Brain-targeted ginsenoside Rg1 derivative and application thereof in preparation of medicine for treating Alzheimer's disease

Abstract

The invention discloses design and synthesis of a series of brain-targeted ginsenoside Rg1 derivatives and application of the brain-targeted ginsenoside Rg1 derivatives in treatment of Alzheimer's disease. According to the invention, ginsenoside Rg1 and polyethylene glycol with a specific chain length are covalently linked to successfully construct the derivative capable of enhancing the penetrating power of the blood-brain barrier. The series of derivatives provided by the invention not only solve the problems of poor brain targeting and insufficient stability of natural Rg1, but also can inhibit neuroinflammation by regulating and controlling an NLRP3 / caspase-1 signal channel in an LPS-induced neuroinflammation model, and finally, the learning and memory ability is remarkably improved. The product is simple and convenient in preparation process and good in biological safety, and a new candidate compound is provided for developing a new generation of Alzheimer disease treatment medicines.

Description

Technical Field

[0001] This invention relates to the fields of pharmaceutical technology and new materials technology, specifically to a series of brain-targeting ginsenoside Rg1 derivatives, their preparation methods, and their applications in the prevention or treatment of neurodegenerative diseases, especially Alzheimer's disease. Background Technology

[0002] Alzheimer's disease (AD) is a central nervous system degenerative disease characterized by progressive cognitive impairment and memory decline. Its typical pathological features include senile plaques formed by β-amyloid (Aβ) deposition, neurofibrillary tangles formed by tau protein hyperphosphorylation, and persistent neuroinflammatory responses. With the increasing aging of the global population, the incidence of AD continues to rise, imposing a heavy economic and care burden on patients' families and society. Currently, FDA-approved AD treatments, such as acetylcholinesterase inhibitors (donepezil, etc.) and NMDA receptor antagonists (memantine), can only alleviate symptoms to a certain extent and cannot effectively stop or reverse disease progression. In recent years, monoclonal antibodies targeting Aβ (such as aducanumab and lecanemab) have shown some disease-modifying potential in clinical trials, but their efficacy is limited and they have significant adverse reactions such as cerebral edema and microbleeds. Furthermore, the high cost of treatment restricts their widespread application. Therefore, developing novel, safe, and effective treatment strategies that can intervene in the core pathological aspects of AD at multiple targets remains a key focus and challenge of current research.

[0003] Ginsenoside Rg1, one of the main active components of ginseng, a traditional Chinese medicine, has been shown in numerous studies to exhibit multifaceted protective effects on the nervous system, including antioxidant activity, inhibition of Aβ deposition and Tau protein phosphorylation, anti-inflammatory effects, anti-apoptosis, and promotion of synaptic plasticity. These pharmacological properties make it a potential candidate drug for the treatment of Alzheimer's disease (AD). However, the natural Rg1 molecule itself has significant pharmacokinetic defects: firstly, its oral bioavailability is extremely low; secondly, due to its large molecular weight and hydrophilicity, it is difficult to cross the blood-brain barrier, resulting in insufficient effective drug concentrations in the central nervous system, which severely limits its clinical efficacy.

[0004] To improve the brain-targeted delivery efficiency of Rg1, researchers have explored various strategies, among which polyethylene glycol (PEG) modification is a commonly used technique. PEGylation can effectively prolong the circulating half-life of drugs in vivo by increasing their molecular weight and altering their surface properties, and can also enhance their accumulation in diseased tissues to some extent by utilizing the enhanced penetration and retention effect (EPR effect). However, existing PEGylation modification studies have largely focused on general long-circulation purposes. Research on how to precisely design PEG chain lengths to maximize blood-brain barrier penetration efficiency and systematically evaluate the multi-target efficacy (such as the inhibitory effect on neuroinflammation) of different PEGylated derivatives in real AD animal models is still insufficient. Furthermore, conventional PEGylation methods may lead to reduced product activity or increased side effects due to improper connecting arms or reaction conditions. Summary of the Invention

[0005] Therefore, based on the shortcomings of the existing technology, this invention aims to construct a series of brain-targeting ginsenoside Rg1 derivatives with different PEG chain lengths through rational drug design, systematically solve the problem of its intrabrain delivery, and explore its synergistic inhibitory effect in Alzheimer's disease models, providing new candidate compounds and experimental evidence for the development of a new generation of multi-target AD therapeutic drugs.

[0006] The primary objective of this invention is to provide a series of brain-targeting ginsenoside Rg1 derivatives with significantly enhanced blood-brain barrier penetration. Another objective is to provide a method for preparing the aforementioned brain-targeting ginsenoside Rg1 derivatives, a method that is simple, mild, and suitable for large-scale preparation. A further objective is to elucidate the novel use of these brain-targeting ginsenoside Rg1 derivatives in the preparation of drugs for the prevention and / or treatment of neurodegenerative diseases, particularly in the treatment of Alzheimer's disease, where they exert a therapeutic effect by inhibiting neuroinflammation. Specifically, this invention employs the following technical solutions:

[0007] Firstly, the brain-targeting ginsenoside Rg1 derivative described in this invention is obtained by the condensation reaction of ginsenoside Rg1 and polyethylene glycol.

[0008] Preferably, the ginsenoside Rg1 is purified. The purification process for ginsenoside Rg1 can be as follows: dissolving free ginsenoside Rg1 in anhydrous ethanol, stirring vigorously, and then rapidly adding water; removing ethanol and small molecule impurities by dialysis; followed by solvent replacement and freeze-drying to obtain purified Rg1 powder.

[0009] The polyethylene glycol is a polyethylene glycol chain compound with a molecular weight of 100-10000, preferably with a molecular weight of 200-4000, more preferably 400-1000, and most preferably 500-800. The polyethylene glycol can be selected from PEG 400, PEG 600, or PEG 1000.

[0010] Secondly, the preparation method of the brain-targeting ginsenoside Rg1 derivative of the present invention may be as follows: ginsenoside Rg1 is reacted with polyethylene glycol, DIC and DMAP at room temperature and then post-treated; wherein DIC is a condensing agent N,N'-diisopropylcarbodiimide and DMAP is a catalyst 4-dimethylaminopyridine.

[0011] In the preparation method described above, preferably, the molar ratio of ginsenoside Rg1 to polyethylene glycol, DIC, and DMAP is 1.0~1.5 : 1 : 1 : 0.05~0.15, more preferably 1.2~1.3 : 1 : 1 : 0.08~0.12, and even more preferably 1.2 : 1 : 1 : 0.1.

[0012] In the preparation method described above, preferably, the post-treatment involves rotary evaporation to concentrate the reaction solution, then adding 1,4-dioxane to dissolve and concentrate the product, followed by dialysis (500-1000 Da) to remove impurities, and finally freeze-drying. The post-treatment is a step for purifying the product. As a preferred purification scheme, it can specifically involve: after the reaction is complete, rotary evaporation to concentrate the reaction solution, adding 1,4-dioxane to dissolve and concentrate the product, then dialysis to remove unreacted small molecule byproducts and impurities, and finally freeze-drying to obtain the target powder of the brain-targeting ginsenoside Rg1 derivative.

[0013] A preferred embodiment of the preparation method described above is as follows: dissolve the obtained purified Rg1s powder in dichloromethane, then add a polyethylene glycol chain compound of a specific chain length, a condensing agent N,N'-diisopropylcarbodiimide (DIC), and a catalyst 4-dimethylaminopyridine (DMAP) to the solution, and stir the reaction at room temperature for 20-28 hours.

[0014] Thirdly, the brain-targeting ginsenoside Rg1 derivative described in this invention can be used in the preparation of drugs for the prevention and / or treatment of neurodegenerative diseases. Preferably, the neurodegenerative disease is Alzheimer's disease.

[0015] Fourth, the application of the brain-targeting ginsenoside Rg1 derivative of the present invention in the preparation of drugs, wherein the drugs have at least one of the following applications: inhibiting neuroinflammatory responses; improving brain-targeting delivery efficiency; improving anxiety-depression-like behavior in animals; increasing PSD-95 protein levels while decreasing Caspase-1 and ASC protein levels; and resisting oxidative stress.

[0016] The drug of this invention exerts its effect by inhibiting neuroinflammatory responses. Simultaneously, the brain-targeting ginsenoside Rg1 derivative also enhances brain-targeting delivery efficiency and improves anxiety- and depression-like behaviors in living animals. The brain-targeting ginsenoside Rg1 derivative of this invention can be used in the preparation of drugs for the prevention and / or treatment of neurodegenerative diseases via methods including, but not limited to, common pharmaceutical administration methods such as oral formulations and intravenous injection.

[0017] This invention successfully constructed derivatives with enhanced blood-brain barrier penetration by covalently linking ginsenoside Rg1 to polyethylene glycol of a specific chain length. These derivatives not only address the poor brain targeting and instability of natural Rg1, but also significantly improve learning and memory abilities in an LPS-induced neuroinflammation model by regulating inflammation-related signaling pathways. The preparation process is simple, and the products exhibit good biosafety, providing new candidate compounds for the development of next-generation Alzheimer's disease treatments.

[0018] To address the problems of poor brain targeting, low bioavailability, and limited single-target effect of natural ginsenoside Rg1 in existing technologies, this invention provides an innovative brain-targeting ginsenoside Rg1 derivative. This derivative cleverly combines a specific chemical structure with a biological response mechanism, offering a new strategy for the intervention of neurodegenerative diseases, exemplified by Alzheimer's disease. Specifically, this invention has the following technical features:

[0019] 1. Excellent brain targeting

[0020] By specifically PEGylating ginsenoside Rg1, this invention successfully overcomes the bottleneck of its low intracerebral delivery efficiency. The derivative significantly increases the concentration of the drug in brain tissue, providing a prerequisite for effective treatment of the central nervous system.

[0021] 2. Multi-target synergistic therapy

[0022] The derivative provided by this invention inherits the neuroprotective activity of natural Rg1, and on this basis, it exhibits a synergistic inhibitory effect on the core pathological link of neuroinflammation in the Alzheimer's disease model, realizing a leap from single symptom relief to target disease modification.

[0023] 3. Good biosafety

[0024] The raw materials and reagents used in the preparation of these derivatives all exhibit good biocompatibility, and the final products have low impurity content after purification. Preliminary in vitro and in vivo safety evaluations show that this series of derivatives did not exhibit significant toxic reactions at effective doses, demonstrating excellent prospects for clinical translation.

[0025] 4. The preparation process is simple and controllable.

[0026] The preparation method provided by this invention has clear steps, mild reaction conditions, and does not require complex and expensive equipment. Furthermore, by optimizing the ratio of reactants and the purification process, it can stably and efficiently obtain high-purity target products, making it suitable for industrial-scale production. Attached Figure Description

[0027] Figure 1 These are particle size measurement images of purified Rg1s and a series of brain-targeting Rg1 derivatives.

[0028] Figure 2 This is an in vivo and ex vivo organ imaging of mice after injection of Rg1s, Rg1s-PEG-400, Rg1s-PEG-600, and Rg1s-PEG-1000. Figure A: Representative in vivo imaging; Figure B: Representative ex vivo organ imaging of brain, heart, liver, spleen, lung, and kidney.

[0029] Figure 3 This study describes the effects of Rg1s, Rg1s-PEG-400, Rg1s-PEG-600, and Rg1s-PEG-1000 treatments on spontaneous exploration behavior in mice during the hole-and-board test. Figure A: Representative diagram of the hole-and-board test; Figure B: Number of hole explorations; Figure C: Hole exploration time.

[0030] Figure 4 This study describes the effects of Rg1s, Rg1s-PEG-400, Rg1s-PEG-600, and Rg1s-PEG-1000 treatments on spontaneous exploratory behavior in mice during an open field experiment. Figure A: Representative diagram of the open field experiment; Figure B: Distance traveled; Figure C: Number of times threading the string; Figure D: Movement speed; Figure E: Number of times standing up.

[0031] Figure 5 This study describes the effects of Rg1s, Rg1s-PEG-400, Rg1s-PEG-600, and Rg1s-PEG-1000 treatments on anxiety-depression-like behaviors in mice during the cross-shaped elevated arm test. Figure A: Representative diagram of the cross-shaped elevated arm test; Figure B: Time to enter the open arm; Figure C: Number of times to enter the open arm.

[0032] Figure 6This study describes the effects of Rg1s, Rg1s-PEG-400, Rg1s-PEG-600, and Rg1s-PEG-1000 treatments on the learning and memory functions of mice in a water maze experiment. Figure A: Representative diagram of the water maze experiment; Figure B: Escape latency period for the first four days; Figure C: Swimming time in the quadrant containing the platform; Figure D: Number of times the platform was crossed; Figure E: Swimming distance; Figure F: Latency period upon first entry into the platform.

[0033] Figure 7 This study investigated the effects of injections of Rg1s, Rg1s-PEG-400, Rg1s-PEG-600, and Rg1s-PEG-1000 on the expression of synaptic and inflammation-related proteins in mouse brain tissue. Figure A: Representative images of synaptic-related proteins PSD-95 and SYN; Figure B: Relative expression of PSD-95; Figure C: Relative expression of SYN; Figure D: Representative images of inflammation-related proteins ASC and Caspase-1; Figure E: Relative expression of ASC; Figure F: Relative expression of Caspase-1.

[0034] Figure 8 This study investigates the effects of injecting Rg1s, Rg1s-PEG-400, Rg1s-PEG-600, and Rg1s-PEG-1000 on reactive oxygen species (ROS) production in HT-22 cells. Figure A: Representative graph of ROS detection; Figure B: Quantitative analysis of ROS generation. Detailed Implementation

[0035] The following embodiments are further illustrations of the present invention and serve as explanations of the technical content of the present invention. However, the essence of the present invention is not limited to the embodiments described below. Those skilled in the art can and should know that any simple changes or substitutions based on the spirit of the present invention should fall within the protection scope claimed by the present invention.

[0036] Instruments and reagents

[0037] Dynamic light scattering instrument (DLS, BI-200SM, Brookhaven Instruments Corporation); rotary evaporator (IKA RV 10); freeze dryer (Christ Alpha 1-2 LDplus); analytical balance (METTLER TOLEDO, 0.01%). Ginsenoside Rg1 (purity ≥98%, Chengdu Desite Company); polyethylene glycol (PEG 400, PEG 600, PEG 1000, Shanghai Aladdin Biochemical Technology Co., Ltd.); N,N'-diisopropylcarbodiimide (DIC, purity 99%), 4-dimethylaminopyridine (DMAP, purity ≥99%), dichloromethane (analytical grade), anhydrous ethanol (analytical grade), and 1,4-dioxane (analytical grade) were all purchased from Sinopharm Chemical Reagent Co., Ltd. ANY-maze video tracking system (Stoelting, USA); VisuTrack animal behavior analysis software (Shanghai Xinruan Company). Dialysis bag (molecular weight cutoff: 500 Da, Spectrum Labs).

[0038] Example 1

[0039] The method for preparing a series of brain-targeting ginsenoside Rg1 derivatives according to the present invention includes the following steps:

[0040] (1) Preparation and purification of Rg1s precursor: 10 mg of ginsenoside Rg1 was accurately weighed and placed in a 50 mL round-bottom flask. 5 mL of anhydrous ethanol was added, and the mixture was vigorously stirred magnetically for 2 hours at room temperature. Subsequently, the solution was quickly poured into a dialysis bag (MWCO: 1000 Da) containing 10 mL of ultrapure water, and the dialysis bag was placed in 2 L of ultrapure water. Dialysis was performed at 4 °C for 48 hours, with the dialysis fluid replaced every 6 hours to thoroughly remove ethanol and small molecule impurities. After dialysis, the solution in the bag was solvent-replaced and then freeze-dried to obtain a white flocculent purified Rg1s powder.

[0041] (2) Condensation reaction: Accurately weigh 50 mg of the purified Rg1s powder obtained in step (1), dissolve it in 5 mL of anhydrous dichloromethane, and place it in a 25 mL round-bottom flask. Add the calculated equivalent amounts of PEG, condensing agent DIC, and catalyst DMAP to this solution in sequence, wherein the molar ratio of the reactants is Rg1s : PEG : DIC : DMAP = 1.2 : 1 : 1 : 0.1. Stir the reaction system magnetically at low temperature (about 4°C) for 24 hours.

[0042] (3) Product purification: After the reaction was completed, the reaction solution was concentrated to near dryness using a rotary evaporator at a water bath temperature of 50°C. 5 mL of 1,4-dioxane was added to the concentrate to dissolve it completely. The solution was then transferred to a pretreated dialysis bag (MWCO: 1000 Da), and dialyzed with 2 L of ultrapure water at 4°C for 72 hours to remove unreacted PEG, byproducts, and other small molecule impurities. The dialysis fluid was replaced every 8 hours. After dialysis, the solution in the bag was collected and freeze-dried to obtain the solid powder of the brain-targeting ginsenoside Rg1 derivative.

[0043] The particle size evaluation methods for a series of brain-targeting ginsenoside Rg1 derivatives are as follows:

[0044] Take 1 mg each of the three derivative powders prepared above—Rg1s-PEG-400, Rg1s-PEG-600, and Rg1s-PEG-1000—and disperse them separately in 1 mL of phosphate-buffered saline (PBS, pH = 7.4). Vortex gently to ensure uniform dispersion. Measure the hydrated particle size of each derivative using dynamic light scattering (DLS) at 25°C. The particle sizes of all three derivatives were significantly larger than those of Rg1s. Results are as follows: Figure 1 As shown, all three derivatives can form a uniformly distributed nano-dispersion system with suitable particle size in PBS, indicating that the system has good stability and is suitable for subsequent biomedical applications.

[0045] Example 2

[0046] The brain-targeting efficiency evaluation methods for a series of brain-targeting ginsenoside Rg1 derivatives are as follows:

[0047] To verify the brain-targeting ability of the derivatives of this invention, an in vivo imaging experiment was conducted. Several healthy ICR mice were randomly divided into four groups and injected via tail vein with equal doses of free Rg1s, Rg1s-PEG-400, Rg1s-PEG-600, and Rg1s-PEG-1000 (all labeled with Rhodamine B fluorescent dye). Two hours after injection, the distribution of fluorescence throughout the mice was observed and photographed using an animal in vivo imaging system. Figure 2 A). The mice were then euthanized, and major organs such as the brain, heart, liver, spleen, lungs, and kidneys were removed for in vitro organ fluorescence imaging (A). Figure 2 B). The results showed that, compared with the free Rg1s group, the three PEGylated derivatives, especially Rg1s-PEG-600, exhibited significantly enhanced fluorescence signals in mouse brain tissue, demonstrating their superior intrabrain-targeted delivery efficiency.

[0048] Example 3

[0049] Figure 3 The procedure for the perforated plate experiment is as follows:

[0050] 5xFAD mice in the model group were intraperitoneally injected with LPS for 21 days (once a day, while the control group received an equal volume of saline), while Rg1s and Rg1s-PEG derivative groups were administered the drug via tail vein injection (once a day, every 3 days). This continuous intervention for 3 weeks established a mouse model of chronic inflammation. A hole-plate experiment (e.g.) was then performed. Figure 3 (As shown in A) The effect of the assay on improving spontaneous exploration behavior in mice was investigated, and their behavioral characteristics in novelty exploration and avoidance conflict environments were assessed. Results are as follows... Figure 3 As shown, compared with the normal control group (control), the number of times the model control group (LPS) mice explored holes was significantly reduced, indicating that their spontaneous exploration behavior and curiosity about new things were significantly impaired. Compared with the model control group, the number of times mice in each drug-treated group explored holes increased to varying degrees, with the Rg1s-PEG-600 group showing the most significant effect, and its number of explorations approaching the level of the normal control group. Figure 3 (BC). This indicates that the brain-targeting derivative of the present invention, particularly Rg1s-PEG-600, can effectively improve spontaneous exploration behavior and lack of curiosity in AD model mice.

[0051] Example 4

[0052] Figure 4 The procedure for open field experiments is as follows:

[0053] Following the animal grouping and intervention described in Example 3, mice were placed individually in the center of an open field test chamber and allowed to explore freely for 10 minutes. The total distance the mice traveled, the number of times they entered the central area, and the time they spent in the central area were recorded using a video tracking system. The results are as follows: Figure 4 As shown, compared with the normal control group, the model control mice exhibited a reduced total movement distance, significantly shortened frequency and time spent entering the central region, and demonstrated decreased spontaneous activity and marked anxiety-like behavior. After treatment with the derivative of this invention, in all treatment groups, especially the Rg1s-PEG-600 group, the total movement distance of mice significantly increased, and the frequency and time spent entering the central region were also significantly prolonged. Figure 4 (BE). This indicates that the brain-targeting derivative of the present invention can effectively enhance the autonomous activity ability of AD model mice and alleviate their anxiety-like behavior.

[0054] Example 5

[0055] Figure 5 The procedure for the cross-shaped elevated test is as follows:

[0056] Following the animal grouping and intervention described in Example 3, mice were placed in the central area of ​​the cruciform elevated experimental setup, with their heads facing the open arm, and allowed to explore freely for 5 minutes. The number of times the mice entered the open and closed arms, as well as the time spent in the open arm, were recorded. Results are as follows: Figure 5As shown, compared with the normal control group, the model control group mice exhibited typical anxiety-like behavior, namely, a significant reduction in the number of times they entered the open arm and the time spent in the open arm. After intervention with the derivative of this invention, the number of times and the time spent entering the open arm increased in all treatment groups, with the Rg1s-PEG-600 group showing the most significant effect, and its time spent in the open arm was significantly longer than that of the model control group. Figure 5 (BC). This result confirms that the brain-targeting derivative of the present invention can effectively alleviate anxiety-depressive-like behavior in AD model mice.

[0057] Example 6

[0058] Figure 6 The procedure for the water maze experiment is as follows:

[0059] To evaluate the effect of the derivative of this invention on improving the core symptom of AD—learning and memory impairment—a Morris water maze test was conducted. Following the animal grouping and intervention described in Example 3, a 4-day orientation and navigation test was performed: mice were placed in the water facing the pool wall from different entry points each day, and the time required for them to find the hidden platform (escape latency) was recorded. On day 5, a spatial exploration test was conducted: the platform was removed, and the number of times the mice crossed the original platform location within 90 seconds was recorded. The results are as follows: Figure 6 As shown, in the positioning and navigation experiment, the escape latency of mice in the model control group was significantly longer than that in the normal control group; while the escape latency of mice in each drug administration group decreased with the increase of training days, with the Rg1s-PEG-600 group having the shortest escape latency. Figure 6 B). In the space exploration experiment, the Rg1s-PEG-600 group mice traversed the original platform location significantly more times than the model control group ( Figure 6 These results fully demonstrate that the brain-targeting derivatives of the present invention, particularly Rg1s-PEG-600, can significantly improve spatial learning and memory abilities in AD model mice.

[0060] Example 7

[0061] Figure 7 The experimental procedure for protein blot analysis is as follows:

[0062] To elucidate the mechanism of action of the derivatives of this invention at the molecular level, Western blot analysis was performed on mouse hippocampal tissue after the behavioral experiments.

[0063] Using β-actin as an internal control, the proteins detected included: postsynaptic density protein 95 (PSD-95, a synaptic functional marker), SYN, Caspase-1, and ASC. Results are as follows: Figure 7As shown, compared with the normal control group, the expression level of PSD-95 protein in the brain tissue of the model control group mice was significantly downregulated, while the expression level of Caspase-1 protein was significantly upregulated. Figure 7 (AF). Treatment with the derivatives of this invention, particularly Rg1s-PEG-600, significantly reversed the abnormal expression of the aforementioned proteins, namely, increasing PSD-95 levels while decreasing Caspase-1 and ASC levels. This indicates that the derivatives of this invention exert neuroprotective and therapeutic effects by protecting the integrity of synaptic structures and inhibiting inflammatory pathways.

[0064] Example 8

[0065] To verify the neuroprotective activity of the derivatives of this invention at the cellular level, the inhibitory effect on oxidative stress was evaluated using the mouse hippocampal neuronal cell line HT-22 as a model.

[0066] An in vitro inflammation model was established by stimulating HT-22 cells with LPS (10 μg / ml), and simultaneously intervened by administering an Rg1s-PEG derivative (1 μM). Intracellular ROS levels were detected using the reactive oxygen species (ROS) fluorescent probe DCFH-DA. Results are as follows: Figure 8 As shown, compared with the normal control group, the fluorescence intensity of cells in the LPS model group was significantly enhanced, indicating a sharp increase in intracellular ROS levels. However, compared with the LPS model group, the Rg1s-PEG-600 intervention group was able to dose-dependently reduce fluorescence intensity and significantly decrease LPS-induced ROS production. Figure 8 (AB). This result demonstrates that the brain-targeting derivative of the present invention has good antioxidant stress resistance, which may be one of the important mechanisms by which it inhibits neuroinflammation and thus exerts neuroprotective effects.

[0067] The aforementioned animal experimental results demonstrate that the series of brain-targeting ginsenoside Rg1 derivatives described in this application not only successfully overcome the key bottleneck of poor brain targeting of natural Rg1, but also exert remarkable therapeutic effects through multiple pathways in an LPS-induced neuroinflammatory mouse model. This application is the first to achieve the construction of Rg1 derivatives with both highly efficient brain-targeting delivery and multi-target disease modification functions through a precise PEGylation modification strategy, and their therapeutic efficacy has been fully confirmed in complex in vivo animal models. Furthermore, the preparation process of this series of derivatives is simple and mild, and most importantly, it exhibits rapid, efficient, and specific intervention effects on intracranial pathological processes and excellent biosafety, providing novel candidate drugs and treatment strategies for the prevention and treatment of neurodegenerative diseases such as Alzheimer's disease.

[0068] It should be noted that the above-described technical content of this invention is merely an explanation and clarification to enable those skilled in the art to understand the technical essence of this invention, and therefore is not intended to limit the scope of protection of this invention. The scope of protection of this invention should be determined by the claims. Those skilled in the art should understand that any modifications, equivalent substitutions, and improvements made based on the essential spirit of this invention should be within the scope of protection of this invention.

Claims

1. A brain-targeting ginsenoside Rg1 derivative, characterized in that, It is obtained by the condensation reaction of ginsenoside Rg1 and polyethylene glycol.

2. The brain-targeting ginsenoside Rg1 derivative as described in claim 1, characterized in that, The ginsenoside Rg1 was purified.

3. The brain-targeting ginsenoside Rg1 derivative as described in claim 1, characterized in that, The polyethylene glycol is a polyethylene glycol chain compound with a molecular weight of 100-10000, preferably with a molecular weight of 200-4000, more preferably 400-1000.

4. The brain-targeting ginsenoside Rg1 derivative as described in claim 1, characterized in that, The polyethylene glycol is selected from PEG400, PEG600 or PEG1000.

5. The method for preparing the brain-targeting ginsenoside Rg1 derivative according to any one of claims 1-4, characterized in that, Ginsenoside Rg1 was reacted with polyethylene glycol, DIC and DMAP at room temperature and then post-treated; DIC was a condensing agent N,N'-diisopropylcarbodiimide and DMAP was a catalyst 4-dimethylaminopyridine.

6. The preparation method according to claim 5, characterized in that, Ginsenoside Rg1 with polyethylene glycol, DIC, and DMAP The molar ratio is 1.0~1.5 : 1 : 1 : 0.05~0.15, preferably 1.2~1.3 : 1 : 1 : 0.08~0.12, and more preferably 1.2 : 1 : 1 : 0.

1.

7. The preparation method according to claim 5, characterized in that, The post-treatment involves rotary evaporation to concentrate the reaction solution, then adding a solvent to dissolve the concentrate, followed by dialysis to remove impurities, and freeze-drying.

8. The use of the brain-targeting ginsenoside Rg1 derivative as described in claim 1 or obtained by any one of claims 5-7 in the preparation of a medicament for the prevention and / or treatment of neurodegenerative diseases.

9. The application as described in claim 8, characterized in that, The neurodegenerative disease mentioned is Alzheimer's disease.

10. The use of the brain-targeting ginsenoside Rg1 derivative as described in claim 1 or obtained by any one of claims 5-7 in the preparation of a drug, wherein the drug has at least one of the following applications: inhibiting neuroinflammatory responses; improving brain-targeting delivery efficiency; improving anxiety-depression-like behavior; increasing PSD-95 protein levels while decreasing Caspase-1 and ASC protein levels; and resisting oxidative stress.

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