Pharmaceutical composition for treating degenerative diseases and application thereof

Abstract

The invention relates to a pharmaceutical composition for treating degenerative diseases and application thereof. The pharmaceutical composition is particularly suitable for preventing and treating Alzheimer's disease (AD). The pharmaceutical composition disclosed by the invention comprises a combination of a PDE4 inhibitor and a PDE10A inhibitor, and can be used for remarkably activating a cAMP-PKA-CREB signal channel, enhancing the stress tolerance of neurons, reducing the pathological accumulation of A beta and p-tau and improving the plasticity of nerves. The invention provides an innovative medicine composition with potential clinical application value, and a new strategy is provided for intervention of neurodegenerative diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, and relates to a pharmaceutical composition for treating degenerative diseases and application thereof, in particular to a pharmaceutical composition for treating Alzheimer's disease and application thereof. BACKGROUND

[0002] Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive decline, Aβ plaque accumulation, tau hyperphosphorylation and neuroinflammation. These pathological features lead to neuronal dysfunction, synapse loss and progressive deterioration of cognitive ability. Studies have shown that the cAMP-PKA-CREB signaling pathway plays a key role in synaptic plasticity, memory formation and neuroprotection, which enables neurons to adapt to new information and recover from injury, and is the molecular basis of learning and memory. However, in AD patients, the disorder of the pathway will aggravate cognitive dysfunction and disease progression.

[0003] Phosphodiesterases (PDEs) are a class of proteases that selectively degrade important second messengers cGMP (cyclic guanosine monophosphate) and cAMP (cyclic adenosine monophosphate) in the body, thereby participating in important physiological processes in the body. According to the sequence homology of the gene and the selectivity to cGMP or cAMP, PDEs can be divided into 11 members (PDE1-PDE11). Among them, PDE4 is mainly expressed in the brain and immune cells, responsible for cAMP degradation, and is crucial for synaptic plasticity, memory formation and neuroprotection. Studies have shown that PDE4A inhibitors are used for treating diseases caused by cognitive impairment due to central nervous system disorders. PDE10A is mainly expressed in the striatum and can hydrolyze cAMP and cGMP, participating in learning, cognition and motor control. Studies have shown that inhibiting PDE4 alone (such as Rolipram) can increase cAMP levels and enhance CREB activation, but is often accompanied by significant side effects such as nausea and vomiting, limiting its clinical application. PDE10A inhibitors (such as TAK-063) show potential in cognition and neuroprotection, but their clinical research mainly focuses on schizophrenia, and there is no AD-related clinical data. cAMP and cGMP, two nucleotides, are important second messengers that play a core role in cell signaling processes; they mainly activate protein kinases: activated by cAMP, called protein kinase A (PKA), and activated by cGMP, called protein kinase G (PKG). Activated PKA and PKG can phosphorylate many cellular effector proteins, such as ion channels, G-protein coupled receptors, structural proteins, and transduction factors. Therefore, cAMP and cGMP can control most physiological processes in many organs in this way, and at the same time, cAMP and cGMP can also directly act on effector proteins to play the same role.

[0004] However, the existing research has the following shortcomings: 1. Single PDE inhibitor has limited efficacy in AD treatment, and is accompanied by significant side effects; 2. The synergistic effect of PDE4 / 10A inhibition on the cAMP-PKA-CREB pathway and its mechanism in AD is not clear; 3. There is still a big gap in the translation between clinical and animal models. It is urgent to provide a new drug that can solve the above problems. SUMMARY

[0005] In view of the deficiencies of the prior art and the actual needs, the present application provides a pharmaceutical composition for treating degenerative diseases and its application. The present application synergistically activates the cAMP-PKA-CREB pathway by combining two inhibitors, providing a new method for treating degenerative diseases.

[0006] To achieve this purpose, the present application adopts the following technical solutions:

[0007] In a first aspect, the present application provides a pharmaceutical composition for treating degenerative diseases, which comprises a combination of phosphodiesterase-4 (PDE4) inhibitors and phosphodiesterase-10 (PDE10A) inhibitors.

[0008] In the present application, the combination of PDE4 and PDE10A inhibitors can enhance the activation of the cAMP-PKA-CREB signaling pathway, increase the expression of brain neurotrophic factor (BNDF), thereby reducing the accumulation of Aβ, reducing the hyperphosphorylation of tau protein, relieving neuroinflammation, improving synaptic plasticity, restoring cognitive function, and enhancing the adaptability of neurons.

[0009] The present application further explores whether the combination of PDE4 and PDE10A inhibitors can synergistically regulate the cAMP-PKA-CREB signaling pathway, alleviate the pathological characteristics of AD, and improve the stress tolerance of neurons. In the APP / PS1 AD mouse model, we found that the combination of PDE4 / 10A inhibitors can significantly improve cognitive function and enhance the survival ability of neurons. This finding indicates that the combination strategy of PDE4 and PDE10A inhibitors has potential innovation and application value in AD treatment, providing scientific basis and experimental basis for the development of new AD treatment drugs.

[0010] In the present application, the combination of PDE4 and PDE10A inhibitors (Rolipram and TAK-063) effectively reduces the accumulation of Aβ and restores it to the normal level of wild-type neurons, while significantly reducing the level of phosphorylated tau protein (p-Tau231), thereby alleviating tau protein pathology.

[0011] In a second aspect, the combination of PDE4 and PDE10A inhibitors (Rolipram and TAK-063) improves synaptic connectivity. Electrophysiological results show that Rolipram and TAK-063 treated mice have increased synaptic activity and functional inhibitory networks are established. This indicates that the combination of the present application is able to modulate synaptic function, enhance neuronal resilience and alleviate AD related synaptic dysfunction.

[0012] By promoting the formation of functional inhibitory networks and resistance to Aβ-induced toxicity through the above two aspects, the combination of PDE4 and PDE10A inhibitors improves the adaptability of neurons.

[0013] In the present application, the PDE4 inhibitor includes a compound having effective PDE4 inhibitory activity, which can be any one or a combination of at least two of Rolipram, Roflumilast, Ibudilast, Cilomilast, Apremilast, Tanimilast and Flavoxate, and is preferably Rolipram.

[0014] In the present application, the dose of the PDE4 inhibitor is 0.1-50 mg / kg, which can be 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, and is preferably 0.3-1 mg / kg.

[0015] In the present application, the PDE10A inhibitor includes a compound having effective PDE10A inhibitory activity, which can be any one or a combination of at least two of TAK-063, MP-10 (PDM-042), PF-2545920, TAK-128 and AMG 579, and is preferably TAK-063.

[0016] In the present application, the dosage of the PDE10A inhibitor is 0.1-50 mg / kg, for example, it can be 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, preferably 0.3-1 mg / kg.

[0017] In the present application, the degenerative disease is a neurodegenerative disease, including Alzheimer's disease, Parkinson's disease or Huntington's disease, preferably Alzheimer's disease.

[0018] The pharmaceutical composition of the present application is used for treating Alzheimer's disease, especially targeting key pathological features such as Aβ accumulation, tau protein hyperphosphorylation and neuroinflammation, which provides a more comprehensive treatment strategy compared with single-target therapy.

[0019] In the present application, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0020] If necessary, one or more pharmaceutically acceptable carriers can be added to the above-mentioned drugs, which include excipients, diluents, carriers, flavorings, binders and fillers commonly used in the pharmaceutical field, and can be any one or a combination of at least two thereof.

[0021] In the second aspect, the present application provides a use of a combination of PDE4 and PDE10A inhibitors or pharmaceutically acceptable salts, esters and solvates thereof in the preparation of a medicament for treating degenerative diseases.

[0022] Specifically, the combination of PDE4 and PDE10A inhibitors or pharmaceutically acceptable salts, esters and solvates thereof as active ingredients can be prepared into injection solutions, tablets, powders, granules, capsules, oral solutions and other forms. The above-mentioned various dosage forms can be prepared according to the conventional methods in the pharmaceutical field.

[0023] In the present application, the degenerative disease is a neurodegenerative disease, including Alzheimer's disease, Parkinson's disease or Huntington's disease, preferably Alzheimer's disease.

[0024] In the third aspect, the present application provides a method for treating degenerative diseases, comprising administering a therapeutically effective dose of the pharmaceutical composition of any one of the first aspect.

[0025] In the present application, the drug can be introduced into the body such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue by injection, spraying, nose drops, eye drops, penetration, absorption, physical or chemical mediated methods; or mixed or wrapped with other substances and then introduced into the body.

[0026] In the present application, the effective dose is 0.1-50mg / kg, for example, it can be 0.1mg / kg, 0.2mg / kg, 0.3mg / kg, 0.4mg / kg, 0.5mg / kg, 0.6mg / kg, 0.7mg / kg, 0.8mg / kg, 0.9mg / kg, 1mg / kg, 2mg / kg, 4mg / kg, 6mg / kg, 8mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg, 50mg / kg, preferably 0.3-1mg / kg.

[0027] In the present application, the administration mode is 1-3 times a day, for example, it can be 1 time, 2 times or 3 times, preferably 1 time.

[0028] In the present application, the degenerative disease is a degenerative disease, including Alzheimer's disease, Parkinson's disease or Huntington's disease, preferably Alzheimer's disease.

[0029] In the present application, the pharmaceutical composition can also be used for individuals with high risk (such as APOEε4 carriers) of developing, for preventing neurodegenerative diseases.

[0030] Compared with the prior art, the present application has the following beneficial effects:

[0031] (1) The pharmaceutical composition of the present application increases the intracellular cAMP and cGMP levels by combining PDE4 and PDE10A inhibitors, thereby activating the PKA and CREB pathways, and then promoting synaptic plasticity, reducing Aβ accumulation and reducing tau protein hyperphosphorylation, the activation of the pathway enhances neuronal survival and cognitive function, thereby providing therapeutic benefits in the treatment of degenerative diseases;

[0032] (2) The pharmaceutical composition of the present application not only helps to treat cognitive deficits in Alzheimer's disease patients by promoting synaptic plasticity and neuronal adaptability, but also improves the overall brain function of patients with neurodegenerative diseases. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1The effect of the combination of PDE4 and PDE10A inhibitors on the activation of the cAMP-PKA-CREB signaling pathway is shown. Figure A is the experimental design for the treatment of iPSC-derived neurons with the combination of inhibitors; Figures B-C are the intracellular cAMP levels measured by ELISA after 48 hours of treatment with the combination of PDE4 / 10A inhibitors at different concentrations (0-20 mM); Figures D-E are the PKA kinase activity measured under the same conditions; Figures F-I are the expression of proteins related to the cAMP-PKA-CREB signaling pathway in APP mutant neurons detected by Western blot. (All experiments were repeated at least three times, and the data are expressed as mean ± SEM. Statistical significance was determined using one-way ANOVA with Tukey's post-hoc analysis and two-tailed unpaired Student's t-test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001).

[0034] Figure 2 The combination of PDE4 and PDE10A inhibitors can alleviate Alzheimer's disease pathology. Figure A is the experimental design for the treatment of neurons with the combination of inhibitors; Figures B-C are the quantitative analysis of the changes in the concentrations of Aβ42 and Aβ40 in wild-type (WT), APP mutant (APPswe), and APP-CREB1-KO groups of 2-month-old iPSC-derived human cortical neurons after treatment with the combination of inhibitors; Figure D is a representative immunofluorescence image, scale bar = 10 pm; Figure E is a quantitative analysis of the relative intensity of Aβ staining in 2-month-old iPSC-derived human cortical neurons after treatment with different combinations of inhibitors, n = 20 neurons / group; Figure F is a representative immunofluorescence image showing the co-staining of MAP2 (red) and ptau231 (green) in 2-month-old iPSC-derived human cortical neurons of the WT, APPswe, and APP-CREB1-KO groups after treatment with Rolipram, TAK-063, or both. Scale bar = 10 pm, n = 20 neurons / group; Figure H is the expression of Aβ, APP full-length protein, p-tau231, and total tau protein detected by Western blot. (Statistical significance was determined using one-way ANOVA with Tukey's post-hoc analysis and two-tailed unpaired Student's t-test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001).

[0035] 42and Aβ40concentrations in wild-type (WT), APP mutant (APPswe), and APP-CREB1-KO groups of 2-month-old iPSC-derived human cortical neurons after treatment with the combination of inhibitors; Figure D is a representative immunofluorescence image, scale bar = 10 pm; Figure E is a quantitative analysis of the relative intensity of Aβ staining in 2-month-old iPSC-derived human cortical neurons after treatment with different combinations of inhibitors, n = 20 neurons / group; Figure F is a representative immunofluorescence image showing the co-staining of MAP2 (red) and ptau231 (green) in 2-month-old iPSC-derived human cortical neurons of the WT, APPswe, and APP-CREB1-KO groups after treatment with Rolipram, TAK-063, or both. Scale bar = 10 pm, n = 20 neurons / group; Figure H is the expression of Aβ, APP full-length protein, p-tau231, and total tau protein detected by Western blot. (Statistical significance was determined using one-way ANOVA with Tukey's post-hoc analysis and two-tailed unpaired Student's t-test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001).

[0036] Figure 3The combined application of the PDE4 and PDE10A inhibitors of this invention is crucial for alleviating Aβ pathology and improving cognitive deficits in mice. Figure A shows the experimental design of intranasal delivery of the inhibitor combination in an fAD mouse model. Figure B shows immunofluorescence images of the co-staining results of Thioflavin-S (green) and Aβ (6E10) from the cerebral cortex of fAD mice treated with the combined inhibitor combination. Scale bar = 20 μm. Figure C shows the quantitative analysis of Aβ plaque volume in the cerebral cortex, with results expressed in cubic micrometers (μm). 3 The percentage of the total cortical volume represented by the area is shown in Figure D (n=8 mice). Figure E shows the quantitative analysis of the percentage of Thioflavin-S and Aβ co-stained positive areas (n=8 mice), and Figure F shows the quantitative analysis of the relative intensity of Aβ (n=8 mice). Figure F1 shows the spatial memory assessment in the maze task. (Statistical significance was determined by one-way ANOVA supplemented by Tukey's post-hoc analysis and two-tailed unpaired Student's t-test. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001).

[0037] Figure 4 Mice were administered a combination of PDE4 and PDE10A inhibitors via nasal delivery and treated with Rolipram, TAK-063, or a combination of both for four weeks. Figures AB show the measurement of miniature excitatory postsynaptic currents (mEPSCs) in the brain tissue of APP / PS1 mice (n=8 mice, 4 males and 4 females). Figures CD show the measurement results of miniature inhibitory postsynaptic currents (mIPSCs) in the brain tissue of APP / PS1 mice (n=8 mice, 4 males and 4 females). Data are expressed as mean ± SEM. Statistical significance was determined by one-way ANOVA combined with Tukey's post-hoc test and two-tailed unpaired Student's t-test. **p<0.01, ****p<0.0001). Detailed Implementation

[0038] To further illustrate the technical means and effects of the present invention, the technical solution of the present invention will be further explained below with reference to the accompanying drawings and specific embodiments. However, the present invention is not limited to the scope of the embodiments.

[0039] The processes, conditions, reagents, and experimental methods used in implementing this invention, except as specifically mentioned below, are all common knowledge and general knowledge in the field, and this invention does not have any particular limitations. Experimental methods in the embodiments that do not specify specific conditions are generally performed under conventional conditions, such as those described in Sambrook et al., or according to the manufacturer's recommendations.

[0040] Unless otherwise indicated, all technical and scientific terms and any scientific nomenclature used herein have the same meaning as those that are generally understood by one of ordinary skill in the art in the field of the application. In case of a conflict between the name of a substance in its common name and its IUPAC name, the latter prevails.

[0041] Rolipram: Product No. 67177.LB0, Thermo Fisher Scientific

[0042] TAK-063: Product No. S8459, Selleck Chemicals LLC

[0043] Example 1 in vitro experiments

[0044] In the in vitro experiments, researchers treated APPswe-induced pluripotent stem cell-derived human cortical neurons with the combination of PDE4 inhibitor Rolipram and PDE10A inhibitor TAK-063. The experimental design included three groups of treatment conditions: 20 mM Rolipram, 20 mM TAK-063, and a combination of both (20 mM each) for a treatment duration of 48 hours. All inhibitors were applied to the cells under standard culture conditions, and their effects were evaluated by enzyme-linked immunosorbent assay (ELISA), Western blotting (WB) secreted detection, and results are shown in Figure 1 .

[0045] The combination of PDE4 and PDE10A inhibitors can activate the cAMP-PKA-CREB signaling pathway in human cortical neurons. Previous studies have shown that PDE inhibitors can enhance CREB1 activity by elevating intracellular cAMP levels and activating PKA. To verify whether the combined application of PDE4 / 10A inhibitors can activate the cAMP-PKA-CREB pathway, we applied the combination of PDE4 inhibitor Rolipram and PDE10A inhibitor TAK-063 to APPswe mutant human cortical neurons to stimulate cAMP levels and CREB1 activity Figure 3 (A). First, we confirmed that both Rolipram and TAK-063 can activate cAMP and PKA levels in neurons; subsequently, we optimized the concentration of the combined application of both (0-20 mM range), and the results showed that intracellular cAMP and PKA levels significantly increased with increasing concentration, reaching a peak at 20 mM Figure 1 (B and 1D). Importantly, the effect of using Rolipram and TAK-063 in combination was superior to using either inhibitor alone Figure 1C and 1E). Next, to investigate the effect of the combination on the cAMP-PKA-CREB pathway, we performed Western blot analysis of the relevant proteins in APPswe mutant neurons. The results showed that the combination of PDE4 and PDE10A inhibitors significantly increased the expression level of PKA (F and 1H), indicating that the combination of PDE4 and PDE10A inhibitors effectively activated the cAMP-PKA-CREB signaling pathway. Figure 1 F and 1H), indicating that the combination of PDE4 and PDE10A inhibitors effectively activated the cAMP-PKA-CREB signaling pathway.

[0046] Example 2 In vitro experiment

[0047] In the in vitro experiment, the researchers applied the combination of PDE4 inhibitor Rolipram and PDE10A inhibitor TAK-063 to APP-CREB1-KO neurons. The results showed that the combination effectively reduced the concentration of Aβ42 while increasing the concentration of Aβ40. The combination reduced the concentration of Aβ42 while increasing the concentration of Aβ40, which could reduce the level of highly toxic Aβ42 and retain relatively non-toxic Aβ40 by adjusting the γ-secretase cleavage bias or enhancing the selective clearance of Aβ42.

[0048] In APP-CREB1-KO neurons, the combination restored the concentrations of Aβ42 and Aβ40 to levels comparable to wild-type neurons (WT), suggesting the existence of alternative pathways independent of the cAMP-PKA-CREB pathway that could alleviate amyloid pathology. Figure 2 B and 2C). Immunofluorescence (IF) results further showed that the Aβ signal in the combination group was significantly reduced compared to untreated APP mutant neurons (D and 2E). In addition, the p-tau231 signal intensity was also significantly reduced in the combination group (p<0.0001, Figure 2 F and 2G). Consistent with the IF results, Western blot analysis showed that the combination of the combination group significantly reduced the levels of Aβ and p-tau231 proteins (H-J). Notably, the expression levels of Aβ and p-tau231 in the combination group were not significantly different from WT neurons (H-J). Figure 2 H-J). Notably, the expression levels of Aβ and p-tau231 in the combination group were not significantly different from WT neurons (H-J). Figure 4 E, 4G, 4I and 4J). The above results show that the combination of Rolipram and TAK-063 can effectively alleviate Alzheimer's disease-related pathological changes in APP mutant neurons, thereby demonstrating that the combination of PDE4 / 10A inhibitors can be a potential intervention strategy in vitro. Figure 2 Example 3 Verification of the effect of the combination in vivo at the animal level

[0049]

[0050] ​All procedures performed in this experiment were approved by the Institutional Animal Care and Use Committee (IACUC) of Soochow University. All live animals were housed in specific pathogen-free (SPF) grade facilities. Male and female mice with a mixed genetic background (C57BL / 6J) were used in the experiment, with the sole exception of germline mutant mice (APP / PS1) – this strain had been backcrossed to the C57BL / 6J genetic background for at least five generations. All animals were housed in groups, with control and mutant groups consisting of littermates. To control for strain / background variability, littermates with the same genetic hybrid combination were used as controls in each group. Genotyping of all animals was performed according to the Jackson Laboratory standard procedure.

[0051] To further verify the in vivo effects of the combination of PDE4 and PDE10A inhibitors on Alzheimer's disease, we administered Rolipram and TAK-063 via nasal administration.

[0052] APP / PS1 mice. The specific method involved administering 1 mg / kg of a combination (Rolipram and TAK-063, 0.5 mg / kg each) intranasally to 6-month-old APP / PS1 mice daily for four weeks, followed by behavioral tests and brain tissue analysis (Figure 6A). The results showed that the combined application group significantly reduced the number of Aβ plaques and the area of ​​Thioflavin-S and Aβ co-staining positive regions (…). Figure 3 BE). In contrast, while monotherapy can reduce Aβ plaque volume and area, its effects are weaker than those of combination therapy. Figure 3 BE). In behavioral assessments, the combined application group showed an approximately 32% increase in the percentage of spontaneous alternations in the Y-maze experiment, an approximately 22% increase in the percentage of new arm entry, and an approximately 3-meter increase in total walking distance. Figure 3 FG); Open-field experiments showed that the dwell time in the central area increased by approximately 28 seconds, and the walking distance increased by approximately 2.1 meters. Figure 3 H); In the new object recognition experiment, the percentage of contact with new objects increased by approximately 26%, and the exploration time was extended by approximately 12 seconds. Figure 3 I). In summary, this embodiment demonstrates that the combination of Rolipram and an inhibitor of TAK-063 can effectively alleviate Aβ pathology in APP / PS1 mice and significantly improve cognitive function by enhancing spontaneous alternation behavior, increasing neoarm entry frequency, improving motor activity, and improving spatial memory, thus providing a feasible and safe drug combination strategy for AD treatment.

[0053] Example 4: Validation of the in vivo effects of the composition at the animal level.

[0054] To further verify the effect of the combination of PDE4 and PDE10A inhibitors on synaptic function, we performed electrophysiological recording on the brain tissue of APP / PS1 mice. The results showed that the miniature excitatory postsynaptic currents (mEPSCs) of mice treated with the combination of Rolipram and TAK-063 were significantly increased, and the synaptic activity was enhanced Figure 4 A, B), which had a statistically significant difference compared with untreated mice. At the same time, the measurement of miniature inhibitory postsynaptic currents (mIPSCs) showed that the mice treated with the combination established a functional inhibitory network Figure 4 C, D). These results indicate that the combination of PDE4 and PDE10A inhibitors not only enhances synaptic activity, but also promotes the formation of functional inhibitory networks, thereby improving the synaptic function of AD mice, providing experimental evidence for the combination to enhance neuronal stress tolerance and cognitive function.

[0055] In summary, the pharmaceutical composition of the present application increases the intracellular cAMP level by combining PDE4 and PDE10A inhibitors, thereby activating the PKA and CREB pathway, which in turn promotes synaptic plasticity, reduces Aβ accumulation, and reduces tau protein hyperphosphorylation. The activation of this pathway enhances neuronal survival and cognitive function, thereby providing therapeutic benefits in the treatment of neurodegenerative diseases.

[0056] The applicant states that the present application is illustrated by the above examples to explain the detailed method of the present application, but the present application is not limited to the above detailed method, i.e. it does not mean that the present application must rely on the above detailed method to be implemented. It should be understood by those skilled in the art that any improvement of the present application, equivalent replacement of each raw material of the product of the present application, addition of auxiliary ingredients, selection of specific methods, etc. fall within the scope of protection and disclosure of the present application.

Claims

1. A pharmaceutical composition for treating degenerative diseases, characterized in that, The pharmaceutical composition comprises a combination of a phosphodiesterase-4 (PDE4) inhibitor and a phosphodiesterase-10 (PDE10A) inhibitor.

2. The pharmaceutical composition according to claim 1, characterized in that, The PDE4 inhibitors include any one or a combination of at least two of the following: Rolipram, Roflumilast, Ibudilast, Cilmimilast, Apremilast, Tanimilast, and Flavoxate, preferably Rolipram. Preferably, the dosage of the PDE4 inhibitor is 0.1-50 mg / kg, and more preferably 0.3-1 mg / kg.

3. The pharmaceutical composition according to claim 1, characterized in that, The PDE10A inhibitor includes any one or a combination of at least two of TAK-063, MP-10 (PDM-042), PF-2545920, TAK-128 and AMG 579, preferably TAK-063; Preferably, the dosage of the PDE10A inhibitor is 0.1-50 mg / kg, and more preferably 0.3-1 mg / kg.

4. The pharmaceutical composition according to claim 1, characterized in that, The degenerative disease is a neurodegenerative disease, preferably including Alzheimer's disease, Parkinson's disease, or Huntington's disease, and more preferably Alzheimer's disease.

5. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition also includes pharmaceutically acceptable excipients; Preferably, the excipient is any one or a combination of at least two of the following: excipient, diluent, carrier, flavoring agent, binder, and filler.

6. Use of PDE4 inhibitors and PDE10A inhibitors, or pharmaceutically acceptable salts, esters, or solvates thereof, in the preparation of medicaments for the treatment of degenerative diseases.

7. The use according to claim 6, characterized in that, The degenerative disease is a neurodegenerative disease, preferably including Alzheimer's disease, Parkinson's disease, or Huntington's disease, and more preferably Alzheimer's disease.

8. A method for treating degenerative diseases, characterized in that, This includes administering a therapeutically effective dose of the pharmaceutical composition according to any one of claims 1-5.

9. The method according to claim 8, characterized in that, The effective dose is 0.1-50 mg / kg, preferably 0.3-1 mg / kg; Preferably, the administration method is 1-3 times daily, preferably once daily.

10. The method according to claim 8, characterized in that, The degenerative disease is a neurodegenerative disease, preferably including Alzheimer's disease, Parkinson's disease, or Huntington's disease, and more preferably Alzheimer's disease.

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