Application of salidroside derivative in preparation of medicine for preventing and / or treating cognitive impairment caused by cerebrovascular lesion

Abstract

The invention provides application of a salidroside derivative in preparation of a medicine for preventing and / or treating cognitive impairment caused by cerebrovascular lesion, and belongs to the technical field of biological medicine. The invention discloses application of a salidroside derivative SHPL-49 in preparation of a medicine for preventing and / or treating cognitive impairment caused by cerebrovascular lesion. The SHPL-49 can effectively improve the learning and memory functions after brain injury, recover the exercise coordination ability, relieve corpus callosum region myelin sheath loss above the hippocampus region and further protect the brain-sea horse region synapses. The SHPL-49 has the efficacy of treating the vascular cognitive impairment and the vascular dementia. According to the application, the medical application of the SHPL-49 is widened, and a new way is provided for treating cognitive impairment diseases caused by cerebrovascular lesion.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and particularly relates to the application of salidroside derivatives in the preparation of drugs for preventing and / or treating cognitive dysfunction caused by cerebrovascular lesions. Background Art

[0002] Vascular cognitive impairment (VCI) and vascular dementia (VaD) are both cognitive dysfunctions caused by cerebrovascular lesions and their risk factors. The synaptic damage caused by these lesions disrupts the signal transmission of neural networks, thereby leading to a decline in cognitive function. Myelin is a multi-layered lipid membrane structure formed by oligodendrocytes (in the central nervous system) or Schwann cells (in the peripheral nervous system), which wraps around the axon surface, accelerates nerve impulse conduction, maintains axonal metabolic homeostasis, and supports long-distance signal transmission. Myelin loss is the core manifestation of white matter brain injury. After myelin loss, nerve signal conduction is impaired, triggering neuronal apoptosis or loss of function, and forming a vicious cycle with the differentiation disorder of oligodendrocyte progenitor cells, promoting the progression of cognitive dysfunction.

[0003] Currently, the treatment of vascular dementia mainly relies on cholinesterase inhibitors (such as donepezil, rivastigmine, galantamine) and N-methyl-D-aspartic acid receptor (NMDA) antagonists (memantine). Although they have certain efficacy in improving the cognitive function of patients with mild VaD, the improvement of daily living ability is minimal, and long-term use of drugs may cause adverse reactions such as dizziness, insomnia, and vomiting. Summary of the Invention

[0004] In view of this, the purpose of the present invention is to provide the application of salidroside derivative SHPL-49 in the preparation of drugs for preventing and / or treating cognitive dysfunction caused by cerebrovascular lesions.

[0005] The present invention provides the application of salidroside derivative SHPL-49 in the preparation of drugs for preventing and / or treating cognitive dysfunction caused by cerebrovascular lesions.

[0006] Preferably, the cognitive dysfunction caused by cerebrovascular lesions includes vascular cognitive impairment and / or vascular dementia.

[0007] Preferably, the vascular cognitive impairment includes at least one of the following: learning and memory ability impairment, motor behavior disorder, brain tissue cell damage, and synaptic damage.

[0008] Preferably, the vascular dementia includes at least one of the following: learning and memory ability impairment, motor behavior disorder, and lesions of the cerebral white matter and / or myelin in the corpus callosum region.

[0009] Preferably, the cognitive dysfunction caused by cerebrovascular lesions includes cerebral vascular cognitive impairment caused by cerebral blood flow hypoperfusion.

[0010] Preferably, the drug has the following functions: improving the learning and memory functions after brain injury, enhancing behavioral accuracy, reducing myelin loss in the corpus callosum area above the hippocampal region, and thus protecting the synapses in the hippocampal region of the brain.

[0011] Preferably, the drug comprises at least one of the following: oral dosage form, injection, nasal administration dosage form, and transdermal administration dosage form.

[0012] Preferably, the oral dosage form comprises at least one of the following: tablets, granules, capsules, powders, coating agents, effervescent tablets, and oral liquids.

[0013] Preferably, the injection comprises injection powder and / or injection solution.

[0014] The present invention provides an application of salidroside derivative SHPL-49 in the preparation of a drug for preventing and / or treating cognitive dysfunction caused by cerebrovascular lesions. In the present invention, a rat model of bilateral common carotid artery occlusion (BCCAO) simulating cerebral hypoperfusion is established, and the preventive and therapeutic effects of SHPL-49 on vascular cognitive impairment are verified by evaluating the pharmacodynamic effects of SHPL-49 on learning and memory and behavioral disorders in vascular cognitive impairment. The results show that SHPL-49 at a dose of 90 mg / kg has an improving effect on the learning and memory ability of cerebral ischemic rats, and at the same time has a restorative effect on the motor coordination ability of cerebral ischemic rats. Meanwhile, by detecting the pathological changes in the hippocampal region of the rat brain tissue, the results show that SHPL-49 can protect the structural integrity of neurons, effectively promote neuron repair, and enhance synaptic connection and efficacy, thereby achieving the recovery of nerve function. In the prevention and treatment of vascular dementia, the present invention establishes a rat model of bilateral common carotid artery occlusion (BCCAO) simulating cerebral hypoperfusion. After 28 days of cerebral ischemia in rats, Morris water maze experiments are carried out to screen for vascular dementia rats, and they are continuously intragastrically administered for 28 days to evaluate the pharmacodynamic effects of SHPL-49 on improving learning and memory and behavioral disorders in vascular dementia, and to detect the effect of SHPL-49 on the myelin sheath in the corpus callosum area above the hippocampal region of rats. The results show that SHPL-49 can improve the spatial learning and memory ability of vascular dementia rats, reduce the memory impairment of vascular dementia rats. At the same time, SHPL-49 can protect the cell morphology of the hippocampal CA1 region in vascular dementia rats, reduce myelin sheath damage and the expression of myelin-related markers in vascular dementia rats, and promote the proliferation of OLCs and the expression of mature OLs. It can be seen that the said SHPL-49 has the pharmacodynamic effects of treating vascular cognitive impairment and vascular dementia, broadens the medical uses of SHPL-49, and at the same time provides a new way for the treatment of cognitive dysfunction diseases caused by cerebrovascular lesions. Description of the Drawings

[0015] Figure 1The results of the water maze latency experiment for 28 consecutive days of SHPL-49 administration in BCCAO model rats;

[0016] Figure 2 The results of the water maze swimming distance experiment for 28 consecutive days of SHPL-49 administration in BCCAO model rats;

[0017] Figure 3 The results of the water maze time spent in the quadrant where the platform is located experiment on the 28th day of consecutive SHPL-49 administration in BCCAO model rats;

[0018] Figure 4 The results of the water maze number of shuttle times in the area where the platform is located experiment on the 28th day of consecutive SHPL-49 administration in BCCAO model rats;

[0019] Figure 5 The results of the step-through passive avoidance experiment for 28 consecutive days of SHPL-49 administration in BCCAO model rats;

[0020] Figure 6 The results of the rotarod speed experiment when falling from the rotarod for 28 consecutive days of SHPL-49 administration in BCCAO model rats;

[0021] Figure 7 The results of the rotarod retention time experiment for 28 consecutive days of SHPL-49 administration in BCCAO model rats;

[0022] Figure 8 The results of the running wheel exercise time experiment for 28 consecutive days of SHPL-49 administration in BCCAO model rats;

[0023] Figure 9 The results of the running wheel exercise distance experiment for 28 consecutive days of SHPL-49 administration in BCCAO model rats;

[0024] Figure 10 The results of the average running wheel exercise speed experiment for 28 consecutive days of SHPL-49 administration in BCCAO model rats;

[0025] Figure 11 The results of the gait analysis experiment on the 28th day of consecutive SHPL-49 administration in BCCAO model rats;

[0026] Figure 12 The results of the H&E staining experiment on the 28th day of consecutive SHPL-49 administration in BCCAO model rats;

[0027] Figure 13 The results of the Nissl staining experiment on the 28th day of consecutive SHPL-49 administration in BCCAO model rats

[0028] Figure 14 Results of Golgi staining experiment on day 28 of continuous administration of SHPL-49 to BCCAO model rats

[0029] Figure 15 Results of dendritic spine density experiment on day 28 of continuous administration of SHPL-49 to BCCAO model rats;

[0030] Figure 16 Results of cerebral blood flow detection on day 28 of screening for vascular dementia in BCCAO model rats

[0031] Figure 17 Results of the change in escape latency over time from day 24 to day 28 of screening for vascular dementia in BCCAO model rats;

[0032] Figure 18 Results of the change in distance to the target quadrant over time from day 24 to day 28 of screening for vascular dementia in BCCAO model rats;

[0033] Figure 19 Swimming trajectory map in the place navigation experiment on day 28 of screening for vascular dementia in BCCAO model rats;

[0034] Figure 20 Results of the percentage of time spent in the target quadrant on day 28 of screening for vascular dementia in BCCAO model rats;

[0035] Figure 21 Results of the number of shuttle times experiment in the spatial exploration experiment on day 28 of screening for vascular dementia in BCCAO model rats;

[0036] Figure 22 Swimming trajectory map in the spatial exploration experiment on day 28 of screening for vascular dementia in BCCAO model rats;

[0037] Figure 23 Results of the cerebral blood flow detection experiment on vascular dementia rats on day 28 of continuous administration of SHPL-49;

[0038] Figure 24 Results of the experiment on escape latency of vascular dementia rats from day 24 to day 28 of continuous administration of SHPL-49;

[0039] Figure 25 Results of the experiment on the distance of vascular dementia rats to the target quadrant from day 24 to day 28 of continuous administration of SHPL-49;

[0040] Figure 26 Swimming trajectory map of vascular dementia rats in the place navigation experiment on day 28 of continuous administration of SHPL-49;

[0041] Figure 27 Results of the percentage of time spent by vascular dementia rats in the target quadrant on the 28th day of continuous administration of SHPL-49;

[0042] Figure 28 Results of the number of times of crossing the platform by vascular dementia rats on the 28th day of continuous administration of SHPL-49;

[0043] Figure 29 Swimming trajectory map of spatial exploration of vascular dementia rats on the 28th day of continuous administration of SHPL-49;

[0044] Figure 30 Schematic diagram of the adaptation period and test period of the novel object recognition experiment

[0045] Figure 31 Trajectory map of novel object recognition of vascular dementia rats on the 28th day of continuous administration of SHPL-49;

[0046] Figure 32 Results of the novel object recognition index of vascular dementia rats on the 28th day of continuous administration of SHPL-49;

[0047] Figure 33 Results of the number of active avoidance of vascular dementia rats on the 28th day of continuous administration of SHPL-49;

[0048] Figure 34 Results of the number of passive avoidance of vascular dementia rats on the 28th day of continuous administration of SHPL-49;

[0049] Figure 35 Results of the number of errors of vascular dementia rats on the 28th day of continuous administration of SHPL-49;

[0050] Figure 36 Results of the effect of SHPL-49 on neurons in the CA1 region of the hippocampus of vascular dementia rats on the 28th day of continuous administration;

[0051] Figure 37 Results of the effect of SHPL-49 on myelin in the corpus callosum region of vascular dementia rats on the 28th day of continuous administration;

[0052] Figure 38 Quantitative analysis results of the mRNA expression of MBP in the brain tissue of vascular dementia rats on the 28th day of continuous administration of SHPL-49;

[0053] Figure 39 Quantitative analysis results of the mRNA expression of PLP in the brain tissue of vascular dementia rats on the 28th day of continuous administration of SHPL-49;

[0054] Figure 40Quantitative analysis results of MAG mRNA expression in the brain tissue of vascular dementia rats on the 28th day of continuous administration of SHPL-49;

[0055] Figure 41 Quantitative analysis results of MOG mRNA expression in the brain tissue of vascular dementia rats on the 28th day of continuous administration of SHPL-49;

[0056] Figure 42 Results of myelin-associated protein expression in the brain tissue of vascular dementia rats on the 28th day of continuous administration of SHPL-49;

[0057] Figure 43 Quantitative analysis results of MBP protein expression in the brain tissue of vascular dementia rats on the 28th day of continuous administration of SHPL-49;

[0058] Figure 44 Quantitative analysis results of PLP protein expression in the brain tissue of vascular dementia rats on the 28th day of continuous administration of SHPL-49;

[0059] Figure 45 Quantitative analysis results of MAG protein expression in the brain tissue of vascular dementia rats on the 28th day of continuous administration of SHPL-49;

[0060] Figure 46 Quantitative analysis results of MOG protein expression in the brain tissue of vascular dementia rats on the 28th day of continuous administration of SHPL-49;

[0061] Figure 47 Quantitative analysis results of CNPase protein expression in the brain tissue of vascular dementia rats on the 28th day of continuous administration of SHPL-49;

[0062] Figure 48 Results of MBP protein expression in the brain tissue of vascular dementia rats on the 28th day of continuous administration of SHPL-49;

[0063] Figure 49 Quantitative analysis results of MBP protein expression in the brain tissue of vascular dementia rats on the 28th day of continuous administration of SHPL-49;

[0064] Figure 50 Results of Olig2 proliferation in the brain tissue of vascular dementia rats on the 28th day of continuous administration of SHPL-49;

[0065] Figure 51 Quantitative analysis results of Olig2 proliferation in the brain tissue of vascular dementia rats on the 28th day of continuous administration of SHPL-49;

[0066] Figure 52Results of the effect of continuous administration of SHPL-49 on the maturation of Olig2 in the brain tissue of vascular dementia rats on the 28th day;

[0067] Figure 53 Quantitative analysis results of the effect of continuous administration of SHPL-49 on the maturation of Olig2 in the brain tissue of vascular dementia rats on the 28th day. Detailed implementation manners

[0068] The present invention provides the use of salidroside derivative SHPL-49 in the preparation of a drug for preventing and / or treating cognitive dysfunction caused by cerebrovascular lesions.

[0069] In the present invention, the Chinese name of the salidroside derivative SHPL-49 is ((2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-(4-(4-methoxyphenyl)butoxy)tetrahydro-2H-pyran-3,4,5-triol), which is a novel glycoside derivative obtained by modifying the structure of salidroside isolated from the medicinal plant Rhodiola rosea, and the structural formula is shown as Formula I:

[0070]

[0071] In the present invention, the cognitive dysfunction caused by cerebrovascular lesions preferably includes vascular cognitive impairment and / or vascular dementia. The vascular cognitive impairment preferably includes at least one of the following: learning and memory ability impairment, motor behavior disorder, brain tissue cell damage, and synaptic damage. The vascular dementia preferably includes at least one of the following: learning and memory ability impairment, motor behavior disorder, and lesions of the corpus callosum white matter and / or myelin sheath. In the present invention, the drug preferably has the following functions: improving the learning and memory function after brain injury, increasing behavioral accuracy, reducing myelin sheath loss in the corpus callosum region above the hippocampus, and thus protecting the synapses in the hippocampus of the brain.

[0072] In the present invention, the cognitive dysfunction caused by cerebrovascular lesions preferably includes cerebral vascular cognitive impairment caused by cerebral blood flow hypoperfusion. In the embodiments of the present invention, a bilateral common carotid artery occlusion (BCCAO) rat model is used to simulate the cerebral vascular cognitive impairment injury caused by cerebral blood flow hypoperfusion. The results of the water maze experiment, shuttle experiment, rotarod fatigue experiment, running wheel experiment, VisuGait gait analysis, and H&E staining, Nissl staining, and Golgi staining of brain tissue all show that a vascular cognitive impairment rat model has been successfully constructed. In another embodiment of the present invention, using the established BCCAO rat model, a Morris water maze experiment is performed 28 days after cerebral ischemia in rats to screen for a vascular dementia rat model.

[0073] In the embodiments of the present invention, experiments such as Morris water maze, shuttle, gait, rotarod, running wheel, etc. were used to evaluate the effects of SHPL-49 on learning and memory impairment and behavioral disorders in rats with cognitive impairment. By performing H&E, Nissl, and Golgi staining analyses on brain tissue sections, the protective effect of SHPL-49 on brain tissue cells and the influence on synaptic remodeling were detected. The results showed that SHPL-49 at a dose of 90 mg / kg had an improving effect on the learning and memory ability of cerebral ischemia rats and a restorative effect on the motor coordination ability of cerebral ischemia rats. At the same time, by detecting the pathological changes in the hippocampal region of the rat brain tissue, the results showed that SHPL-49 protected the structural integrity of neurons, effectively promoted neuron repair, enhanced synaptic connections and efficacy, thereby achieving the restoration of nerve function.

[0074] In another embodiment of the present invention, experiments such as water maze experiment, shuttle experiment, novel object recognition, etc. were used to investigate its cognitive and memory functions, and the effects of SHPL-49 on cerebral white matter and myelin lesions in the corpus callosum region were detected by immunohistofluorescence and protein quantification analysis experiments on brain tissue. The results showed that SHPL-49 could improve the spatial learning and memory ability of vascular dementia rats, alleviate the memory impairment of vascular dementia rats. At the same time, SHPL-49 could protect the cell morphology in the hippocampal CA1 region of vascular dementia rats, reduce myelin damage and the expression of myelin-related markers in vascular dementia rats, and promote the proliferation of OLCs and the expression of mature OLs.

[0075] In the present invention, the drug preferably includes at least one of the following: oral dosage form, injection, nasal administration dosage form, and transdermal administration dosage form. The oral dosage form preferably includes at least one of the following: tablets, granules, capsules, powders, coating agents, effervescent tablets, and oral liquids. The injection preferably includes injection powder and / or injection solution.

[0076] The following is a detailed description of the application of the salidroside derivative provided by the present invention in the preparation of a drug for preventing and / or treating cognitive dysfunction caused by cerebrovascular diseases in combination with embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0077] Example 1

[0078] Protective effect of salidroside derivative SHPL-49 on vascular cognitive impairment rats

[0079] 1. A bilateral common carotid artery occlusion (BCCAO) rat model was used to simulate cognitive impairment caused by cerebral hypoperfusion. The model was established as follows: After the rats were fasted for 6 - 8 h, they were induced with 4% isoflurane and maintained with 2% isoflurane anesthesia. At the same time, a heating pad was used to control the rectal temperature at 36 - 37 °C. The necks of the rats were wiped and disinfected with iodophor. A longitudinal incision about 1.5 cm was made in the middle of the neck. The subcutaneous tissue was bluntly dissected with forceps, and the left common carotid artery, external carotid artery, and internal carotid artery were carefully exposed, taking care to avoid the vagus nerve accompanying the common carotid artery. The bilateral common carotid arteries were doubly ligated with 4 - 0 silk thread, and a successful model was defined as a more than 50% decrease in cerebral blood flow after ligation. After the operation, the rats were placed in a warm and quiet environment, and after waking up, the rats were allowed to freely ingest water and food.

[0080] 2. According to the experimental design, the rats were randomly divided into a Sham group, a Model group, a 90 mg / kg SHPL - 49 group, and a 90 mg / kg salidroside (SAL.) group, with 6 rats in each group. Starting 30 min after ischemia in the BCCAO rat model, continuous intragastric administration was carried out for 28 days. Since SHPL - 49 is a new glycoside derivative obtained by structural modification of salidroside (SAL.), SAL. was used as a positive control in this study. The experimental procedure was as follows: The step - through avoidance test was carried out on the 7th, 14th, 21st, and 28th days, and the Morris water maze test was carried out from the 24th to 28th days.

[0081] 3. The water maze test is a classic method for detecting the learning and memory ability of rodents, including the spatial exploration test and the place navigation test. In this experiment, the place navigation test was carried out on the 24th - 28th days of intragastric administration of SHPL - 49. For 5 consecutive days, the rats were placed into the water maze facing the pool wall from 4 different quadrants of the water maze bath respectively, and each rat was placed into a different quadrant once a day. The time required for it to find the platform hidden 1 cm below the water surface was recorded. After 28 days of administration, the platform was removed for the spatial exploration test. The rats were placed into the water maze pool from a random quadrant, and their swimming trajectories within 90 s and the number of times they explored the platform were recorded to examine the rats' memory ability of the original platform.

[0082] The experimental results showed that compared with the Sham group, in the Model group, the latency of the rats to climb onto the platform was significantly increased ( Figure 1 ), the swimming distance of the rats to climb onto the platform was significantly increased ( Figure 2 ), the proportion of the time the rats stayed in the platform quadrant was significantly decreased ( Figure 3 ), and the number of times the rats passed through the platform was significantly decreased ( Figure 4 )( ## P < 0.01, ***P < 0.001), indicating that the BCCAO model was successfully established. Rats were intragastrically administered with 90 mg / kg of SHPL-49. Compared with the Model group, the latency of rats to climb onto the platform was significantly reduced from the 25th day to the 28th day of administration. The swimming distance of rats to climb onto the platform was reduced on the 25th day and the 28th day. The results of the spatial exploration experiment on the 28th day of administration showed that SHPL-49 could significantly increase the proportion of time rats stayed in the platform quadrant and the number of times rats passed through the platform ( # P < 0.05, ## P < 0.01). The 90 mg / kg of SAL raw drug had no such preventive effect. It indicated that within 28 days of administration, 90 mg / kg of SHPL-49 had a restorative effect on the learning and memory ability of BCCAO rats with cerebral ischemia.

[0083] 4. A BCCAO rat model was established. Shuttle experiments were conducted on the 7th day, 14th day, 21st day, and 28th day after administration. Each time the test was carried out, the rats were first placed in the light chamber to adapt to the environment for 30 s. Subsequently, the light and sound generator were turned on to emit conditioned stimulus signals, and the rats were given electrical stimulation. The number of errors of the rats within 5 min was recorded. Before the experiment started, the rats were given an adaptation period of 1 - 2 days. Every day, the rats were placed in the step-through shuttle box to freely explore the light chamber and the dark chamber for 10 min without electrical stimulation to make them familiar with the experimental box environment, and then the formal experiment began.

[0084] The experimental results showed that: compared with the Sham group, the number of errors of rats in the Model group increased significantly ( Figure 5 )( ** P < 0.01), indicating that the BCCAO model was successfully established. Compared with the Model group, rats were continuously intragastrically administered with SHPL-49 for 28 days, and the number of errors after cerebral ischemia injury in rats could be significantly reduced ( # P < 0.05). However, 90 mg / kg of SAL had no significant difference in the number of shuttle errors after cerebral ischemia injury in rats (ns: P > 0.05). It indicated that within 28 days of administration, 90 mg / kg of SHPL-49 had an improving effect on the learning and memory ability of cerebral ischemia rats.

[0085] 5. Establish a BCCAO rat model, and perform rotarod fatigue experiments on the 7th, 14th, 21st and 28th days after administration. Three days of adaptive training were arranged before each experiment. The rotating rod speed was set to a low and constant 8r / min, and the rats were allowed to perform adaptive training on the rotating rod for 5 minutes every day. During the formal experiment on the 28th day, the rotarod instrument was uniformly accelerated to 40r / min with an initial speed of 4r / min. The time from the placement of each rat on the rotating rod to the fall (i.e., the residence time) and the rotation speed of the rotating rod when it fell (i.e., the falling speed) were recorded. If the rat stays on the rotating rod for 5 minutes without falling, the residence time is recorded as 5 minutes and the falling speed is 40r / min.

[0086] The results showed that compared with the Sham group, the rotarod speed of the Model group rats when falling was significantly reduced ( Figure 6 ), the time that rats stayed on the rotarod was significantly reduced ( Figure 7 )( *** P<0.001), indicating that the BCCAO model was successfully established. Compared with the Model group, oral administration of 90 mg / kg SHPL-49 and 90 mg / kg SAL. could significantly increase the speed of the rats falling and the time the rats stayed on the rotarod ( ## P<0.01, ### P<0.001). This indicates that within 28 days of administration, 90 mg / kg of SHPL-49 and 90 mg / kg of SAL. have a restorative effect on the motor coordination ability of rats with cerebral ischemia.

[0087] 6. Establish a BCCAO rat model. After the 28th day of SHPL-49 administration, a running wheel experiment was performed. The experiment used an automatic recording running wheel system. The rats were given a 2-day adaptation period on the 26th and 27th days. Each rat was placed in a running wheel device and allowed to freely explore the running wheel environment for 1 hour. In the formal experiment, the running time, running distance and average speed of each rat within 1 hour were recorded using the data software provided by the running wheel system.

[0088] The results showed that compared with Sham, the exercise time of rats in Model group was significantly reduced ( Figure 8 ), the movement distance of rats was significantly reduced ( Figure 9 ), the average speed of rat movement was significantly reduced ( Figure 10 ),( ** P<0.01, ***P<0.001), indicating that the BCCAO model was successfully established. Compared with the Model group, rats were given 90 mg / kg of SHPL-49 by gavage on the 25th and 26th days, which could significantly prolong the time and distance of the rats' running wheel exercise. On the 25th and 27th days after administration, the average speed of the rats' running wheel exercise could be significantly increased ( # P<0.05, ## P<0.01, ### P<0.001). However, SAL. could significantly prolong the running wheel time and average speed of rats only on the 25th day of administration, and could significantly increase the running wheel distance of rats on the 26th day of administration.

[0089] 7. The experiment used the VisuGait gait analysis system, which mainly consists of a special transparent runway, a high-resolution camera and professional image analysis software. A three-day training period was arranged from the 25th day to the 27th day. The rats were placed at the starting point of the runway every day and gently driven to walk along the runway. The rats were allowed to walk 5 back and forth each time. The formal experiment was conducted on the 28th day of drug administration, and the camera recorded the entire walking process of the rats from the starting point to the end point. The image analysis software that comes with the VisuGait gait analysis system was used for analysis, and the normal step sequence ratio and gait disorder coefficient of the rats were calculated.

[0090] In the rat BCCAO model, SHPL-49 was administered intragastrically at 90 mg / kg 30 minutes after ischemia for 28 consecutive days. The results showed that compared with the Sham group, the proportion of normal step sequence in the Model group was significantly decreased ( Figure 11 ),( *** P<0.001), indicating that the BCCAO model was successfully established. Rats given 90 mg / kg of SHPL-49 by intragastric administration can significantly increase the proportion of normal steps in rats compared with the Model group treated with 0.9% sodium chloride by intragastric administration ( ### P<0.001). Rats given 90 mg / kg of SAL by gavage can significantly increase the proportion of normal steps in rats compared with the Model group ( # P<0.05). This indicates that within 28 days of administration, 90 mg / kg of SHPL-49 and SAL. have a restorative effect on the motor coordination ability of rats with cerebral ischemia.

[0091] 8. H&E staining to evaluate the effect of SHPL-49 on pathological changes in rat brain tissue

[0092] In the rat BCCAO model, SHPL-49 was administered intragastrically at 90 mg / kg SHPL-49 30 minutes after ischemia. Brain tissue was obtained after continuous administration for 28 days, fixed with paraformaldehyde for 48 hours, embedded in paraffin, sectioned, and stained with H&E.

[0093] The results showed that compared with the Sham group, the cells in the CA3 region of the hippocampus in the Model group were arranged more loosely and disorderly, and vacuoles appeared in the tissue ( Figure 12 ). Compared with the Model group, the brain tissue morphology of the 90 mg / kg SHPL-49 group was complete, with clear layers, neatly arranged cells, full cell bodies in regular polygons, clear and centered nucleoli, evenly distributed chromatin, normal cytoplasmic basophilia, and no obvious vacuoles or shrinkage, indicating that the drug effectively improved the pathological state of brain tissue by protecting the structural integrity of neurons.

[0094] 9. Nissl staining to evaluate the effect of SHPL-49 on Nissl bodies in rat brain tissue

[0095] Immerse the alcohol-hydrated brain tissue slices in Nissl staining solution preheated to 60°C for 20 minutes to stain the Nissl bodies dark blue. After staining, wash away the excess staining solution, place the slides in 70% alcohol for 5 minutes, and then place the slides in 80% alcohol, 95% alcohol, 100% alcohol I, and 100% alcohol II for 5 minutes each for dehydration. Use xylene for transparency and fix the slides with neutral gum.

[0096] The stained sections were observed using an optical microscope. The Nissl bodies of normal neurons are dark blue granular or blocky and evenly distributed in the cytoplasm. If neurons are damaged, the Nissl bodies may dissolve, decrease or disappear, and typical images are recorded and taken. The experimental results showed that compared with the Sham group, neurons in the Model group showed obvious swelling, nuclear displacement and cell body vacuolation, indicating that the neuronal synthesis function was impaired. Treatment with 90 mg / kg of SHPL-49 improved these adverse effects, and the morphology of neurons in the CA3 region of the hippocampus was significantly improved, with clear cell body boundaries, clear and centered nucleoli, and evenly distributed along the cytoplasm, indicating that SHPL-49 effectively promoted the repair of the neuronal protein synthesis system ( Figure 13 ).

[0097] 10. Golgi staining to detect the effect of SHPL-49 on synaptic remodeling in rats

[0098] In the rat BCCAO model, after 30 minutes of ischemia, SHPL-49 at a dose of 90 mg / kg was administered by gavage. After 28 consecutive days of administration, fresh brain tissues were collected, fixed with 4% paraformaldehyde, and processed using the FD Rapid Golgi Staining Kit (FD NeuroTechnologies, PK401, UCA) according to the kit instructions. The Golgi-stained sections should be stored in the dark at room temperature, and the specimens should be imaged as soon as possible (see Figure 14 ). The density of dendritic spines was quantified using ImageJ software. The quantification method was n (number of dendritic spines) / dendritic length (100 μm). The data were recorded and processed and analyzed. Dendritic spines are the structural basis of synaptic plasticity, and the recovery of their density directly reflects the positive regulatory effect of the drug on neuronal network reorganization. The experimental results showed that compared with the Sham group, the density of neuronal dendritic spines in the Model group decreased significantly ( * P < 0.05), the dendritic branches decreased and the morphology was abnormal, indicating damage to the synaptic connection network. After administration of 90 mg / kg of SHPL-49, the density of dendritic spines increased significantly compared with the Model group ( ### P < 0.001), and the spine morphology tended to be regular ( Figure 15 ). This indicates that SHPL-49 mediates the recovery of nerve function by promoting the structural reconstruction of dendritic spines, enhancing the density and efficacy of synaptic connections.

[0099] Example 2

[0100] Therapeutic effect of SHPL-49 on rats with vascular dementia

[0101] 1. Screening of rats with vascular dementia using the Morris water maze model: On the 24th - 28th day after the establishment of the BCCAO rat model, the Morris water maze experiment was conducted. The escape latency ratio of the experimental group rats and the control group rats (see Formula I) was compared to evaluate whether the model was successful. Note: The 24th - 25th days were for training, and no data statistics were performed.

[0102] Standard ratio for establishing the model of rats with vascular dementia = (Escape latency of Model group rats on the 26th - 28th day - Escape latency of Sham group rats on the 26th - 28th day) / Escape latency of Model group rats on the 26th - 28th day × 100% Formula I;

[0103] When the standard ratio for establishing the model of rats with vascular dementia > 20%, it is considered to be vascular dementia.

[0104] When 20% < standard ratio for establishing the model of rats with vascular dementia ≤ 30%, it is mild vascular dementia;

[0105] When 30% < standard ratio for establishing the model of rats with vascular dementia ≤ 40%, it is moderate vascular dementia;

[0106] The modeling standard ratio of rats with vascular dementia > 40% is severe vascular dementia.

[0107] According to the changes in cerebral blood flow of rats after 28 days of modeling ( Figure 16 ) and the evaluation results of the Morris water maze experiment ( Figures 17 - 22 ) vascular dementia model rats were obtained. Except for the rats in the normal group (Sham group), the remaining vascular dementia rats were randomly divided into 4 groups: the model group (Model group), the SHPL-49 60mg / kg administration group, the SHPL-49 90mg / kg administration group, and the Ginkgo biloba extract EGb761 group (60mg / kg). After obtaining the vascular dementia rats, it was counted as the 0th day of administration, and then continuous intragastric administration was carried out for 28 days. The administration volume was 10 mL / kg. The normal group and the model group were given normal saline, and the drug was administered once a day at the same time period. The experimental process was as follows: The vascular dementia model rats were screened and continuously administered for 28 days. During this period, the Morris water maze experiment was carried out on days 24 - 28, and the novel object recognition experiment was carried out on days 26 - 28.

[0108] 2. Detection of the change in cerebral blood flow of vascular dementia rats after 28 consecutive days of administration of SHPL-49 by a Doppler blood flow meter.

[0109] In the Doppler blood flow meter experiment, a laser probe was used to detect the change in cerebral vascular blood flow of rats. Cerebral blood flow was detected 28 days after administration of SHPL-49 to vascular dementia rats. The results showed that the cerebral blood flow of rats in the Model group increased, but was still significantly lower than that in the Sham group (P < 0.001). Compared with the Model group, after treatment with 60mg / kg SHPL-49 and 60mg / kg Ginkgo biloba extract (EGb761), the cerebral blood flow of rats increased (P < 0.05), and after treatment with 90mg / kg SHPL-49, the cerebral blood flow of rats increased extremely significantly (P < 0.01)( Figure 23 )

[0110] 3. Detection of the effect of SHPL-49 on the spatial learning and memory ability of vascular dementia rats after 28 consecutive days of administration

[0111] The Morris water maze experiment includes a place navigation experiment and a spatial exploration experiment. The place navigation experiment was carried out on days 24 - 28 after administration of SHPL-49 to vascular dementia rats, and it was continuously measured for 5 days.

[0112] The experimental results showed that on days 24 - 28 of administration, the escape latency ( Figure 24 ) and the distance to the target quadrant ( Figure 25) was significantly longer than that of the Sham group (P<0.001). After treatment with 60 mg / kg SHPL-49 and 60 mg / kg of Ginkgo biloba extract EGb761 for 24-28 days, the escape latency of rats was shortened compared with the Model group (P<0.05), and the distance of rats to the target quadrant was shortened compared with the Model group (P<0.001). After treatment with 90 mg / kg SHPL-49 for 24-28 days, the escape latency of rats was shortened more significantly (P<0.001), and the distance to the target quadrant was shortened (P<0.001). Compared with the Model group, the spatial exploration swimming trajectories of vascular dementia rats in the SHPL-49 administration group and the Ginkgo biloba extract EGb761 administration group were clearer ( Figure 26 ). Although the escape latency and the distance to the target quadrant of rats in the 90 mg / kg SHPL-49 administration group were shorter than those of rats in the 60 mg / kg SHPL-49 administration group during the 24-28 days of administration, there was no statistical difference (P>0.05). After 28 days of SHPL-49 administration, the platform was removed and a spatial exploration experiment was carried out. The results showed that the percentage of time that rats in the Model group stayed in the target quadrant was shorter than that of rats in the Sham group ( Figure 27 )(P<0.001), and the number of times of crossing the platform was less ( Figure 28 )(P<0.001). Compared with the Model group, after treatment with 60 mg / kg SHPL-49 and 60 mg / kg of Ginkgo biloba extract EGb761, the percentage of time that rats stayed in the target quadrant was longer (P<0.05), and the number of times of crossing the platform was more (P<0.001). After treatment with 90 mg / kg SHPL-49, the percentage of time that rats stayed in the target quadrant was significantly longer (P<0.01), and the number of times of crossing the platform was significantly more (P<0.001). It was shown that the treatment with SHPL-49 significantly alleviated the spatial learning and memory impairment of vascular dementia rats. There were statistical differences in the percentage of time that rats in the 90 mg / kg SHPL-49 administration group stayed in the target quadrant and the number of times of crossing the platform compared with rats in the 60 mg / kg SHPL-49 administration group and the Ginkgo biloba extract EGb761 administration group during the 28th day of administration (P<0.05). Compared with the Model group, the positioning navigation swimming trajectories of vascular dementia rats in the SHPL-49 administration group and the Ginkgo biloba extract EGb761 administration group were clearer, and there were more trajectories staying in the target quadrant ( Figure 29 ).

[0113] 4. Detection of the effect of continuous administration of SHPL-49 on the spatial learning and memory ability of vascular dementia rats on the 28th day

[0114] Novel object recognition makes use of the curiosity of rodents for novel objects and their memory of old and new objects, and is used to evaluate the memory function of rodents ( Figure 30)。The experimental box was 60 cm × 60 cm × 60 cm in size. The rats for modeling were experimented on days 54 - 56 and divided into 3 stages: ① Adaptation stage: The rats were placed in a box without any objects for 5 minutes to adapt to the experimental environment, twice a day for 3 consecutive days; ② Familiarization stage: Two identical objects (F1 and F2) were placed in the box at a position 10 cm away from the side wall. The rats were placed into the box from the opposite direction of the objects and allowed to move freely for 5 minutes to familiarize themselves with the objects, and the movement trajectories in the box were recorded; ③ Testing stage: After the familiarization stage, one of the objects (F2) was replaced with a new object (N), and the rats were allowed to freely explore in the experimental box for 5 minutes, and the movement trajectories were recorded. After each test, 75% ethanol was used to remove the smell to avoid interference with the rats. The animal behavior Smart software system was used to record the exploration time of the rats for the new object and the old object respectively, and the novel object recognition index was calculated according to the ratio of the difference between the sniffing time of the new object and the familiar object time to the total time. In this experiment, the rats with vascular dementia were given the novel object recognition behavioral training on days 26 - 27 of drug administration, and then the novel object recognition behavioral detection was carried out on day 28.

[0115] The results showed that the exploration time of the rats in the Model group for the new object was shorter than that in the Sham group, and the recognition index was significantly decreased compared with the Sham group (P < 0.001). Compared with the Model group, after treatment with 60 mg / kg SHPL - 49 and 60 mg / kg of the ginkgo biloba extract EGb761, the exploration time of the rats for the new object was prolonged and the recognition index increased (P < 0.01). After treatment with 90 mg / kg SHPL - 49, the exploration time of the rats for the new object was significantly prolonged and the recognition index was significantly increased (P < 0.001)( Figure 31 ). Among them, the recognition index of the rats in the SHPL - 49 90 mg / kg administration group increased compared with that of the rats in the SHPL - 49 60 mg / kg administration group within 28 days of drug administration( Figure 32 ), with statistical difference (P < 0.05). It indicated that the treatment with SHPL - 49 significantly alleviated the memory impairment of the rats with vascular dementia.

[0116] 5. Detection of the effect of continuous administration of SHPL - 49 on the learning and memory ability of rats with vascular dementia on the 28th day

[0117] Shuttle training enables animals to learn to avoid harmful stimuli under specific conditions, thereby observing their active and passive avoidance responses and the number of errors, so as to evaluate their learning and memory ability. The shuttle behavioral detection was carried out on the rats with vascular dementia after the end of drug administration on the 28th day. The results showed that the number of active avoidance responses( Figure 33 ), the number of passive avoidance responses( Figure 34 ) of the rats in the Model group were significantly less than those in the Sham group (P < 0.001), and the number of errors( Figure 35) It was significantly increased compared with the Sham group (P<0.001); compared with the Model group, after treatment with 60 mg / kg SHPL-49 and 60 mg / kg of Ginkgo biloba extract EGb761, the active avoidance times and passive avoidance times of rats were significantly increased compared with the Model group (P<0.05), and the error times were significantly reduced compared with the Model group (P<0.01). After treatment with 90 mg / kg SHPL-49, the active avoidance times of rats were significantly increased compared with the Model group (P<0.001), the passive avoidance times were significantly increased compared with the Model group (P<0.001), and the error times were significantly reduced compared with the Model group (P<0.001). Among them, the active avoidance times and passive avoidance times of rats in the SHPL-49 90 mg / kg administration group were increased, and the error times were reduced compared with those in the SHPL-49 60 mg / kg administration group and the Ginkgo biloba extract EGb761 administration group within 28 days after administration, with statistical differences (P<0.05). However, the passive avoidance times of rats in the SHPL-49 90 mg / kg administration group were increased compared with those in the Ginkgo biloba extract EGb761 administration group within 28 days after administration, without statistical differences. It shows that the treatment of SHPL-49 significantly alleviates the memory impairment of rats with vascular dementia.

[0118] 6. Detection of the effect of continuous administration of SHPL-49 on the pathology of the hippocampal CA1 region of rats with vascular dementia on the 28th day by hematoxylin-eosin (HE) staining

[0119] To test the integrity of the hippocampal structure of rats in each group, in this experiment, H&E staining was used to observe the hippocampal CA1 region. After 28 days of administration, the rats were anesthetized with isoflurane, cerebral blood flow was detected, and whole brains were taken by abdominal aortic bloodletting, and then H&E staining of brain tissue sections was performed. Observation was carried out under an optical microscope, and photos were taken of the hippocampal CA1 region.

[0120] The results showed that the neurons in the hippocampal CA1 region of rats in the Sham group were arranged closely, with uniform staining, normal cell morphology, moderate size, large and round cell nuclei, and clear nucleoli; while the number of neurons in the hippocampal CA1 region of rats in the Model group was significantly reduced, arranged loosely, with irregular morphology, spindle-shaped or polygonal, cell nuclei shrank, and nucleoli disappeared. The loss of neurons in the hippocampal CA1 region of rats in the SHPL-49 group and the Ginkgo biloba extract EGb761 group was significantly reduced, the cell arrangement was relatively close and uniform, the cell morphology was more plump, and the shrinkage of cell nuclei was significantly reduced, and the improvement was most obvious in the 90 mg / kg treatment group of SHPL-49 ( Figure 36 ). The results show that the treatment of SHPL-49 can protect the cell morphology of the hippocampal CA1 region of rats with vascular dementia.

[0121] 7. Detection of the effect of continuous administration of SHPL-49 on myelin injury of rats with vascular dementia on the 28th day by luxol fast blue (LFB) staining

[0122] Myelin damage to nerve cells in the white matter of the brain can cause white matter lesions. Therefore, in this paper, LFB staining was performed on the myelin sheath in the corpus callosum region of rats. After dewaxing the paraffin sections of the corpus callosum layer with xylene and gradient ethanol, they were placed in an LFB staining cylinder preheated to 60 °C and placed in an oven at 60 °C for continuous heating for 4 hours. After the sections were taken out and cooled to room temperature, they were rinsed with running tap water (pay attention to the flow rate to avoid washing away the brain slices) to remove the staining solution. Then the sections were alternately placed in 70% ethanol and 0.05% lithium carbonate solution for color separation, and the degree of color separation was controlled under a microscope. After sufficient color separation, the color separation was terminated with tap water. Then the sections were dehydrated with gradient ethanol, placed in a fume hood for transparency with xylene, sealed with neutral resin, air-dried, and then images were collected using a microscope. The degree of myelin sheath demyelination in the corpus callosum was calculated using Image J software.

[0123] The results showed that the white matter fibers in the corpus callosum region of the rats became loose after modeling. More vacuoles were visible in the corpus callosum region of the Model group. After treatment with SHPL-49, the arrangement in the corpus callosum region of the rats was relatively tight and the vacuoles decreased. The results are shown in Figure 37 , indicating that SHPL-49 can reduce myelin sheath damage in rats with vascular dementia.

[0124] 8. Detection of the effect of continuous administration of SHPL-49 on the mRNA expression of myelin sheath markers in rats with vascular dementia on the 28th day by real-time fluorescence quantitative PCR (RT-qPCR)

[0125] Approximately 100 mg of rat brain tissue was taken, 1 ml of Trizol was added, and it was ground using a grinder to fully lyse it. A pre-cooled centrifuge was prepared and the whole process was carried out on ice. 200 μl of CHCl3 was added to each centrifuge tube, vortexed for 15 s, and then left to stand at room temperature for 5 min. After centrifugation at 4 °C and 12,000 rpm for 10 min, the resulting solution was divided into three layers: a red organic phase at the bottom, a white middle layer, and a colorless aqueous phase at the top. The colorless aqueous phase containing RNA at the top was transferred to a new 1.5 ml centrifuge tube. An equal volume of isopropanol to the colorless aqueous phase at the top was added, mixed well, and left to stand at room temperature for 10 min. After centrifugation at 4 °C and 12,000 rpm for 10 min, the supernatant was discarded to obtain a white precipitate. 500 μl of 75% ethanol was added and vortexed thoroughly. Under the condition of 4 °C, centrifugation was carried out at 7,500 rpm for 5 min. The upper layer of liquid was carefully discarded, the centrifuge tube cap was opened, and it was placed at room temperature to completely volatilize the ethanol. An appropriate amount of DEPC water was added to fully dissolve the RNA, and Rt-qPCR experiments were carried out to analyze the mRNA expression levels of myelin-related markers MBP (myelin basic protein), PLP (proteolipid protein), MAG (myelin-associated glycoprotein), and MOG (myelin oligodendrocyte glycoprotein).

[0126] The results showed that the mRNA expression of myelin-related markers in the Model group was significantly lower than that in the Sham group (P<0.001); compared with the Model group, after treatment with 60 mg / kg SHPL-49 and 60 mg / kg of Ginkgo biloba extract EGb761, the mRNA expression of myelin-related markers in rats increased (P<0.05), and after treatment with 90 mg / kg SHPL-49, the mRNA expression of myelin-related markers in rats increased significantly (P<0.001). Among them, the mRNA expression of myelin-related markers in the rats in the SHPL-49 90 mg / kg administration group was increased compared with that in the rats in the SHPL-49 60 mg / kg administration group and the Ginkgo biloba extract EGb761 administration group within 28 days of administration, with statistical significance( Figures 38 - 41 )(P<0.05). It is indicated that SHPL-49 can reduce the mRNA expression of myelin-related markers in rats with vascular dementia.

[0127] 9. Detection of the effect of SHPL-49 on the expression of myelin protein in rats with vascular dementia by Western Blot (WB) experiment

[0128] After cutting the brain tissue samples into pieces, 1 ml of lysis buffer (RIPA protein lysis buffer: protease inhibitor: phosphatase inhibitor = 100:2:2) was added. Then, it was transferred to a pre-cooled grinder for grinding. After grinding into a homogenate, the sample was placed on ice and allowed to stand for lysis for 30 min. After centrifugation at 4°C and 12,000 rpm for 10 min, the supernatant was transferred to a new tube, which was the total protein in the brain tissue, and protein analysis was performed by Western Blot experiment. In this part, the expression of myelin-related markers MBP, PLP, MAG, MOG, and CNPase (2',3'-cyclic nucleotide 3'-phosphodiesterase) proteins was observed.

[0129] The results showed that the myelin protein density in the Model group was significantly lower than that in the Sham group (P<0.001); compared with the Model group, after treatment with 60 mg / kg SHPL-49 and 60 mg / kg of Ginkgo biloba extract EGb761, the myelin protein density in rats increased (P<0.05), and after treatment with 90 mg / kg SHPL-49, the myelin protein density in rats increased significantly (P<0.001). Among them, the myelin protein density in the rats in the SHPL-49 90 mg / kg administration group was increased compared with that in the rats in the SHPL-49 60 mg / kg administration group and the Ginkgo biloba extract EGb761 administration group within 28 days of administration, with statistical significance (P<0.05)( Figures 42 - 47 ). It is indicated that SHPL-49 can reduce myelin damage in rats with vascular dementia.

[0130] 10. Immunofluorescence (IF) experiment was conducted to detect the effect of SHPL-49 on the myelin MBP immunofluorescence in rats with vascular dementia

[0131] After the sections were dewaxed, antigen repaired, and blocked with 10% goat serum, the corresponding fluorescent primary and secondary antibodies were added sequentially for incubation. After DAPI counterstaining and mounting, the sections were observed and images were collected using a fluorescence confocal microscope. The excitation wavelength of DAPI was 330 - 380 nm, the emission wavelength was 420 nm, showing blue light. The excitation wavelength of FITC was 465 - 495 nm, the emission wavelength was 515 - 555 nm, showing green light. The excitation wavelength of Cy3 was 510 - 560 nm, the emission wavelength was 590 nm, showing red light.

[0132] The myelin MBP immunofluorescence staining was used to observe the white matter damage in the corpus callosum area of rats. The results showed that the optical density value of MBP in the Model group decreased significantly, with statistical significance (P < 0.001). After treatment with SHPL-49, the optical density value of MBP in the corpus callosum area of rats increased significantly (P < 0.001). The results are shown in Figure 48 and Figure 49 , indicating that SHPL-49 can reduce the myelin damage in rats with vascular dementia.

[0133] 11. Immunofluorescence (IF) experiment was conducted to detect the effect of SHPL-49 on oligodendrocyte lineage cells (OLCs) and mature oligodendrocytes (OLs) in the myelin of the corpus callosum area in rats with vascular dementia

[0134] To verify the survival of OLCs and mature OLs in the corpus callosum area of rats with vascular dementia after SHPL-49 intervention, Olig2 was used to label oligodendrocyte lineage cells in the corpus callosum area, Ki67 was used to label proliferating cells, and CC1 was used to label mature oligodendrocytes.

[0135] The results showed that the proliferation of Olig2 in the corpus callosum area of rats with vascular dementia decreased significantly, with significant difference (P < 0.01), and the expression of CC1 decreased, with significant difference (P < 0.001). After treatment with SHPL-49, the proliferation of Olig2 in the corpus callosum area of rats with vascular dementia increased significantly (P < 0.01) (the results are shown in Figure 50 and Figure 51 ), and at the same time, after treatment with SHPL-49, the expression of CC1 increased significantly (P < 0.01) (the results are shown in Figure 52 and Figure 53 ). The above results indicate that SHPL-49 can significantly promote the proliferation of OLCs and the expression of mature OLs.

[0136] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. Use of salidroside derivative SHPL-49 in the preparation of drugs for preventing and / or treating cognitive dysfunction caused by cerebrovascular diseases.

2. The application according to claim 1, characterized in that: The cognitive dysfunction caused by cerebrovascular lesions includes vascular cognitive impairment and / or vascular dementia.

3. The application according to claim 2, characterized in that: The vascular cognitive impairment includes at least one of the following: impairment of learning and memory ability, motor behavior disorder, brain tissue cell damage and synaptic damage.

4. The application according to claim 2, characterized in that: The vascular dementia includes at least one of the following: impairment of learning and memory ability, motor behavior disorder, and lesions of the white matter and / or myelin sheath in the corpus callosum area.

5. The use according to claim 1, characterized in that: The cognitive dysfunction caused by cerebrovascular lesions includes cerebral vascular cognitive impairment caused by cerebral blood flow hypoperfusion.

6. The use according to claim 1, characterized in that: The drug has the following functions: improving learning and memory function after brain injury, restoring motor coordination ability, alleviating myelin loss in the corpus callosum area above the hippocampus, and thus protecting synapses in the hippocampus.

7. The use according to any one of claims 1 to 6, characterized in that: The medicine comprises at least one of the following: oral dosage form, injection dosage form, nasal dosage form and transdermal dosage form.

8. The use according to claim 6, characterized in that: The oral dosage form includes at least one of the following: tablets, granules, capsules, powders, coatings, effervescent tablets and oral solutions.

9. The use according to claim 7, characterized in that: The injection includes injection powder and / or injection solution.

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