New use of compound salvia miltiorrhiza preparation

Abstract

Provided is a use of a compound salvia miltiorrhiza preparation in the preparation of drugs for preventing or treating post-stroke cognitive impairment with no dementia. The compound salvia miltiorrhiza preparation is prepared from active ingredients, i.e., salvia miltiorrhiza, radix notoginseng, and borneolum syntheticum in a mass ratio of (450+ / -50):(141+ / -5):(8+ / -2).

Description

New applications of compound salvia miltiorrhiza preparations

[0001] The present invention claims priority to Chinese patent application No. 2023107021027, filed with the Patent Office of China on June 14, 2023, entitled “New Application of Compound Danshen Preparations,” the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of medicine, and in particular relates to a new application of a compound danshen preparation in clinical practice. Background Art

[0003] Vascular dementia (VaD) refers to a dementia syndrome caused by brain tissue damage due to various cerebrovascular diseases. It is a common type of senile dementia in clinical practice, and its prevalence ranks second among senile dementia types, second only to Alzheimer's disease. Vascular dementia is not a single disease entity but a general term for a large category of diseases. Its clinical manifestations are complex and diverse due to the nature, number, size and location of vascular lesions. [2] In recent years, scholars have gradually realized that the concept of vascular dementia is not enough to cover all levels of cognitive impairment related to vascular factors or vascular diseases. According to this concept, it is easy to miss patients with mild cognitive impairment but not yet at the level of dementia. Early diagnosis and treatment of these patients may slow down or even prevent the onset of dementia. Therefore, scholars proposed the concept of vascular cognitive impairment and continuously improved it (Iadecola C. The Pathobiology of Vascular Dementia. Neuron. 2013; 80(4): 844-866). It is generally believed that vascular cognitive impairment refers to a large category of syndromes ranging from early cognitive impairment to dementia caused by cerebrovascular risk factors such as hypertension, diabetes and hyperlipidemia, and obvious (cerebral infarction and cerebral hemorrhage, etc.) or subtle cerebrovascular diseases (leukoaraiosis and chronic cerebral ischemia, etc.). Vascular cognitive impairment includes three types: early non-dementia vascular cognitive impairment that has not yet reached dementia, vascular dementia, and mixed dementia (Iadecola C, Duering M, Hachinski V, et al. Vascular Cognitive Impairment and Dementia: JACC Scientific Expert Panel. J Am Coll Cardiol. 2019; 73(25): 3326-3344).

[0004] In addition, according to the TOAST classification method, ischemic stroke can be divided into unknown etiology, small artery occlusion, atherosclerosis, cardioembolism and other clear etiology types. [8]Therefore, vascular cognitive impairment can be divided into vascular inflammatory cognitive impairment, PSCI-ND and atherosclerotic cognitive impairment according to its different pathogenesis (Villeneuve S, Belleville S, Massoud F, et al. Impact of vascular risk factors and diseases on cognition in persons with mild cognitive impairment [J]. Dementia and Geriatric Cognitive Disorders. 2009, 27 (4): 375-381). The main cause of vascular inflammatory cognitive impairment is excessive vascular inflammatory response; atherosclerotic cognitive impairment is caused by hyperlipidemia leading to atherosclerosis, which in turn leads to cognitive impairment.

[0005] Post-stroke cognitive impairment (PSCI) refers to a spectrum of symptoms that meet diagnostic criteria for cognitive impairment within six months of a stroke event. This emphasizes the potential causal relationship between stroke and cognitive impairment and the relevance of their clinical management. Based on the severity of cognitive impairment, it can be divided into post-stroke cognitive impairment without dementia (PSCI-ND) and post-stroke dementia (PSD). Clinically, there is a clear distinction between PSCI-ND and PSD: The diagnosis of PSCI-ND must be based on cognitive testing that assesses at least four cognitive domains—executive function, memory, language, and visuospatial ability. The diagnosis must be based on the assumption of baseline cognitive decline and impairment in at least one cognitive domain. The diagnosis of PSD requires a confirmed diagnosis of cerebrovascular disease and dementia, while excluding other causes of cognitive impairment. Dementia must develop within three months of a confirmed stroke. MRI examinations of brain tissue from patients with PSD and PSCI-ND revealed that, compared with PSD, PSCI-ND patients exhibited hippocampal volume distortion and even atrophy, significantly reduced entorhinal cortex surface area, and wider nasal grooves. Furthermore, research evidence indicates that levels of IL-1β, IL-6, IL-10, and CRP in the brain tissue of PSD patients were significantly higher than those of PSCI-ND patients. This evidence suggests that the progression of PSCI-ND patients to PSD may be closely related to inflammatory responses. However, the prevention and treatment strategies for PSCI-ND and PSD differ, with different emphases.

[0006] Currently, the internationally recognized treatment for post-stroke cognitive impairment still primarily relies on compound drugs. However, these drugs are associated with long treatment cycles and significant side effects. Patients with cognitive impairment often have poor medication compliance, and long-term medication use can exacerbate certain adverse reactions or lead to recurrent episodes. Therefore, there is an urgent need to identify effective alternatives. Traditional Chinese herbal medicines offer unique advantages, such as widespread availability, low cost, and minimal adverse reactions, and hold great promise for their application. Developing traditional Chinese medicines or Chinese patent medicines for the prevention and treatment of post-stroke cognitive impairment (PSCI-ND) is a crucial area of ​​drug research and development.

[0007] Compound Danshen preparations are made from the three active ingredients of Danshen, Panax notoginseng, and borneol. Common dosage forms include tablets, capsules, drop pills, pills, micropellets, sprays, aerosols, oral solutions, injections, or granules. Compound Danshen preparations have the properties of promoting blood circulation and removing blood stasis, regulating qi and relieving pain. They are used to treat chest pain caused by qi stagnation and blood stasis, characterized by chest tightness and stabbing pain in the precordial area, as well as angina pectoris due to coronary heart disease. They are also used to treat intellectual impairment, slow thinking, apathy, and amnesia caused by cerebral blood stasis after stroke. They are widely used in clinical treatment and daily health care. Extensive basic and clinical research evidence demonstrates that compound Danshen preparations have anti-inflammatory effects, reduce post-stroke cerebral infarction size, and protect the brain, effectively improving various types of cognitive impairment. Cognitive impairment in patients with vascular dementia emphasizes the role of vascular factors in the development of cognitive impairment. This broad concept encompasses causes and risk factors ranging from atherosclerotic lesions to cerebral vasculitis, and from ischemic stroke to hemorrhagic stroke. However, given the complexity of the course of post-stroke cognitive impairment without dementia, it is still unknown whether compound Danshen preparations can have a preventive or therapeutic effect on it.

[0008] Summary of the Invention

[0009] Based on this, the purpose of the present invention is to provide a new application of a compound Danshen preparation.

[0010] The technical solutions for achieving the above-mentioned objectives include the following.

[0011] The invention relates to an application of a compound danshen preparation in preparing a medicine for preventing or treating post-stroke cognitive impairment other than dementia, wherein the active ingredients of the compound danshen preparation are prepared from danshen, panax notoginseng and borneol.

[0012] In some embodiments, the compound danshen preparation is in the form of tablets, capsules, dripping pills, pills, micropills, sprays, aerosols, oral liquids, injections or granules.

[0013] In some embodiments, the mass ratio of Salvia miltiorrhiza, Panax notoginseng and Borneol is (450±50): (141±5): (8±2).

[0014] In some embodiments, the compound Danshen preparation is in the form of a tablet.

[0015] In some embodiments, the mass ratio of Salvia miltiorrhiza, Panax notoginseng and Borneol is (450±10):(141±3):(8±1).

[0016] In some embodiments, the mass ratio of Salvia miltiorrhiza, Panax notoginseng and Borneol is (450±5): (141±2): (8±0.5).

[0017] In some embodiments, the compound Danshen preparation contains 0.3-0.48 mg / tablet of Tanshinone IIA, 5.6-7.1 mg / tablet of Salvianolic Acid B, and 7.0-8.9 mg / tablet of Panax notoginseng total saponins.

[0018] In some preferred embodiments, the compound Danshen preparation contains 0.38-0.48 mg of tanshinone IIA per tablet, 6.6-7.1 mg of salvianolic acid B, and 8.2-8.9 mg of notoginseng total saponins per tablet; more preferably, it contains 0.38-0.39 mg of tanshinone IIA per tablet, 7.0-7.1 mg of salvianolic acid B, and 8.6-8.9 mg of notoginseng total saponins per tablet.

[0019] The present invention provides for the first time a new application of a compound danshen preparation in the preparation of a drug for preventing or treating post-stroke cognitive impairment without dementia. During the research process, we found that the compound danshen preparation (especially the compound danshen tablets with tanshinone ⅡA of 0.3-0.48 mg / tablet, salvianolic acid B of 5.6-7.1, and notoginseng total saponins of 7.0-8.9 mg / tablet) had no effect on improving the cognitive function of mice with atherosclerotic cognitive impairment, but had a good preventive and therapeutic effect on post-stroke cognitive impairment without dementia. The study found that the effect of the compound danshen preparation on improving cerebral infarction and cognitive function in MCAO model rats was achieved by affecting the inflammatory response in brain tissue, especially by reducing the content of inflammatory factors IL-6, IL-1β and TNF-α. The results showed that the compound danshen preparation had a good effect on improving the cognitive function of post-stroke cognitive impairment without dementia. DETAILED DESCRIPTION

[0020] The experimental methods in the following examples of the present invention, where specific conditions are not specified, are generally carried out under conventional conditions or conditions recommended by the manufacturers. The various commonly used chemical reagents used in the examples are all commercially available products.

[0021] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0022] Explanation of terms:

[0023] PSCI: Post-stroke cognitive impairment. It refers to a series of syndromes that meet the diagnostic criteria for cognitive impairment within 6 months after the clinical event of stroke.

[0024] PSCI-ND: Post-stroke cognitive impairment not dementia. Its diagnosis must be based on cognitive testing that assesses at least four cognitive domains—executive function, memory, language, and visuospatial ability. The diagnosis must be based on the assumption of cognitive decline at baseline and impairment in at least one cognitive domain.

[0025] PSD: Post-stroke dementia, diagnosed as dementia caused by cerebrovascular disease, while excluding cognitive impairment caused by other reasons. Dementia must occur within 3 months after a clear stroke.

[0026] MCAO: middle cerebral artery occlusion and reperfusion.

[0027] CRP: C-reactive protein.

[0028] IL-1β: interleukin-1β; IL-6: interleukin-6; IL-10: interleukin-10.

[0029] Aβ 41-42 : beta-amyloid protein.

[0030] The compound Danshen tablets used in the present invention are produced by Guangzhou Baiyunshan Hutchison Whampoa Chinese Medicine Co., Ltd. The mass ratio of Danshen, Panax notoginseng, and borneol is 450:141:8. Tanshinone IIA is 0.3-0.48 mg / tablet, salvianolic acid B is 5.6-7.1 mg / tablet, and Panax notoginseng total saponins are 7.0-8.9 mg / tablet. The compound Danshen tablets used in the following examples are batch number D17A008.

[0031] The above determination methods of tanshinone ⅡA, salvianolic acid B and Panax notoginseng total saponins were in accordance with the conventional method, i.e., the method described in Pharmacopoeia General Chapter 0512.

[0032] Danshen tanshinone ⅡA was determined according to high performance liquid chromatography (Pharmacopoeia General Chapter 0512).

[0033] The chromatographic conditions and system suitability test used octadecylsilane bonded silica gel as the filler, methanol-water (73:27) as the mobile phase, and a detection wavelength of 270 nm. The theoretical plate number calculated based on the tanshinone IIA peak should be no less than 2000.

[0034] Preparation of reference solution: Take an appropriate amount of Tanshinone IIA reference substance, accurately weigh it, place it in a brown volumetric flask, and add methanol to make a solution containing 40 μg per 1 ml.

[0035] Preparation of test solution: Take 10 tablets of this product, remove the sugar coating from the sugar-coated tablets, accurately weigh, grind, take about 1g, accurately weigh, place in a brown bottle with a stopper, accurately add 25ml of methanol, stopper, weigh the weight, ultrasonically treat (power 250W, frequency 33kHz) for 15 minutes, let cool, weigh again, make up the lost weight with methanol, shake well, filter, take the filtrate, place in a brown bottle, and obtain.

[0036] Determination method: Accurately aspirate 10 μl of reference solution and test solution respectively, inject into liquid chromatograph, and determine.

[0037] Salvianolic acid B was determined according to the high performance liquid chromatography method (Pharmacopoeia General Chapter 0512).

[0038] Chromatographic conditions and system suitability test: Octadecylsilane bonded silica gel was used as the filler; acetonitrile-methanol-formic acid-water (10:30:1:59) was used as the mobile phase; the detection wavelength was 286 nm. The theoretical plate number calculated based on the salvianolic acid B peak should be no less than 4000.

[0039] Preparation of reference solution: Take an appropriate amount of salvianolic acid B reference substance, weigh accurately, and add water to make a solution containing 60 μg per 1 ml.

[0040] Preparation of test solution: Take 10 tablets of this product, remove the sugar coating from the sugar-coated tablets, accurately weigh, grind, take 0.15g, accurately weigh, place in a 50ml volumetric flask, add appropriate amount of water, ultrasonically treat (power 300W, frequency 50kHz) for 30 minutes, cool, add water to the scale, shake well, centrifuge, and take the supernatant.

[0041] Determination method: Accurately aspirate 10 μl of reference solution and test solution respectively, inject into liquid chromatograph, and determine.

[0042] The content of Panax notoginseng was determined by HPLC (Pharmacopoeia General Chapter 0512).

[0043] Preparation of reference solution: Take appropriate amounts of ginsenoside Rg1 reference, ginsenoside Rb1 reference, notoginsenoside R1 reference and ginsenoside Re reference, accurately weigh them, and add 70% methanol to make a mixed solution containing 0.2 mg each of ginsenoside Rg1 and ginsenoside Rb1, and 0.05 mg each of notoginsenoside R1 and ginsenoside Re per 1 ml.

[0044] Preparation of test solution: Take 10 tablets of this product, remove the coating, accurately weigh, grind, take about 1g, accurately weigh, accurately add 50ml of 70% methanol and weigh the weight, ultrasonically treat (power 250W, frequency 33kHz) for 30 minutes, let cool, weigh again, make up the lost weight with 70% methanol, shake well, filter, and take the filtrate.

[0045] Determination method: Accurately aspirate 20 μl of reference solution and test solution respectively, inject into liquid chromatograph, and determine.

[0046] The present invention is further described in detail below with reference to specific embodiments.

[0047] Example 1

[0048] Effects of Fufang Danshen Tablets on the prevention and treatment of post-stroke cognitive impairment without dementia (PSCI-ND)

[0049] 1. Experimental Reagents

[0050] IL-6 ELISA kit (NOVUS Biologicals, USA); IL-10 ELISA kit (NOVUS Biologicals, USA); IL-1β ELISA kit (NOVUS Biologicals, USA); Aβ 41-42 Monoclonal antibody (Abcam); GAPDH monoclonal antibody (Abcam).

[0051] 2. Experimental Animals and Grouping

[0052] Experimental groups: 60 male SD rats were randomly divided into 4 groups, with 15 rats in each group, namely: 1. sham operation group; 2. model group; 3. model + compound Danshen tablets (0.6 g / kg) group; 4. model + donepezil (0.49 mg / kg) group.

[0053] 3. Experimental Equipment

[0054] Ultrapure water machine (Guangzhou Feidi Biotechnology Co., Ltd.), Nikon Eclipse Ts2R+FL microscope (Shandong Academy of Medical Sciences Equipment Station), water maze behavioral analysis system (Shanghai Yishu Information Technology Co., Ltd.)

[0055] 4. Experimental Methods

[0056] 4.1 Preparation of rat middle cerebral artery occlusion (MCAO) model

[0057] A modified Zea Longa suture method was used to establish a MCAO model. Rats were anesthetized with an intraperitoneal injection of 10% chloral hydrate at a rate of 0.3 mL / kg. A midline cervical incision was performed, and the subcutaneous tissue was bluntly dissected. The right common carotid artery (CCA), external carotid artery (ECA), and internal carotid artery (ICA) were gradually isolated. The proximal end of the ECA was ligated, and a 0.25 mm incision was made in the CCA (0.5 cm from the intersection of the ECA and ICA). A suture was inserted through the ICA to the entrance of the middle cerebral artery, with a length of 18-20 mm. The suture was then secured to the CCA, and the skin was sutured, leaving the tail of the suture exposed. After 2 hours, the suture was gently removed. Rats in the sham-operated group received only anesthesia and vascular dissection followed by skin suture. All procedures were identical to those in the sham-operated group, except that the nylon suture was not inserted. Rectal temperature was maintained at 37°C throughout the experiment. Neurological function scores were used to assess model success after model establishment, and animals with successful models were used in subsequent experiments.

[0058] 4.2 Administration

[0059] Administration: Compound Danshen Tablets and Donepezil were administered by oral gavage immediately after MCAO surgery for 7 consecutive days. Rats in the sham operation group and MCAO model group were administered with an equal volume of normal saline by oral gavage.

[0060] 4.3 Neurological function evaluation:

[0061] Seven days after administration, all rats were assessed for neurobehavioral assessment according to Longa's 5-point scale (n=10). Longa's scale is as follows: 0, normal, no neurological deficit; 1, left forelimb extension disorder, weakened function; 2, leftward circular motion, left forelimb paralysis, severely weakened function; after the tail was lifted, the rat repeatedly twisted toward the damaged area; 3, toppling to the left while walking; 4, limb paralysis, coma.

[0062] 4.4 Morris water maze test of rat cognitive memory function:

[0063] Seven days after administration, animals (n=10) were subjected to the Morris water maze test:

[0064] Positioning and navigation experiment: This test tests the rat's ability to learn the location of the platform. Training is carried out continuously for 5 days. In each training session, the rat is placed into the water from the entry point of each quadrant. If the rat climbs onto the platform within 90 seconds and stays on the platform for more than 3 seconds, it is considered to have found the platform, and this is the escape latency. If the rat fails to find the platform within 90 seconds, it is dragged by the tail to guide it to the platform and familiarize it with it for 10 seconds. In this case, the latency is calculated as 90 seconds. Each training session is separated by 5 minutes. The average of the four directional latencies in each session is calculated as the swimming result for that day.

[0065] The spatial exploration test is primarily used to test the rats' ability to remember the platform's location after they learn to find it. Following the navigation test, on the morning of the sixth day of the water maze experiment, the platform is removed and the rat is placed into the water at any entry point. The number of times the rat crosses the original platform area within 90 seconds is observed and recorded.

[0066] 4.5 Determination of inflammatory factor content:

[0067] Seven days after administration, ELISA kits for IL-1β, IL-6, and IL-10 were used to detect the concentrations of inflammatory factors in the hippocampal tissue of rats in each group (n=10). Samples were processed and prepared strictly according to the instructions of the kits. The wavelength of the microplate reader was adjusted to 368 nm, the absorbance values ​​of the samples in each group were measured, and the concentrations were calculated.

[0068] 4.6 Western-blot assay for Aβ detection 41-42 Protein content determination:

[0069] Hippocampal tissue (n=3) was collected from rats in each group and RIPA lysis buffer was added according to the mass / volume ratio. The tissue was pulverized at 4°C until no large tissue fragments were visible to the naked eye. The tissue homogenate was transferred to a new centrifuge tube and centrifuged at 4°C and 12,000g for 10 minutes. The supernatant was collected in a new pre-cooled centrifuge tube to obtain the total protein solution of the tissue. After protein quantification, the total protein concentration of the sample was calculated for subsequent experiments. An appropriate amount of freshly prepared electrophoresis buffer was poured into the electrophoresis tank, and the prepared gel was transferred to the electrophoresis tank. An appropriate amount of protein sample was added according to the sample concentration, and a marker was added to indicate the molecular weight of the protein. Electrophoresis was performed and the electrophoresis was stopped after the sample was completely separated. The sample was transferred to the membrane using wet transfer. The transfer buffer was prepared and poured into the transfer tank for transfer. After the transfer was completed, the PVDF membrane was removed and blocked with 5% skim milk powder freshly prepared with TBST for 1 hour at room temperature. After blocking, remove the PVDF membrane and excise the target bands according to the size of the target protein, as indicated by the marker. Wash the bands with TBST for 5 minutes to remove residual milk and prevent damage to the antibodies. Incubate the target bands with the corresponding antibodies at 4°C overnight. Wash each band with TBST for 5 minutes each time for a total of three times. Incubate each target protein with the corresponding secondary antibody conjugated with horseradish peroxidase for 2 hours at room temperature. Wash each band with TBST for 5 minutes each time for a total of three times. Add equal volumes of ECL solution prepared with luminescent solution A and luminescent solution B and drip onto each target band. Expose and develop the bands on a Bio-rad imager. Calculate and analyze the grayscale values ​​of the target bands using Image J software to calculate the relative expression level of the target protein in each sample group.

[0070] Experimental Result 1: Aβ 41-42 Protein content

[0071] Western-blot assay was used to detect Aβ in the brain tissue of rats in each group. 41-42 The results showed that the Aβ 41-42 There was no statistically significant difference in the content between the rats in the control group and those in the control group, indicating that the rats in each group were in the clinical stage of non-dementia and met the requirements of this experiment. Experimental result 2: Neurological function score

[0072] ** P<0.01

[0073] After treatment with Compound Danshen Tablets, the neurological function scores of the model group rats were significantly reduced (P < 0.01), while the neurological function scores of the donepezil group rats were not statistically different from those of the model group (P > 0.05). This indicates that Compound Danshen Tablets can improve cerebral infarction in MACO model rats, while donepezil has no effect.

[0074] Experimental results 3: Morris water maze test

[0075] ** P<0.01

[0076] The Morris water maze test was used to evaluate the cognitive function of rats in each group, and the escape latency and the number of times crossing the platform position were used as statistical criteria. The results showed that both Compound Danshen Tablets and Donepezil could improve the cognitive function of rats, reduce the escape latency (P < 0.01, P < 0.01), and increase the number of times crossing the platform position (P < 0.01, P < 0.01).

[0077] Experimental result 4: Inflammatory factor content

[0078] ** P<0.01

[0079] ELISA kits were used to measure the levels of inflammatory factors in the brain tissue of rats in each group. The results showed that Fudanshen Tablets could reduce the levels of inflammatory factors IL-6, IL-1β, and TNF-α (P < 0.01, P < 0.01, P < 0.01), while donepezil had no such effect. This suggests that Fudanshen Tablets improves cerebral infarction and cognitive function in MCAO model rats by affecting the inflammatory response in brain tissue.

[0080] Example 2

[0081] Effects of Compound Danshen Tablets on the Prevention and Treatment of Atherosclerotic Cognitive Impairment

[0082] Construction of a mouse model of atherosclerotic cognitive impairment: 50 SPF male SD rats, 10 rats per group, weighing (260 ± 10) g each, aged 6 weeks, were purchased from Beijing Huafukang Biotechnology Co., Ltd., Animal Production License No.: SCXK (Beijing) 2019-0008. The model rats were fed a high-fat diet (3% cholesterol, 0.5% sodium cholate, 0.2% propylthiouracil, 5.0% white sugar, 10.0% lard, 81.3% basal feed) for 1 week and then intraperitoneally injected with 7.0 × 10 5 IU / kg vitamin D2 was administered. Successful establishment of the atherosclerotic cognitive impairment model was determined by significant increases in serum TC, TG, and LDL-C levels, as well as thickening of the vascular wall and intima. Successful modeling was performed on rats undergoing the Morris water maze test, while rats with cognitive impairment were selected as the atherosclerotic cognitive impairment mouse model. Similar experimental procedures can be found in Example 1.

[0083] Experimental results 1: Neurological function score

[0084] ## P<0.01 compared with the control group

[0085] Compared with the control group, the neurological function scores of rats in the model group were significantly lower. After treatment with Compound Danshen Tablets and Donepezil, the neurological function scores of rats in the Compound Danshen Tablets and Donepezil groups were not statistically different from those in the model group (P>0.05). This indicates that Compound Danshen Tablets has no protective effect on the neurological function of mice with atherosclerotic cognitive impairment.

[0086] Experimental results 2: Morris water maze test

[0087] **P<0.01 compared with the model group, ## P<0.01 compared with the control group

[0088] The Morris water maze test was used to evaluate the cognitive function of rats in each group, with escape latency and the number of platform crossings used as statistical criteria. The results showed that donepezil improved the cognitive function of rats, reducing escape latency (P < 0.01) and increasing the number of platform crossings (P < 0.01). However, compound danshen tablets had no effect on the escape latency (P > 0.05) or the number of platform crossings (P > 0.05) of the model mice. This suggests that compound danshen tablets have no effect on the cognitive function of mice with atherosclerotic cognitive impairment.

[0089] Experimental result 3: Inflammatory factor content

[0090] *P<0.05 compared with the model group, ## P<0.01 compared with the control group

[0091] ELISA kits were used to measure the levels of inflammatory factors in the brain tissues of rats in each group. The results showed that Compound Danshen Tablets could reduce the level of inflammatory factor IL-6 (P < 0.05), while donepezil had no such effect. This suggests that Compound Danshen Tablets can reduce the levels of inflammatory factors in mice with atherosclerotic cognitive impairment, but has no effect on improving cognitive function.

[0092] Experimental Result 4: Aβ41-42 Protein Content

[0093] **P<0.01 compared with the model group, ## P<0.01 compared with the control group

[0094] Western-blot experiments were used to detect the content of Aβ41-42 in the brain tissue of rats in each group. The results showed that the Aβ41-42 content of the model group rats was significantly higher than that of the control group. Donepezil can significantly reduce the Aβ41-42 content of the model group rats. Compound Danshen tablets had no effect on the Aβ41-42 content, indicating that Compound Danshen tablets had no effect on the Aβ41-42 content in the brain of mice with atherosclerotic cognitive impairment.

[0095] The above experiments proved that Compound Danshen Tablets had a significant improvement effect on the cognitive function of PSCI-ND rats, but had no effect on the cognitive function of mice with atherosclerotic cognitive impairment.

[0096] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0097] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention shall be determined by the appended claims.

Claims

1. Use of a compound salvia miltiorrhiza preparation in the preparation of a drug for preventing or treating post-stroke cognitive impairment other than dementia, characterized in that: The active ingredients of the compound danshen preparation are prepared from danshen, panax notoginseng and borneol, and the mass ratio of danshen, panax notoginseng and borneol is (450±50):(141±5):(8±2).

2. The use according to claim 1, characterized in that: The mass ratio of salvia miltiorrhiza, panax notoginseng and borneol is (450±10):(141±3):(8±1).

3. The use according to claim 2, characterized in that: The mass ratio of salvia miltiorrhiza, panax notoginseng and borneol is (450±5):(141±2):(8±0.5).

4. The use according to claim 3, characterized in that: The mass ratio of salvia miltiorrhiza, panax notoginseng and borneol is 450:141:

8.

5. The use according to any one of claims 1 to 4, characterized in that: The dosage form of the compound salvia miltiorrhiza preparation is tablets, capsules, dripping pills, micropills, sprays, aerosols, oral liquids, injections or granules.

6. The use according to claim 5, characterized in that: The dosage form of the compound salvia miltiorrhiza preparation is tablets.

7. The use according to claim 6, characterized in that: The compound danshen preparation contains 0.3-0.48 mg / tablet of tanshinone ⅡA, 5.6-7.1 mg / tablet of tanshinone B, and 7.0-8.9 mg / tablet of notoginseng total saponins.

8. The use according to claim 7, characterized in that: The compound danshen preparation contains 0.38-0.48 mg / tablet of tanshinone ⅡA, 6.6-7.1 mg / tablet of tanshinone B, and 8.2-8.9 mg / tablet of notoginseng total saponins.

9. The use according to claim 1, characterized in that: The prevention or treatment of post-stroke cognitive impairment without dementia comprises reducing the contents of inflammatory factors IL-6, IL-1β and TNF-α in the drug user.

10. The use according to claim 1 or 9, wherein: The prevention or treatment of post-stroke cognitive impairment without dementia includes improving cognitive function of the person using the drug.

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