments and features can be combined with each other.

[0032] This invention provides a traditional Chinese medicine composition for treating cognitive impairment in Parkinson's disease. The composition consists of the following raw materials in parts by weight: 180-220 parts of vinegar-processed tortoise shell, 90-110 parts of Morinda officinalis, 90-110 parts of Angelica sinensis, 90-110 parts of Curcuma longa, 55-65 parts of Acorus tatarinowii, 55-65 parts of Polygala tenuifolia, 180-220 parts of calcined dragon bone, 180-220 parts of Spatholobus suberectus, and 1-3 parts of borneol.

[0033] It should be noted that, depending on the physical condition and symptoms of Parkinson's disease patients, the dosage of each of the above-mentioned Chinese herbal ingredients can be adjusted within the given range to achieve the best therapeutic effect.

[0034] Pharmacological analysis of the active pharmaceutical ingredient used in this invention:

[0035] Vinegar-processed tortoise plastron: This is a traditional Chinese medicine made from the plastron of the turtle (Tortoise spp.) processed with vinegar. It has the effects of nourishing yin and suppressing yang, and strengthening muscles and bones. Its content can 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] Morinda officinalis: The dried root of Morinda officinalis, a plant of the Rubiaceae family. It is sweet and pungent in taste and slightly warm in nature. It has the effects of tonifying kidney yang, strengthening tendons and bones, and dispelling wind and dampness. Its content can 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 sinensis is a perennial herb belonging to the genus Angelica of the Apiaceae family. It has a sweet and pungent taste and is warm in nature. It has the effects of nourishing blood and promoting blood circulation, regulating menstruation and relieving pain, and moistening the intestines and relieving constipation. Its content can 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] Turmeric: The dried tuberous root of Curcuma longa, Curcuma zedoaria, Curcuma zedoaria or Curcuma zedoaria, plants of the ginger family. It is pungent and bitter in taste and cold in nature. It has the effects of promoting qi circulation and relieving depression, cooling blood and breaking up blood stasis, and clearing the heart and gallbladder. Its content can 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] Acorus calamus: The dried rhizome of Acorus calamus, a plant of the Araceae family. It has a pungent and bitter taste and is slightly warm in nature. It has the effects of resolving dampness and stimulating appetite, opening the orifices and resolving phlegm, and refreshing the mind and improving intelligence. Its content can be, for example, 55 parts, 56 parts, 58 parts, 59 parts, 60 parts, 62 parts, 63 parts or 65 parts.

[0040] Yuanzhi: The dried root of Yuanzhi, a plant of the Polygalaceae family, has a bitter and slightly pungent taste and is warm in nature. It has the effects of calming the mind and improving intelligence, harmonizing the heart and kidneys, resolving phlegm, and reducing swelling. Its content can be, for example, 55 parts, 56 parts, 58 parts, 59 parts, 60 parts, 62 parts, 63 parts, or 65 parts.

[0041] Calcined dragon bone: Fossilized bones of ancient large mammals such as elephants, three-toed horses, rhinoceroses, deer, and cattle. It has the effects of calming the nerves, astringing sweat and consolidating essence, stopping bleeding and astringing the intestines, and promoting tissue regeneration and wound healing. Its content can 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] Chicken blood vine: The dried vine stem of the legume plant *Dendrobium nobile*, which is bitter and sweet in taste and warm in nature. It has the effects of nourishing blood, promoting blood circulation, and clearing the meridians. Its content can 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] Borneol: Colorless, transparent or white translucent flaky crystalline flakes. It is a natural crystalline compound precipitated from the resin of the camphor tree, a plant that produces camphor. It has the effects of clearing the orifices, dispersing internal heat, removing nebula and improving eyesight, reducing swelling and relieving pain, clearing heat and detoxifying, and dispersing fire and detoxifying. Its content can be, for example, 1 part, 2 parts or 3 parts.

[0044] The herbal composition of this invention is uniquely and rationally formulated. Based on the formula of Kong Sheng's Pillow Pill (containing vinegar-processed tortoise shell, calcined dragon bone, calamus, and polygala) from *Essential Prescriptions Worth a Thousand Gold Pieces*, it is supplemented with five raw materials: Morinda officinalis, Angelica sinensis, Curcuma longa, Spatholobus suberectus, and borneol. Vinegar-processed tortoise shell, sweet and salty in taste, enters the liver and kidney meridians and is a pure yin herb, essential for replenishing kidney essence. Morinda officinalis, sweet and pungent in taste, also enters the liver and kidney meridians and can tonify kidney yang and benefit essence and blood. These two herbs work synergistically, mutually generating yin and yang, tonifying kidney yang and replenishing kidney essence, making it the principal herb. Angelica sinensis and Spatholobus suberectus tonify and invigorate blood, while Curcuma longa promotes qi circulation and invigorates blood. The three herbs work together to invigorate blood to remove blood stasis and to distribute kidney essence and qi into the brain. The ingredients are: calcined dragon bone (for the heart and mind), combined with Polygala tenuifolia (for calming the mind), which are used as adjuvant herbs; Acorus tatarinowii (for opening the orifices, refreshing the mind, and improving intelligence), combined with borneol (for opening the orifices), which guides the medicine into the brain marrow, serving as the guiding herb; the entire formula tonifies both Yin and Yang, simultaneously tonifying the kidneys and resolving blood stasis, with both tonifying and dispersing properties, achieving the effects of tonifying the kidneys, activating blood circulation, resolving blood stasis, and refreshing the mind. Pharmacological experiments have shown that the herbal composition of this invention can improve chronic hypoperfusion caused by unilateral common carotid artery ligation and alleviate cognitive impairments such as spatial navigation, spatial exploration, and working memory in Parkinson's disease cognitive impairment model mice caused by chronic hypoperfusion, indicating that the herbal composition has a therapeutic effect on Parkinson's disease cognitive impairment.

[0045] In some embodiments, the traditional Chinese medicine composition for treating cognitive impairment in Parkinson's disease provided by the present invention comprises the following raw materials in parts by weight: 200 parts of vinegar-processed tortoise shell, 100 parts of Morinda officinalis, 100 parts of Angelica sinensis, 100 parts of Curcuma longa, 60 parts of Acorus tatarinowii, 60 parts of Polygala tenuifolia, 200 parts of calcined dragon bone, 200 parts of Spatholobus suberectus, and 2 parts of borneol.

[0046] Numerous experimental studies have shown that this specific formulation ratio can maximize the efficacy of each active ingredient, thereby achieving better therapeutic results.

[0047] like Figure 1 As shown, the present invention proposes a method for preparing a traditional Chinese medicine composition for treating cognitive impairment in Parkinson's disease, comprising steps S101 to S103.

[0048] Step S101: Weigh each raw material according to the weight proportions, add vinegar-processed tortoise shell and calcined dragon bone to water and decoct to obtain a mixed solution.

[0049] Because vinegar-processed tortoise shell and calcined dragon bone are relatively hard, long-term boiling can fully dissolve the active ingredients. Therefore, in the preparation process, vinegar-processed tortoise shell and calcined dragon bone are first boiled with water to obtain a mixed solution.

[0050] In some embodiments, when vinegar-treated tortoise shell and calcined dragon bone are decocted with water, the decoction time is 1-1.5 hours, for example, the decoction time can be 1 hour, 1.1 hours, 1.2 hours, 1.3 hours, 1.4 hours or 1.5 hours, and the amount of water added is 10-12 times the weight of the raw materials, specifically 10, 11 or 12 times the weight of the raw materials. By controlling the decoction time and the amount of water added, the extraction efficiency of the effective components in the vinegar-treated tortoise shell and calcined dragon bone raw materials can be further improved.

[0051] Step S102: Add Morinda officinalis, Angelica sinensis, Curcuma longa, Acorus tatarinowii, Polygala tenuifolia and Spatholobus suberectus to the mixed solution, add water and decoct twice to obtain the extract.

[0052] Because the active 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 components will quickly enter the solution, but some tightly bound or low-soluble components will not be fully dissolved. Through the second decoction, these components 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 active ingredients in the extract reaches a high level.

[0053] In some embodiments, during the two-stage decoction extraction, the first decoction time is 1-1.5 hours, for example, the first decoction time can be 1 hour, 1.1 hours, 1.2 hours, 1.3 hours, 1.4 hours, or 1.5 hours. The amount of water added in the first decoction is 10-12 times the weight of the raw medicinal materials, for example, the first water addition can be 10, 11, or 12 times the weight of the raw medicinal materials. The second decoction time is 1-1.5 hours, for example, the second decoction time can be 1 hour, 1.1 hours, 1.2 hours, 1.3 hours, 1.4 hours, or 1.5 hours. The amount of water added in the second decoction is 10-12 times the weight of the raw medicinal materials, for example, the second water addition can be 10, 11, or 12 times the weight of the raw medicinal materials. By controlling the second decoction time and the second water addition, the extraction efficiency of the effective components in each raw material can be further improved.

[0054] Step S103: Combine the secondary extracts, concentrate under reduced pressure to a certain concentration of raw medicinal materials, then add borneol and mix to obtain the traditional Chinese medicine composition.

[0055] The secondary extracts are combined to integrate the effective components from both decoctions, ensuring that the composition contains all the active substances of each raw material. Reduced pressure concentration (below atmospheric pressure) is used to avoid the decomposition and destruction of heat-sensitive components through low-temperature evaporation, maximizing the preservation of efficacy. The extract is concentrated to the target concentration of raw medicinal materials. Borneol has the effect of opening the orifices and refreshing the mind; when combined with other medicinal materials in the formula, it can enhance the effects of guiding the medicine into the brain and resolving blood stasis and refreshing the mind. Borneol is added to the concentrated solution and fully mixed to form a stable and homogeneous system, ultimately yielding the traditional Chinese medicine composition.

[0056] In some embodiments, the concentration of raw medicinal materials is 2.00-2.50 g / ml or 6.50-7.00 g / ml. The 2.00-2.50 g / ml concentration is a low-dose concentration, such as 2.00 g / ml, 2.24 g / ml, 2.30 g / ml, 2.40 g / ml, or 2.50 g / ml. Low-dose concentrations are primarily used to initially explore the lowest effective dose range of the drug, and also to provide medication references for patients with different disease severity and individual tolerance differences. The 6.50-7.00 g / ml concentration is a high-dose concentration, such as 6.50 g / ml, 6.73 g / ml, 6.80 g / ml, 6.90 g / ml, or 7.00 g / ml. Pharmacodynamic experiments have shown that high-dose concentrations of traditional Chinese medicine compositions are more effective in treating cognitive impairment in Parkinson's disease.

[0057] The preparation method of this invention involves stepwise decoction and extraction. First, vinegar-processed tortoise shell and calcined dragon bone are decocted with water. Since these two raw materials are relatively hard, long-term decoction can fully dissolve the active ingredients. Then, Morinda officinalis, Angelica sinensis, and other medicinal materials are added to the mixed solution for a second decoction. The second decoction ensures that all kinds of components are extracted to the maximum extent. This preparation method is simple and conducive to the preparation of traditional Chinese medicine compositions for treating cognitive impairment in Parkinson's disease, and can effectively reduce the production cost of drugs.

[0058] This invention provides a traditional Chinese medicine preparation containing the above-mentioned traditional Chinese medicine composition, or a traditional Chinese medicine composition prepared according to the above-mentioned preparation method.

[0059] For example, traditional Chinese medicine preparations can be in liquid form, which has advantages such as rapid onset of action, high bioavailability, and flexible dosage adjustment, and is not restricted here.

[0060] The traditional Chinese medicine preparation of this invention has the effects of tonifying the kidney and promoting blood circulation, removing blood stasis and refreshing the mind. It can alleviate the cognitive impairments such as spatial navigation, spatial exploration and working memory in mice with Parkinson's disease cognitive impairment caused by chronic hypoperfusion, and achieve the therapeutic effect on Parkinson's disease cognitive impairment.

[0061] This invention provides an application of the above-mentioned traditional Chinese medicine composition, or a traditional Chinese medicine composition prepared according to the above-mentioned preparation method, or the above-mentioned traditional Chinese medicine preparation, in the preparation of a drug for treating cognitive impairment in Parkinson's disease.

[0062] In the pharmacodynamic experiment, a mouse model of Parkinson's disease cognitive impairment caused by chronic hypoperfusion was established. Behavioral tests were conducted on cognitive impairments such as spatial navigation, spatial exploration, and working memory to evaluate the therapeutic effects 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 on Parkinson's disease cognitive impairment.

[0063] Pharmacodynamic experiments show that the application of this invention can improve chronic hypoperfusion caused by unilateral common carotid artery ligation and alleviate cognitive impairments such as spatial navigation, spatial exploration, and working memory in Parkinson's disease cognitive impairment model mice caused by chronic hypoperfusion, thus achieving a therapeutic effect on Parkinson's disease cognitive impairment.

[0064] The following detailed description of a traditional Chinese medicine composition for treating cognitive impairment in Parkinson's disease and its application, provided by the present invention, is illustrated through specific embodiments and experimental data.

[0065] Example 1

[0066] Please refer to Figure 1 Weigh out the raw materials according to the following proportions: 200 parts vinegar-processed tortoise shell, 100 parts Morinda officinalis, 100 parts Angelica sinensis, 100 parts Curcuma longa, 60 parts Acorus tatarinowii, 60 parts Polygala tenuifolia, 200 parts calcined dragon bone, 200 parts Spatholobus suberectus, and 2 parts Borneol. Add water to the vinegar-processed tortoise shell and calcined dragon bone and decoct for 1 hour. The amount of water added should be 10 times the weight of the raw materials to obtain a mixed solution.

[0067] Add Morinda officinalis, Angelica sinensis, Curcuma longa, Acorus tatarinowii, Polygala tenuifolia and Spatholobus suberectus to the above mixed solution, add water and decoct twice. The first decoction time is 1 hour and the amount of water added is 10 times the weight of the raw herbs. The second decoction time is 1 hour and the amount of water added is 10 times the weight of the raw herbs to obtain the extract.

[0068] The secondary extracts were combined and concentrated under reduced pressure to a crude drug content of 2.24 g / ml. Borneol was then added and mixed to obtain a traditional Chinese medicine composition with a low concentration of crude drug content.

[0069] Example 2

[0070] Please refer to Figure 1 Weigh out the raw materials according to the following proportions: 200 parts vinegar-processed tortoise shell, 100 parts Morinda officinalis, 100 parts Angelica sinensis, 100 parts Curcuma longa, 60 parts Acorus tatarinowii, 60 parts Polygala tenuifolia, 200 parts calcined dragon bone, 200 parts Spatholobus suberectus, and 2 parts Borneol. Add water to the vinegar-processed tortoise shell and calcined dragon bone and decoct for 1 hour. The amount of water added should be 10 times the weight of the raw materials to obtain a mixed solution.

[0071] Add Morinda officinalis, Angelica sinensis, Curcuma longa, Acorus tatarinowii, Polygala tenuifolia and Spatholobus suberectus to the above mixed solution, add water and decoct twice. The first decoction time is 1 hour and the amount of water added is 10 times the weight of the raw herbs. The second decoction time is 1 hour and the amount of water added is 10 times the weight of the raw herbs to obtain the extract.

[0072] The secondary extracts were combined and concentrated under reduced pressure to a crude drug content of 6.73 g / ml. Borneol was then added and mixed to obtain a traditional Chinese medicine composition with a high concentration of crude drug content.

[0073] Example 3

[0074] Please refer to Figure 1 Weigh out the raw materials according to the following proportions: 180 parts vinegar-processed tortoise shell, 90 parts Morinda officinalis, 90 parts Angelica sinensis, 90 parts Curcuma longa, 55 parts Acorus tatarinowii, 55 parts Polygala tenuifolia, 180 parts calcined dragon bone, 180 parts Spatholobus suberectus, and 1 part borneol. Add water to vinegar-processed tortoise shell and calcined dragon bone and decoct for 1 hour. The amount of water added is 10 times the weight of the raw materials to obtain a mixed solution.

[0075] Add Morinda officinalis, Angelica sinensis, Curcuma longa, Acorus tatarinowii, Polygala tenuifolia and Spatholobus suberectus to the above mixed solution, add water and decoct twice. The first decoction time is 1 hour and the amount of water added is 10 times the weight of the raw herbs. The second decoction time is 1 hour and the amount of water added is 10 times the weight of the raw herbs to obtain the extract.

[0076] The secondary extracts were combined and concentrated under reduced pressure to a crude drug content of 2.00 g / ml. Borneol was then added and mixed to obtain a traditional Chinese medicine composition with a low concentration of crude drug content.

[0077] Example 4

[0078] Please refer to Figure 1 Weigh out the raw materials according to the following proportions: 180 parts vinegar-processed tortoise shell, 90 parts Morinda officinalis, 90 parts Angelica sinensis, 90 parts Curcuma longa, 55 parts Acorus tatarinowii, 55 parts Polygala tenuifolia, 180 parts calcined dragon bone, 180 parts Spatholobus suberectus, and 1 part borneol. Add water to vinegar-processed tortoise shell and calcined dragon bone and decoct for 1 hour. The amount of water added is 10 times the weight of the raw materials to obtain a mixed solution.

[0079] Please refer to Figure 1 Morinda officinalis, Angelica sinensis, Curcuma longa, Acorus tatarinowii, Polygala tenuifolia and Spatholobus suberectus were added to the above mixed solution, and water was added to decoct and extract twice. The first decoction time was 1 hour, and the amount of water added was 10 times the weight of the raw herbs. The second decoction time was 1 hour, and the amount of water added was 10 times the weight of the raw herbs to obtain the extract.

[0080] The secondary extracts were combined and concentrated under reduced pressure to a crude drug content of 2.50 g / ml. Borneol was then added and mixed to obtain a traditional Chinese medicine composition with a low concentration of crude drug content.

[0081] Example 5

[0082] Please refer to Figure 1 Weigh out the raw materials according to the following proportions: 220 parts vinegar-processed tortoise shell, 110 parts Morinda officinalis, 110 parts Angelica sinensis, 110 parts Curcuma longa, 65 parts Acorus tatarinowii, 65 parts Polygala tenuifolia, 220 parts calcined dragon bone, 220 parts Spatholobus suberectus, and 3 parts borneol. Add water to the vinegar-processed tortoise shell and calcined dragon bone and decoct for 1.5 hours. The amount of water added is 12 times the weight of the raw materials to obtain a mixed solution.

[0083] Morinda officinalis, Angelica sinensis, Curcuma longa, Acorus tatarinowii, Polygala tenuifolia, and Spatholobus suberectus were added to the above mixed solution, and water was added to decoct and extract twice. The first decoction time was 1.5 hours, and the amount of water added was 12 times the weight of the raw herbs. The second decoction time was 1.5 hours, and the amount of water added was 12 times the weight of the raw herbs to obtain the extract.

[0084] The secondary extracts were combined and concentrated under reduced pressure to a crude drug content of 6.50 g / ml. Borneol was then added and mixed to obtain a traditional Chinese medicine composition with a high concentration of crude drug content.

[0085] Example 6

[0086] Please refer to Figure 1 Weigh out the raw materials according to the following proportions: 220 parts vinegar-processed tortoise shell, 110 parts Morinda officinalis, 110 parts Angelica sinensis, 110 parts Curcuma longa, 65 parts Acorus tatarinowii, 65 parts Polygala tenuifolia, 220 parts calcined dragon bone, 220 parts Spatholobus suberectus, and 3 parts borneol. Add water to the vinegar-processed tortoise shell and calcined dragon bone and decoct for 1.5 hours. The amount of water added is 12 times the weight of the raw materials to obtain a mixed solution.

[0087] Morinda officinalis, Angelica sinensis, Curcuma longa, Acorus tatarinowii, Polygala tenuifolia, and Spatholobus suberectus were added to the above mixed solution, and water was added to decoct and extract twice. The first decoction time was 1.5 hours, and the amount of water added was 12 times the weight of the raw herbs. The second decoction time was 1.5 hours, and the amount of water added was 12 times the weight of the raw herbs to obtain the extract.

[0088] The secondary extracts were combined and concentrated under reduced pressure to a crude drug content of 7.00 g / ml. Borneol was then added and mixed to obtain a traditional Chinese medicine composition with a high concentration of crude drug content.

[0089] Example 7

[0090] Pharmacodynamic experiments

[0091] To investigate the efficacy of the traditional Chinese medicine composition of this invention in treating cognitive impairment in Parkinson's disease, a chronic hypoperfusion-induced cognitive impairment model of Parkinson's disease was established in α-Syn A53T+ / - mice. Behavioral tests, liver and kidney function tests, and laser speckle analysis were performed on the traditional Chinese medicine composition of this invention to evaluate its therapeutic effect on cognitive impairment in Parkinson's disease.

[0092] 1. Laboratory animals

[0093] α-Syn A53T+ / - mice were purchased from Changzhou Cavens Laboratory Animal Co., Ltd., with animal qualification certificate number NO.202134209. They were housed in a quiet environment with a room temperature of about 22℃ and equal day and night durations, and were allowed free access to water and food. Male and female α-Syn A53T+ / - mice were mated in pairs, and genotyping was performed on the pups at 1 month of age. Forty 9-month-old mice were selected for this experiment, including 10 wild-type mice and 30 α-Syn A53T+ / - mice.

[0094] 2. Animal grouping, model establishment, and drug administration

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

[0096] The modeling and drug administration methods for each group are as follows:

[0097] WT group: Wild-type mice underwent sham surgery with unilateral common carotid artery ligation and were administered distilled water by gavage at a dose of 0.1 ml / kg;

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

[0099] High JWKSZZD group: α-Syn A53T+ / - mice were first administered the Chinese herbal composition prepared in Example 2 by gavage once a day for 2 weeks, with a dosage of 0.1 ml / kg. Then, a sham surgery of unilateral common carotid artery ligation was performed. After the surgery, the Chinese herbal composition prepared in Example 2 was administered by gavage once a day for 4 weeks.

[0100] Low JWKSZZD group: α-Syn A53T+ / - mice were first administered the Chinese herbal composition prepared in Example 1 by gavage once a day for 2 weeks at a dose of 0.1 ml / kg. Then, a sham surgery of unilateral common carotid artery ligation was performed. After the surgery, the Chinese herbal composition prepared in Example 1 was administered by gavage once a day for 4 weeks.

[0101] 3. Behavioral testing

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

[0103] 3.2 Grasp Force Experiment

[0104] When testing the gripping force of mice's forelimbs and limbs using a rat and mouse gripping force tester, first zero the instrument, place the mouse on the lever of the gripping force tester, and make its forelimbs or limbs firmly grip the lever. Then, grasp the mouse's tail and pull it straight back in a horizontal direction. When the mouse loses its grip, the instrument automatically records the maximum gripping force value. The gripping force of each mouse's forelimbs and limbs is measured 3 times, and the maximum value is taken.

[0105] 3.3 Morris Water Maze Experiment

[0106] Before the experiment, fill the Morris water maze pool with a diameter of 120cm with an appropriate amount of water, maintain the water temperature at 25℃ or room temperature, add an appropriate amount of white pigment and mix well to make the water uniformly milky white, place the platform 1-2cm underwater so that it is not visible, and at the same time, in the analysis system, divide the pool into 4 quadrants with equal area based on the center of the pool, define the area from 15cm away from the pool wall as the outer perimeter area, and affix 4 different graphic labels to the pool walls of the 4 quadrants respectively.

[0107] Spatial navigation test: On days 1-5, mice were allowed to enter the water from each of the four quadrants and were given 90 seconds to find a platform. After finding the platform, the mice were required to stay on it for 15 seconds. If the mice did not find the platform within 90 seconds, the experimenter guided them to the platform and they stayed there for 15 seconds. The escape latency (i.e., the time to find the platform) of the mice was recorded. At the same time, the time the mice stayed in the peripheral area and the total distance were also recorded.

[0108] Spatial exploration test: On day 6, the platform was removed and the mice were allowed to enter the water from the quadrant opposite to the platform. The number of times the mice crossed the platform within 90 seconds, 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 clockwise to the next quadrant each day, with 5 different entry points each day. The first test was an adaptation test, and the data from the second to fifth tests were used for analysis. Each observation time was 90 seconds. If the mouse found the new platform, it stayed for 15 seconds. If the mouse could not find the platform, it was artificially guided to the new platform and stayed for 15 seconds. After that, the mouse was put back into the original cage to rest for 1 minute, and then taken out and put back into the second entry point to continue the test. Finally, the average escape latency and the time spent in the platform quadrant were calculated on days 7-9.

[0110] 4. Liver and kidney function tests

[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 Figure 3-4As shown, compared with the WT group and the A53T+U group, there were no significant differences in the serum levels of ALP, ALT, AST, TBIL, DBIL, IBIL, TBA, UREA, Cre, and UA in the Low JWKSZZD group and the High JWKSZZD group (P>0.05). This indicates that neither low-dose nor high-dose concentration of the traditional Chinese medicine composition will cause liver or kidney damage, suggesting that low-dose and high-dose concentration of the traditional Chinese medicine composition has good safety in treating cognitive impairment in Parkinson's disease.

[0118] 6.2 Low-dose and high-dose concentration traditional Chinese medicine compositions can improve chronic hypoperfusion caused by unilateral common carotid artery ligation.

[0119] Laser speckle analysis was used to assess cerebral blood flow perfusion in each group of mice. The results are as follows: Figure 5 As shown, compared with the WT group, the cerebral blood flow perfusion of mice in the A53T+U group, Low JWKSZZD group, and High JWKSZZD group was reduced, and the differences were statistically significant (P<0.05). Furthermore, the cerebral blood flow 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 showed an increase, and the differences were statistically significant (P<0.05). Meanwhile, compared with the A53T+U group, the cerebral blood flow perfusion of mice in the Low JWKSZZD group and the High JWKSZZD group was significantly reduced. All JWKSZZD groups increased blood flow velocity in the middle cerebral artery of mice, but only the HighJWKSZZD group showed a statistically significant difference (P<0.05). These results indicate that unilateral common carotid artery ligation for 4 weeks can lead to stable chronic hypoperfusion, and low-dose and high-dose concentration traditional Chinese medicine compositions can improve congestion caused by chronic hypoperfusion due to unilateral common carotid artery ligation. Among them, the high-dose concentration traditional Chinese medicine composition is more effective than the low-dose concentration traditional Chinese medicine composition.

[0120] 6.3 Low-dose and high-dose concentration traditional Chinese medicine compositions can alleviate cognitive impairments such as spatial navigation, spatial exploration, and working memory in mice with Parkinson's disease cognitive impairment caused by chronic hypoperfusion.

[0121] like Figure 6 As shown, in the claw grip strength test, compared with the WT group, the forelimb claw grip strength of mice in the A53T+U group and the Low JWKSZZD group was significantly decreased. Although the forelimb claw grip strength of mice in the High JWKSZZD group was significantly higher than that of the A53T+U group, the difference was not statistically significant (P>0.05). In addition, there was no significant difference in claw grip strength among the four groups of mice (P>0.05). These results indicate that neither low-dose nor high-dose concentration of the traditional Chinese medicine composition effectively improved the decrease in claw grip strength caused by chronic hypoperfusion.

[0122] like Figure 7 As shown, in the water maze spatial navigation test, the escape latency of mice in the WT group, High JWKSZZD group, and Low JWKSZZD group all showed a decreasing trend from day 1 to day 5, while the escape latency of mice in the A53T+U group remained relatively long. Statistical analysis showed that compared with the WT group, the escape latency of the A53T+U group was significantly prolonged from day 1 to day 5, with statistically significant differences (P<0.05). Compared with the A53T+U group, the escape latency of mice in the High JWKSZZD group and Low JWKSZZD group was significantly shortened on days 3, 4, and 5, with statistically significant differences (P<0.05).

[0123] Meanwhile, during the spatial navigation tests on days 1-5, the percentage of time spent in the peripheral region by mice in the WT, High JWKSZZD, and Low JWKSZZD groups gradually decreased, while the A53T+U group maintained a high level of time spent in the peripheral region during the 5-day training period. Compared with the WT group, the percentage of time spent in the peripheral region by mice in the A53T+U and Low JWKSZZD groups on days 4 and 5 was significantly increased (P<0.05). Compared with the A53T+U group, the percentage of time spent in the peripheral region by mice in the High JWKSZZD group on days 2 and 5 was significantly decreased (P<0.05). In addition, during the spatial navigation tests on days 1-5, the average total distance of mice in the A53T+U group was significantly higher than that of the WT group (P<0.05).

[0124] like Figure 8 As shown, in the spatial exploration test on day 6, the number of times mice in the High JWKSZZD group crossed the platform was significantly greater than that in the A53T+U group, and the difference was statistically significant (P<0.05). However, the low-dose group (Low JWKSZZD) did not significantly increase the number of times mice crossed the platform. The trend of the percentage of time spent in the platform quadrant was consistent with the number of times mice crossed the platform. Although the percentage of time spent in the peripheral region in the High JWKSZZD group and the Low JWKSZZD group was lower than that in the A53T+U group, the difference was not statistically significant (P>0.05). There were no significant differences in the total distance and average speed among the four groups of mice (P>0.05).

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

[0126] The above results indicate that neither low-dose nor high-dose concentrations of the traditional Chinese medicine composition could improve the decrease in claw gripping force caused by chronic hypoperfusion, but they could alleviate cognitive impairments such as spatial navigation, spatial exploration, and working memory in mice with Parkinson's disease cognitive impairment caused by chronic hypoperfusion. Among them, the high-dose concentration of the traditional Chinese medicine composition was more effective than the low-dose concentration.

Claims

1. A traditional Chinese medicine composition for treating cognitive impairment in Parkinson's disease, characterized in that, The traditional Chinese medicine composition consists of the following raw materials in parts by weight: 180-220 parts of vinegar-processed tortoise shell, 90-110 parts of Morinda officinalis, 90-110 parts of Angelica sinensis, 90-110 parts of Curcuma longa, 55-65 parts of Acorus tatarinowii, 55-65 parts of Polygala tenuifolia, 180-220 parts of calcined dragon bone, 180-220 parts of Spatholobus suberectus, and 1-3 parts of borneol.

2. The traditional Chinese medicine composition for treating cognitive impairment in Parkinson's disease according to claim 1, characterized in that, The traditional Chinese medicine composition consists of the following raw materials in parts by weight: 200 parts vinegar-processed tortoise shell, 100 parts Morinda officinalis, 100 parts Angelica sinensis, 100 parts Curcuma longa, 60 parts Acorus tatarinowii, 60 parts Polygala tenuifolia, 200 parts calcined dragon bone, 200 parts Spatholobus suberectus, and 2 parts borneol.

3. A method for preparing a traditional Chinese medicine composition for treating cognitive impairment in Parkinson's disease as described in claim 1 or 2, characterized in that, Includes the following steps: Weigh each raw material according to the weight proportions, add vinegar-processed tortoise shell and calcined dragon bone to water and decoct to obtain a mixed solution; Morinda officinalis, Angelica sinensis, Curcuma longa, Acorus tatarinowii, Polygala tenuifolia and Spatholobus suberectus were added to the mixed solution, and water was added to decoct and extract twice to obtain the extract. The secondary extracts were combined, concentrated under reduced pressure to a certain concentration of raw medicinal material, and then borneol was added and mixed 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 process of decocting vinegar-processed tortoise shell and calcined dragon bone with water, the decoction time is 1-1.5 hours, and the amount of water added is 10-12 times the weight of the raw herbs.

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 two-stage decoction extraction, the first decoction time is 1-1.5 hours, and the amount of water added is 10-12 times the weight of the raw herb. The second decoction time is 1-1.5 hours, and the amount of water added is 10-12 times the weight of the raw herb.

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 specified concentration of raw medicinal material is 2.00-2.50 g / ml or 6.50-7.00 g / ml.

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

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

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