Application of spotted acid in preparation of medicine for treating neurodegenerative diseases

Abstract

The invention belongs to the field of biological medicines, and particularly relates to application of spotted acid in preparation of a medicine for treating neurodegenerative diseases. According to the invention, a natural compound-spotted acid is separated from lichens, and the CAS number of the natural compound-spotted acid is 549-06-4. Experiments find that the spotted acid not only can realize neuroprotection by regulating inflammatory response and apoptosis pathways, but also can efficiently inhibit alpha-synuclein aggregation, and the spotted acid is obviously superior to the anti-aggregation activity and neuroprotection effect of gallocatechin gallate in the existing positive comparison table. Meanwhile, the dot acid has excellent drug absorption, distribution, metabolism, excretion and low toxicity characteristics, and can be used as a candidate therapeutic drug for treating neurodegenerative diseases, especially Parkinson's disease.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of biological medicine, and particularly relates to application of punctiformic acid in preparation of a drug for treating a neurodegenerative disease. BACKGROUND

[0002] A neurodegenerative disease is a central nervous system disease, and common neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, etc. These diseases are mainly caused by the slow and gradual loss of neurons and / or their myelin sheaths in the brain. Neurodegenerative diseases have the common characteristics of gradual reduction in the number of neurons, abnormal aggregation of pathological proteins, activation of neuroinflammatory response, aggravation of oxidative stress to cause cell damage, and disorder of cytoskeleton structure and function, which leads to progressive impairment of neural function and affects the cognitive and motor functions of patients.

[0003] The core pathological feature of Parkinson's disease is the abnormal aggregation of alpha-synuclein to form Lewy bodies, which leads to the death of dopaminergic neurons. Existing drugs such as levodopa only alleviate symptoms and have significant side effects, and the development of small molecule drugs directly targeting alpha-synuclein aggregation is slow. Natural products are of great concern due to their structural diversity and low toxicity, so it is of great significance to mine natural compounds with dual functions of inhibiting alpha-synuclein aggregation and neuroprotection for treating neurodegenerative diseases. SUMMARY

[0004] To solve the above problems, the application discloses application of punctiformic acid in preparation of a drug for treating a neurodegenerative disease. The punctiformic acid is a natural compound isolated from lichens, and the application finds that the natural compound has the dual functions of inhibiting alpha-synuclein aggregation and neuroprotection, thereby providing a new candidate therapeutic drug for neurodegenerative diseases, especially Parkinson's disease.

[0005] To achieve the above object, the specific technical scheme of the application is as follows: The application provides application of punctiformic acid in preparation of a drug for treating a neurodegenerative disease, and the punctiformic acid has a CAS number of 549-06-4 and a structural formula as shown in formula (I): Formula (I).

[0006] Further, the punctiformic acid is used for preparing a drug for inhibiting alpha-synuclein aggregation or a drug for protecting neurons.

[0007] Further, the neurodegenerative disease is Parkinson's disease, Alzheimer's disease, or neurogenic inflammation.

[0008] Further, the drug takes the punctiformic acid as the only active ingredient.

[0009] Further, the medicine is composed of the orsellinic acid and pharmaceutically acceptable excipients.

[0010] Further, the medicine is injection, tablet, nanoliposome targeted delivery system, pill, capsule, granule or emulsion.

[0011] The second aspect of the present application provides a tablet medicine for treating Parkinson's disease, which is composed of the orsellinic acid and pharmaceutically acceptable excipients.

[0012] Further, each tablet contains 50mg-200mg of orsellinic acid as an active ingredient.

[0013] The third aspect of the present application provides a medicine injection for treating Parkinson's disease, which is composed of the orsellinic acid, solvent for injection, stabilizer and pH regulator.

[0014] Further, the concentration of orsellinic acid in the medicine injection is 0.1mg / mL-1mg / mL.

[0015] Further, the solvent for injection is sterile water for injection, the stabilizer is mannitol and the pH regulator is phosphate buffer.

[0016] Compared with the prior art, the present application has the following beneficial effects: The present application isolates a natural compound orsellinic acid from lichens, which has a CAS number of 549-06-4, and discloses for the first time the great potential of orsellinic acid in the field of treatment of neurodegenerative diseases, which can be used for preparing medicines for treating neurodegenerative diseases. (1) In terms of activity, orsellinic acid exhibits a unique dual neuroprotective mechanism, which can not only realize neuroprotection through regulating inflammatory response and apoptosis pathway, but also efficiently inhibit alpha-synuclein aggregation, and orsellinic acid is significantly superior to the anti-aggregation activity and neuroprotective effect of positive control epigallocatechin gallate. (2) In terms of drug property, orsellinic acid has excellent drug absorption, distribution, metabolism, excretion and low toxicity. (3) In terms of resource development, lichens are traditional medicinal resources, and natural product orsellinic acid can be extracted from lichens on a large scale, and the process is mature. BRIEF DESCRIPTION OF DRAWINGS

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

[0018] Figure 1Experimental results of inhibiting α-synuclein fibrillation by pterostilbene; Figure 1 Figure A in FIG. 1 shows the aggregation of α-synuclein monomers after 0, 1, 2, 3, and 5 days of rotation at 800 rpm and 37°C, as analyzed by the thioflavin T fluorescence method. From top to bottom, the three curves represent 20 μM, 40 μM, and 50 μM α-synuclein monomers, respectively, and n = 4 for each group. Figure 1 Figure B in FIG. 1 shows the final thioflavin T fluorescence signal of 10 μM α-synuclein mature fibers after 3 days of incubation with the positive control, epigallocatechin gallate (EGCG). Data are presented as mean ± standard error of the mean, and n = 9 for each group. * indicates p <0.05, and ** indicates p <0.01. Error bars represent standard deviations. Figure 1 Figure C in FIG. 1 shows the final thioflavin T fluorescence signal of 10 μM α-synuclein mature fibers after 3 days of incubation with pterostilbene (SA). Data are presented as mean ± standard error of the mean, and n = 9 for each group. * indicates p <0.05. Error bars represent standard deviations. Figure 1 Figure D in FIG. 1 shows an atomic force microscopy image of 10 μM α-synuclein fibers, with an image size of 5 μm x 5 μm. Figure 1 Figure E in FIG. 1 shows an atomic force microscopy image of 10 μM α-synuclein fibers treated with 30 μM epigallocatechin gallate, with an image size of 5 μm x 5 μm. Figure 1 Figure F in FIG. 1 shows an atomic force microscopy image of 10 μM α-synuclein fibers treated with 30 μM pterostilbene, with an image size of 5 μm x 5 μm.

[0019] Figure 2 Figure in FIG. 1 is a three-dimensional binding diagram showing the stable binding of pterostilbene to α-synuclein, as simulated by XP high-precision molecular docking. Pterostilbene is deeply embedded in the binding pocket of α-synuclein and forms a hydrogen bond with THR72 on the F chain of the protein.

[0020] Figure 3 Figure in FIG. 1 shows the results of the stable binding and key interactions of pterostilbene with α-synuclein, as simulated by dynamics. Figure 3 Figure A in FIG. 1 is a ligand twist diagram showing the two-dimensional schematic diagram of the conformational evolution of the four rotatable bonds of pterostilbene and α-synuclein throughout the entire simulation trajectory. Blue represents rotatable bond 1, green represents rotatable bond 2, pink represents rotatable bond 3, and orange represents rotatable bond 4. Each rotatable bond twist corresponds to Figure 3Figure B. The same colored dial and bar graphs in Figure B. The four dial graphs in panel (a), (c), (e), and (g) of Figure B depict the twisted conformations throughout the course of the dynamics simulation; the four bar graphs in panel (b), (d), (f), and (h) of Figure B summarize the data on the dial graphs by showing the probability density of the twist.

[0021] Figure 4 Figure 6. Time-course heat map of the interactions between the dotacids and different residues of α-synuclein. The vertical axis is labeled by residue / chain, the horizontal axis is simulation time, and the color intensity represents the contact frequency.

[0022] Figure 5 Figure 7. Conformational stability of the dotacid-α-synuclein complex during the 100 ns molecular dynamics simulation. RMSD analysis shows that the structure reached equilibrium after 5 ns with a fluctuation amplitude < 3 Å, confirming the stability of the bound conformation.

[0023] Figure 6 Figure 8. Interaction fingerprint analysis classifies the binding forces between the dotacids and α-synuclein. The key residues: GLU61 of B / F chain, mainly mediate the ion bridge, water bridge and hydrogen bond.

[0024] Figure 7 Figure 9. RMSF plot reveals the high flexibility regions of α-synuclein after binding with the dotacids. The peaks of residues 80-85, 240-245 and 555-560 suggest that these regions undergo dynamic conformational changes.

[0025] Figure 8 Figure 10. Cell viability assay and transcriptome analysis verify the neuroprotective mechanism of the dotacids. Figure 8 Figure 10A. CCK-8 assay for the viability of dopaminergic neuron cells MES23.5. The control group indicates no treatment of MES23.5 cells, α-syn indicates the use of 10 μM α-synuclein to treat MES23.5 cells alone, α-syn SA indicates the use of 10 μM α-synuclein and dotacid to treat MES23.5 cells, and the dotacid concentrations are 10 μM and 30 μM, i.e., the use of 10 μM α-synuclein + 10 μM dotacid to treat MES23.5 cells and the use of 10 μM α-synuclein + 30 μM dotacid to treat MES23.5 cells; the data are expressed as mean ± standard deviation, n = 12 for each group; significance markers: * indicates p <0.05, ** indicates p <0.01. Figure 8Figure B in the figure is a hierarchical clustering heatmap of the transcriptome profiles of the three groups: control group, α-syn group, and 10μM α-synuclein + 30μM dot acid group; the annotation shows the co-expressed gene clusters, key gene tags and regulatory trends. Figure 8 Figure C in the figure shows the number of differentially expressed genes in the control group, the 10 μM α-synuclein group, and the 10 μM α-synuclein + 30 μM dot acid group, with n=3 in each group. Figure 8 Figure D in the diagram is a Venn diagram showing the overlap and unique differentially expressed genes among the three groups: the control group, the α-syn group, and the 10μM α-synuclein + 30μM dot acid group. Each group has n=3. Figure 8 The E-plot in the figure shows the KEGG pathway enrichment analysis between the α-syn group and the control group; the dot plot parameters are: the horizontal axis represents the enrichment factor, i.e., the number of differentially expressed genes in the pathway / the total number of genes in the pathway; the vertical axis represents the KEGG pathway entries; the size of the dots reflects the number of differentially expressed genes in each pathway; the color depth represents statistical significance; the green boxes represent pathways that regulate neurological diseases. Figure 8 The F-plot in the figure represents the KEGG pathway analysis of the 10 μM α-synuclein + 30 μM dot acid group compared to the control group. The visualization parameters are the same as those in the figure. Figure 9 Figure E in the diagram.

[0026] Figure 9 This relates to the transcriptional regulation of α-synuclein and the effects of dot acid intervention; Figure 9 Figure A in the diagram shows the gene set enrichment analysis between α-synuclein overexpressing cells and the blank control group. Figure 9 Figure a in Figure A shows the trajectory of enrichment fraction changes in the sorted gene list, with a peak ES value of -0.52; Figure 9 In Figure A, the vertical line in Figure b indicates the position of the genes in the enriched gene set in the sorting list. Figure 9 In Figure A, Figure c shows the ranking indicators: red corresponds to overexpressed genes in the α-synuclein group, and blue corresponds to overexpressed genes in the control group. Ifna13 Figure B in the diagram is a volcano plot showing the differentially expressed genes in α-synuclein overexpressing cells compared to the control group. Different colors indicate whether the gene is upregulated, downregulated, or not significantly differentially expressed; the default labels are upregulated and downregulated. p The top 10 significantly differentially expressed genes, with the green box indicating significantly downregulated genes. Figure 9 Genes; n=3 per group. Figure 9 Figure C in the figure shows the gene set enrichment analysis of the overexpressing cells in the 10 μM α-synuclein + 30 μM dotted acid group compared to the control group. The visualization parameters are the same as those in the control group. Figure 9 Figure A in the diagram. Ifna13D in FIG. 1 is a volcano plot of differentially expressed genes of 10 mM alpha-synuclein + 30 mM Spotted Acid compared with the control group; the green box shows that the gene expression is significantly higher than that of the alpha-synuclein group, Lobaria spp. Gene expression was significantly increased; n = 3 for each group. DETAILED DESCRIPTION

[0027] The specific embodiments of the present application are described in detail below, but it should be understood that the scope of protection of the present application is not limited by the specific embodiments. Based on the examples in the present application, all other examples obtained by those of ordinary skill in the art without making creative efforts fall within the scope of protection of the present application. The experimental methods described in the embodiments of the present application are conventional methods, and the materials and reagents used in the following examples are commercially available unless otherwise specified.

[0028] Parkinson's disease is a common neurodegenerative disease, and its core pathological feature is the abnormal aggregation of alpha-synuclein to form Lewy bodies, leading to the death of dopaminergic neurons. Existing drugs only relieve symptoms and have significant side effects, and the development of small molecule drugs directly targeting alpha-synuclein aggregation is slow. Natural products are of great concern due to their structural diversity and low toxicity, so it is of great significance to mine natural compounds with both anti-alpha-synuclein aggregation and neuroprotective functions for the treatment of neurodegenerative diseases.

[0029] The present application discloses the application of spotted acid in the preparation of a drug for treating neurodegenerative diseases. Spotted acid is a natural compound isolated from lichens, and the present application finds that this natural compound has the dual functions of inhibiting alpha-synuclein aggregation and neuroprotection, providing a new candidate therapeutic drug for neurodegenerative diseases, especially Parkinson's disease.

[0030] Example 1: Extraction and purification of spotted acid S1, take dry Figure 1 The lichen sample 50 g is crushed and extracted 3 times by ultrasonic extraction with 90 v / v% ethanol.

[0031] S2, combine the extract obtained in step S1, and concentrate under reduced pressure to remove ethanol in the extract. The concentrated extract is separated by silica gel column chromatography, and petroleum ether-ethyl acetate is used as the eluent for gradient elution. The target fraction is collected.

[0032] S3, the target fraction collected in step S2 is further purified by preparative high performance liquid chromatography, with acetonitrile and water as the mobile phase, the volume ratio of acetonitrile and water being 65:35, and the flow rate being 2 mL / min. The eluent containing spotted acid is collected, and after freeze-drying, the spotted acid pure product is obtained. The purity of the spotted acid pure product is determined to be >98%.

[0033] Example 2: Spot acid inhibits alpha-synuclein aggregation Human recombinant alpha-synuclein was dissolved in 1x PBS buffer to prepare alpha-synuclein solutions with final concentrations of 20 μM, 40 μM, and 50 μM, and the solutions were placed in a 37°C constant temperature shaker at a rotation speed of 800 rpm for continuous incubation for 7 days.

[0034] Experimental grouping: (1) Control group: containing only 10 μM alpha-synuclein; (2) Experimental group: 10 μM alpha-synuclein + 10 μM spot acid; 10 μM alpha-synuclein + 30 μM spot acid; (3) Positive control group: 10 μM alpha-synuclein + 10 μM gallocatechin gallate; 10 μM alpha-synuclein + 30 μM gallocatechin gallate.

[0035] The samples in each group were mixed uniformly and placed in a 37°C, 800 rpm shaker for a total of 3 days of incubation. After the incubation was completed, 20 μM of thioflavin T dye was added to the reaction system, and fluorescence detection was performed. In the present application, thioflavin T is labeled as ThT.

[0036] The results, as shown in Figure 2 The fluorescence of ThT detected that 20 μM of alpha-synuclein monomers, 40 μM of alpha-synuclein monomers, and 50 μM of alpha-synuclein monomers gradually fibrillated within 5 days. The 50 μM group reached the maximum ThT fluorescence intensity on the second day, indicating the formation of mature fibers. The depolymerization experiment on preformed fibers showed that 10 μM gallocatechin gallate in the positive control group reduced the alpha-synuclein fibrillation signal by 40%, and 30 μM gallocatechin gallate reduced the alpha-synuclein fibrillation signal by 70%. In comparison, 10 μM and 30 μM spot acid reduced the alpha-synuclein fibrillation signal by 80%, indicating that spot acid had an 80% inhibition rate on alpha-synuclein fibrillation. Therefore, it was shown that spot acid can destroy the structure of mature alpha-synuclein fibers, and the effect is better than that of gallocatechin gallate positive control at the same concentration.

[0037] Example 3: Spot acid can stably bind to alpha-synuclein The three-dimensional structures of spot acid and alpha-synuclein were obtained, and high-precision molecular docking was performed on spot acid and alpha-synuclein to form an initial complex model, which was labeled as the root mean square deviation (RMSD) in the molecular dynamics simulation.

[0038] The results, as shown in Figures 3-7 Spot acid can form a hydrogen bond with THR72 of alpha-synuclein, with a binding energy of -25.84 kcal / mol.

[0039] As shown in Figure 4 , the molecular dynamics simulation results show that the RMSD in the complex molecular dynamics simulation is stable within 3 Å, indicating that there is no significant conformational drift in the 100 ns simulation trajectory of the a-synuclein-punctatin ligand complex. The torsion conformation analysis shows that the intramolecular dihedral angle distribution of punctatin is concentrated, further verifying the stability of its binding pose. In the key interaction network analysis, punctatin forms a stable binding with a-synuclein through multiple types of interactions. First, in the hydrogen bond combination: the B chain GLU61 occupancy rate is 73%, the J chain THR54 occupancy rate is 70%, and the J chain THR72 occupancy rate is 47%; in the water-mediated bridging, it forms an occupancy rate of 36% with the B chain GLU61; at the same time, Na + coordination ionic bond, it combines with the B chain GLU61 with an occupancy rate of 56%, and with the F chain GLU61 / THR72 with an occupancy rate of 66%. The time-course contact analysis shows that the interaction between punctatin and the B / F chain GLU61 is strong and persistent, as shown in Figure 8 the medium deep orange peak, indicating that it is a key anchoring site. The RMSF graph shows that after binding with punctatin, the flexibility of the 80~85, 240~24, and 555~560 residues of a-synuclein is significantly increased, indicating that the binding of the punctatin ligand induces the dynamic adjustment of the local conformation of a-synuclein.

[0040] Therefore, punctatin stably binds to a-synuclein through the triple mechanism of hydrogen bond network, ionic bridging, and water-mediated action, while selectively increasing the conformational flexibility of specific regions. This mode of action may inhibit fibrillation through the following pathways: competitive occupation, i.e., blocking key sites of protein self-aggregation; conformational regulation, i.e., increasing the dynamic nature of the local structure to hinder the ordered accumulation of β-sheets; charge neutralization, i.e., Na + mediated ionic bonds may weaken the aggregation driven by the electrostatic interaction on the surface of the protein.

[0041] Example 4: Neuroprotective effect of punctatin After the dopaminergic neuron cell MES23.5 was cultured to 60%~70% confluence, it was divided into 4 groups for 24 hours of treatment: (1) control group: no treatment on MES23.5 cells; (2) 10 μM a-synuclein alone treated MES23.5 cells; (3) 10 μM a-synuclein + 10 μM punctatin combined treatment group treated MES23.5 cells; (4) 10 μM a-synuclein + 30 μM punctatin combined treatment group treated MES23.5 cells. After the treatment, 10 μL cell counting kit-8 reagent was added, and the absorbance value was measured at 450 nm wavelength by the enzyme-labeled instrument. The control group was used as the reference to calculate the cell viability standardization, and the neuroprotective effect of punctatin on a-synuclein-induced toxicity was evaluated.

[0042] like Figure 8 As shown in Figure A, the CCK-8 assay revealed that after 24 hours of exposure to 10 μM α-synuclein fibromas, the viability of MES23.5 cells decreased by approximately 30%, indicating that α-synuclein fibromas are significantly toxic to cells. However, treatment with dot acid in combination with α-synuclein fibromas could dose-dependently mitigate this toxicity; 10 μM and 30 μM dot acid increased cell viability by 10% and 30%, respectively, suggesting that dot acid can effectively protect MES23.5 cells from damage caused by α-synuclein toxic substances.

[0043] Figure 9 B~F and Figure 8 In the transcriptome sequencing analysis: the untreated MES23.5 cells were designated as the control group; the MES23.5 cells treated with 10 μM α-synuclein alone were designated as the α-syn group; and the MES23.5 cells treated with a combination of 10 μM α-synuclein and 30 μM dot acid were designated as the α-syn group. SA Group. From Figure 8 As can be seen from B and C, 44 upregulated genes and 75 downregulated genes were first identified in the α-syn group. SA Compared with the control group, 73 upregulated and 62 downregulated genes were identified, including α-syn. SA Compared with the α-syn group, a total of 172 differentially expressed genes were found, of which 121 genes were upregulated and 51 genes were downregulated. Figure 8 D in the diagram represents the control group, the α-syn group, and the α-syn group. SA Venn diagram of differentially expressed genes between groups. In this invention, the TNF signaling pathway is labeled as the tumor necrosis factor signaling pathway, the IL-17 signaling pathway as the interleukin-17 pathway, the adipocytokine signaling pathway as the adipokines signaling pathway, the PPAR signaling pathway as the peroxisome proliferator-activated receptor signaling pathway, and the PI3K-Akt signaling pathway as the phosphatidylinositol 3-kinase-protein kinase B signaling pathway, etc. Figure 9E and F in FIG. 1, based on KEGG pathway enrichment analysis, it was found that pachymic acid realized neuroprotection by regulating tumor necrosis factor signaling pathway, interleukin-17 pathway, adipocytokine signaling pathway, peroxisome proliferator-activated receptor signaling pathway, phosphatidylinositol 3-kinase-protein kinase B signaling pathway and other pathways related to Parkinson's disease and other neurological diseases. By detecting the transcriptional regulation of alpha-synuclein and the intervention effect of pachymic acid, such as Figure 9 A and C in FIG. 1 are gene set enrichment analysis of alpha-synuclein overexpression cells and blank control group, respectively, and gene set enrichment analysis of overexpression cells and control group in 10 μM alpha-synuclein + 30 μM pachymic acid group compared with control group, respectively, showing the change trajectory of enrichment score in the sorted gene list in each group. Ifna13 B and C in FIG. 1, by analyzing the top 10 significant differential genes, found that Figure 9 the gene was significantly down-regulated; Ifna13 D in FIG. 1 shows that in the volcano plot analysis of differential expressed genes in 10 μM alpha-synuclein + 30 μM pachymic acid group compared with control group, it was found that ​ the gene expression was significantly increased.

[0044] Example 5: Absorption, distribution, metabolism, excretion and toxicity characteristics of pachymic acid Based on Lipinski's five rules and TPSA screening criteria, the absorption, distribution, metabolism, excretion and toxicity characteristics of pachymic acid were obtained through multi-parameter analysis, and the specific information is shown in Table 1.

[0045] Table 1: ADMET property evaluation table of pachymic acid Example 6: A tablet medicine for treating Parkinson's disease Raw material: pachymic acid with purity ≥98% Excipients: microcrystalline cellulose, crosslinked sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, magnesium stearate, colloidal silicon dioxide, all of which meet the standards of Chinese Pharmacopoeia.

[0046] (1) Pretreatment: Pachymic acid raw material, microcrystalline cellulose, crosslinked sodium carboxymethyl cellulose, magnesium stearate and colloidal silicon dioxide were respectively passed through a 100-mesh sieve for use.

[0047] (2) Mixing Primary mixing: 100.0 g of pachymic acid and 60.0 g of microcrystalline cellulose were mixed by equal incremental method after sieving, with equal volume increment each time, and a three-dimensional mixer was used for mixing for 15 min at a speed of 20 rpm.

[0048] Final mixing: add 60.0 g microcrystalline cellulose, 15.0 g crosslinked sodium carboxymethyl cellulose, 2.5 g colloidal silicon dioxide, continue mixing for 10 min at 20 rpm.

[0049] (3) Granulation Preparation of binder: weigh 6.0 g of hydroxypropyl methyl cellulose and dissolve it in 114 mL of purified water to prepare a 5 w / v% hydroxypropyl methyl cellulose solution, and stir until completely dissolved.

[0050] Wet granulation: transfer the mixed powder after step (2) final mixing into a high-speed shearing granulator, slowly add the hydroxypropyl methyl cellulose solution under the condition of stirring speed 800 rpm and chopping speed 2000 rpm, the addition rate is 10 mL / min, and the soft material preparation time is 3 min. End point judgment: hold in the palm, light pressure and scatter.

[0051] (4) Drying: dry the wet granules in a hot air circulating oven at 50℃ until the moisture content is ≤3.0%; (5) Granulation: dry the granules through a 24 mesh sieve, and add 5.0 g of magnesium stearate and mix for 5 min; (6) Tabletting: use a rotary tablet press to press the tablets, control the tablet weight to be 250 mg±5 mg, each tablet contains 100 mg of spot acid, and the hardness is controlled to be 60 N±10 N.

[0052] Example 7: a medicine injection for treating Parkinson's disease Take 800 mL of sterile water for injection and heat to 40℃, add sodium phosphate dibasic 2.5 g, sodium phosphate monobasic 0.4 g, stir and dissolve, then add mannitol 50.0 g, dissolve, then add spot acid 0.5 g, continue stirring for 30 min until completely dissolved; then adjust the pH of the solution to 7.1~7.3 with phosphate buffer, add sterile water for injection to 1000 mL, add activated carbon 0.1 g, stir for 15 min, then filter and decolorize through a 0.45 μm microporous filter to obtain a medicine injection for treating Parkinson's disease.

[0053] It should be noted that when numerical ranges are involved in the present application, both endpoints of each numerical range and any number between the two endpoints can be selected. Since the same steps and examples are used, in order to prevent repetition, the preferred embodiments of the present application are described. Although the preferred embodiments of the present application have been described, those skilled in the art can make further changes and modifications to these embodiments once they understand the basic inventive concept. Therefore, the appended claims are intended to include the preferred embodiments and all changes and modifications falling within the scope of the present application.

[0054] Obviously, many modifications and variations of the present application are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims and their equivalents, the application can be practiced otherwise than as specifically described.

Claims

1. Use of pitted acid for the manufacture of a medicament for the treatment of a neurodegenerative disease, characterized in that, The CAS number of the said spot acid is 549-06-4. 2.The use of the spot acid according to claim 1 in the preparation of a drug for treating neurodegenerative diseases, characterized in that, The said neurodegenerative disease is Parkinson's disease, Alzheimer's disease or neurogenic inflammation. 3.The use of the spot acid according to claim 1 in the preparation of a drug for treating neurodegenerative diseases, characterized in that, The said medicine takes spot acid as the only active ingredient. 4.The use of the spot acid according to claim 1 in the preparation of a drug for treating neurodegenerative diseases, characterized in that, The said medicine is composed of spot acid and pharmaceutically acceptable adjuvants. 5.The use of the spot acid according to claim 1 in the preparation of a drug for treating neurodegenerative diseases, characterized in that, The said medicine is injection, tablet, nano-liposome targeted delivery system, pill, capsule, granule or emulsion.

6. A tablet medicament for treating Parkinson's disease, characterized by, The said medicine is composed of the spot acid of claim 1 and pharmaceutically acceptable adjuvants, and each of the said tablets contains 50mg-200mg of spot acid as the active ingredient.

7. A pharmaceutical injection for treating Parkinson's disease, characterized by, The said medicine injection is composed of the spot acid of claim 1, injection solvent, stabilizer and pH regulator; the concentration of the spot acid in the said medicine injection is 0.1mg / mL-1mg / mL.

8. The pharmaceutical injection according to claim 7, characterized in that, The said injection solvent is sterile water for injection, the said stabilizer is mannitol, and the said pH regulator is phosphate buffer. The CAS number of the said spot acid is 549-06-4. The said neurodegenerative disease is Parkinson's disease, Alzheimer's disease or neurogenic inflammation. The said medicine takes spot acid as the only active ingredient. The said medicine is composed of spot acid and pharmaceutically acceptable adjuvants. The said medicine is injection, tablet, nano-liposome targeted delivery system, pill, capsule, granule or emulsion. The said medicine is composed of the spot acid of claim 1 and pharmaceutically acceptable adjuvants, and each of the said tablets contains 50mg-200mg of spot acid as the active ingredient. The said medicine injection is composed of the spot acid of claim 1, injection solvent, stabilizer and pH regulator; the concentration of the spot acid in the said medicine injection is 0.1mg / mL-1mg / mL. The said injection solvent is sterile water for injection, the said stabilizer is mannitol, and the said pH regulator is phosphate buffer.

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