CN113041240A - Application of ACT001 in preparation of drugs for treating Parkinson's disease and drugs for treating NLRP3 inflammation body-mediated neuritis - Google Patents
Application of ACT001 in preparation of drugs for treating Parkinson's disease and drugs for treating NLRP3 inflammation body-mediated neuritis Download PDFInfo
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- CN113041240A CN113041240A CN201911379185.0A CN201911379185A CN113041240A CN 113041240 A CN113041240 A CN 113041240A CN 201911379185 A CN201911379185 A CN 201911379185A CN 113041240 A CN113041240 A CN 113041240A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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Abstract
The invention relates to the drug research of neurodegenerative diseases, in particular to the application of ACT001 in preparing drugs for treating Parkinson and drugs for treating NLRP3 inflammation body-mediated neuritis, and ACT001 and pharmaceutically acceptable auxiliary materials are prepared into a medicament. The study found that ACT001 is effective in alleviating parkinson's disease symptoms, and in alleviating NLRP3 inflammation-body-mediated neuritis.
Description
Technical Field
The invention belongs to the field of medicines for neurodegenerative diseases, and particularly relates to application of ACT001 in preparation of medicines for treating Parkinson's disease and medicines for treating NLRP3 inflammation body-mediated neuritis.
Background
L-3, 4-dihydroxyphenylalanine (L-DOPA) is currently the predominant drug used in the treatment of Parkinson's Disease (PD). However, long-term use of L-DOPA causes severe side effects, mainly manifested by massive damage and death of neurons, because other nerve cells in the human body lack feedback mechanism for dopamine storage and elimination, L-DOPA is absorbed and converted into dopamine after entering the human body, and for non-dopaminergic neurons, it is difficult to store and eliminate dopamine, and free dopamine is highly susceptible to oxidation to form quinone, thereby affecting cell activity. Experiments prove that the formed dopaquinone and the dopaquinone can form quinoprotein with tyrosine lightening enzyme (TH) and 5-light tryptamine lightening enzyme, and further, a great amount of neurons of a Parkinson patient are damaged and die in the treatment process. Currently, no drug is available that can effectively alleviate or prevent the side effects caused by L-DOPA.
The inflammatory corpuscle plays an important role in the occurrence and development of inflammation-related diseases, wherein the NLRP3 inflammatory corpuscle can be activated by various pathogen-associated molecular patterns (PAMPs) and injury-associated molecular patterns (DAMPs), so as to activate caspase-1, release mature forms of IL-1 beta and IL-18, cause inflammatory response of the organism, and participate in the occurrence and development of various diseases, including type 2 diabetes, gout, atherosclerosis, neurodegenerative diseases, tumors, inflammatory bowel diseases and the like. Therefore, the research on the action mechanism of NLRP3 inflammatory bodies not only helps to deepen the understanding of the occurrence and development of inflammatory diseases, but also provides a new idea for searching potential therapeutic targets of the diseases
Given the important role of NLRP3 in neurodegenerative diseases, there is some potential for its targeted therapy. However, because the mechanism of the drug is still incompletely studied, the simple application of inhibitors related to NLRP3 inflammasome may cause systemic reaction and bring about serious side effects. Therefore, the research of novel therapeutic methods needs to focus on the specific pathway activated by NLRP3 in the central nervous system, explore possible related receptors or inhibitors, etc.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides application of a sesquiterpene lactone compound, namely ACT001 in preparation of a drug for treating Parkinson's disease and a drug for treating neuroleptic-mediated neuritis caused by NLRP3 inflammation bodies through research.
It is desirable to find a bioactive ingredient that works synergistically with low doses of L-DOPA to achieve the same therapeutic effect as a high dose of L-DOPA. The natural active substance Parthenolide (PTL) is an active ingredient of the medicinal plant parthenolide (tanacetum parthenium), having antioxidant and anti-inflammatory properties. ACT001 is a fumarate form of dimethylamino resorcinol lactone (DMAMCL), is a derivative of parthenolide, has an effect comparable to PTL, but shows higher stability in plasma and is less expensive. In our study, we used ACT001 in combination with L-DOPA to treat 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) -induced mouse Parkinson's disease. Specifically, ACT001 significantly reduced MPTP treatment in mice with motor dysfunction and dopaminergic neurodegenerative disease. In addition, ACT001 abrogated MPTP-induced alpha-synuclein overexpression, astrocyte activation, and interleukin 1 β (IL-1 β) production in the substantia nigra and striatum of mice. In addition, ACT001 increased the level of the anti-apoptotic signaling molecule Bcl-2 and the pAkt/Akt ratio in the substantia nigra and striatum, and decreased the level of the pro-apoptotic signaling molecule Bax and activation of Caspase 3.
The invention adopts the scheme that the sesquiterpene lactone compound with the following molecular formula is applied to the preparation of the medicine for treating Parkinson's disease:
the sesquiterpene lactone compound with the molecular formula is the ACT 001.
In another preferred embodiment of the present invention, the Parkinson is MPTP-induced Parkinson's disease.
In another preferred scheme, the sesquiterpene lactone compounds and pharmaceutically acceptable auxiliary materials are prepared into medicaments.
In another preferred embodiment of the present invention, the pharmaceutical agent is a liquid agent, a gaseous agent, a solid dosage form or a semisolid agent.
In another preferred embodiment of the present invention, the pharmaceutical agent is an injection or an oral preparation.
The invention also provides application of the ACT001 in preparing a medicament for treating NLRP3 inflammation body mediated neuritis.
Preferably, ACT001 is formulated with pharmaceutically acceptable excipients into a medicament.
More preferably, the medicament is a liquid, gaseous, solid dosage form or semisolid.
In another preferred embodiment, the pharmaceutical agent is an injection or an oral agent.
Through studies, we found that in MPTP-induced Parkinson's disease mice, the effect of co-administration of ACT001 and L-DOPA (5mg/kg) was the same as that of co-administration of 8mg/kg L-DOPA. Thus, these data indicate that L-DOPA + ACT001 can be used to treat PD.
Further by study, our findings demonstrate for the first time that ACT001 reduces NLRP 3-mediated neuroinflammation in MPTP-induced PD.
Drawings
Fig. 1 is a diagram showing the result of detecting the total movement distance in embodiment 1 of the present invention.
FIG. 2 is a graph showing the results of average velocity detection in example 1 of the present invention.
FIG. 3 is a graph showing the results of wall contact times detection in example 1 of the present invention.
FIG. 4 is a graphical representation of the results of immunostaining of TH-positive dopaminergic neurons in the substantia nigra of example 1 of the invention. FIG. 5 is a graph showing the quantification of the number of TH-positive neurons in the substantia nigra of FIG. 5 in accordance with example 1 of the present invention.
FIG. 6 is a graphical representation of the immunostaining results for TH-positive fibers in the striatum of example 1 of the present invention.
FIG. 7 is a graph showing the results of quantifying TH positive ends in the striatum using Image Pro Premier software.
FIG. 8 is a graph of the results of quantitative analysis of TH and α -synuclein levels in the striatum by Western blotting.
FIG. 9 is a graph showing the results of quantitative analysis of TH and α -synuclein levels in substantia nigra by Western blotting.
FIG. 10 is a graphical representation of the results of the quantitative analysis of IL-1 β, Bcl-2, Bax and cleaved caspase3 expression in striatum by Western blotting.
FIG. 11 is a graph of the results of a quantitative analysis of IL-1 β, Bcl-2, Bax and cleaved caspase3 expression in substantia nigra by Western blotting.
FIG. 12 is a graph showing the result of immunostaining for GFAP in substantia nigra.
FIG. 13 is a graph of the percentage of astrocytes in the substantia nigra.
FIG. 14 is a graph showing the results of immunostaining for GFAP in the striatum.
FIG. 15 is a graph of the percentage of astrocyte areas in the striatum.
FIG. 16A is a schematic diagram of detection of Akt and phosphorylated Akt (Ser473) expression in striatum by Western blot.
FIG. 16B is a schematic representation of protein level quantification of p-Akt/Akt in striatum.
FIG. 16C is a diagram showing the results of Western blot detection of Akt and phosphorylated Akt (Ser473) in substantia nigra.
FIG. 16D is a graph showing the results of determining the protein level of p-Akt/Akt in substantia nigra.
Fig. 17A is a time representation of the experimental design of example 2.
Fig. 17B is a pole climbing test result chart.
Figure 17C is a hindlimb cinching severity scoring graph.
Fig. 17D is a graph of the results of the mouse cognitive deficit test.
FIG. 18A is a graph of immunostaining of TH-positive dopaminergic neurons in the substantia nigra.
Fig. 18B is a histogram of TH positive neuron counts.
Figure 18C is an immunostaining pattern of TH positive fibers in the striatum.
Figure 18D is a schematic representation of representative western blot bands for TH.
Fig. 18E is a histogram showing quantitative analysis of TH.
FIG. 19A is a graph showing the results of measuring MDA levels.
FIG. 19B is a graph showing the results of measuring SOD activity.
FIG. 19C is a graph showing the results of measuring CAT activity.
FIG. 19D is a graph showing the results for IL-6 levels.
FIG. 19E is a graphical representation of the results for TNF- α levels.
FIG. 19F is a graph showing the results for the level of IL-1 β.
FIG. 20A is a graph of immunostaining for ox42 in substantia nigra.
Figure 20B is a graph of immunostaining for ox42 in the striatum.
FIG. 21A is a schematic representation of the Western blot bands of caspase-8, p65, p-p 65.
FIG. 21B is a caspase-8 quantitative analysis histogram.
FIG. 21C is a p-p65 quantitative analysis histogram.
FIG. 22A is a schematic Western blot analysis of lpr3, Caspase-1, ProIL-1. beta., IL-1. beta.
FIG. 22B is a histogram showing quantitative analysis of Nlpr3, Caspase-1, ProIL-1 β, IL-1 β levels.
Detailed Description
The present invention will now be described in detail with reference to the drawings, which are given by way of illustration and explanation only and should not be construed to limit the scope of the present invention in any way. Furthermore, features from embodiments in this document and from different embodiments may be combined accordingly by a person skilled in the art from the description in this document.
EXAMPLE one reduction of side effects of ACT001 during Parkinsonism treatment
1. Examples sesquiterpene lactones useful in the preparation of medicaments for treating parkinson's disease and for treating NLRP3 inflammasome-mediated neuritis are of the formula:
also known as ACT001, chemical name: (3R,3aS,9R,9aS,9bS) -3- ((dimethylamino) methyl) -9-hydroxy-6, 9-dimethyl-3, 3a,4,5,7,8,9,9 a-octahydroazuno [4, 5-b)]Furan-2 (9bH) -one fumarate, a michelia lactone derivative.
2. Experimental procedure
3. Results of the experiment
3.1 coordination of ACT001 and L-DOPA ameliorates motor dysfunction in Parkinson's disease mice
The synergy of ACT001 and L-DOPA was first evaluated by behavioral tests, including open field experiments and cylinder tests. MPTP treatment can lead to PD-like motor dysfunction, so we examined performance using open-field testing under semi-natural conditions. The motor behavior classification and trajectory showed that mice exhibited significant trembling and stiffness. The total locomotor distance, mean speed and running time were reduced after MPTP administration, and co-administration of ACT001 with L-DOPA significantly improved these measurements (FIG. 1, FIG. 2). These results indicate that ACT001 has a good therapeutic effect on MPTP-induced dyskinesia. Cylinder experiments were then performed to check the number of times each mouse's forelimb contacted the cylinder wall (fig. 3). The results show that MPTP administration significantly reduced the exploratory behavior of the mice, and that, consistent with the results of the open field test, co-administration of ACT001 and L-DOPA increased the number of wall contacts.
ACT001 in cooperation with L-DOPA ameliorated MPTP-induced loss of dopaminergic neurons of the nigrostriatal pathway.
The main pathological features of parkinson's disease are loss of substantia nigra TH positive neurons and reduction of striatal TH, which is the rate-limiting enzyme in dopamine synthesis. We therefore detected TH positive neurons in the nigrostriatal pathway by immunohistochemistry. FIGS. 4-7 are graphs showing the effect of co-administration of L-DOPA and ACT001 on MPTP-induced dopaminergic neurotoxicity in the nigrostriatal pathway, where FIG. 4 is a graphical representation of the immunostaining results for TH-positive dopaminergic neurons in the substantia nigra. In the substantia nigra, MPTP caused a massive loss of dopaminergic neurons (fig. 4). By quantifying the number of TH positive neurons, we found that the MPTP + ACT001 and MPTP + LD5 groups increased the number of TH positive neurons in the substantia nigra, but there was still a significant difference compared to the control group. Furthermore, we found that the effect of co-administration of ACT001 and L-DOPA (5mg/kg) was equivalent to that of L-DOPA (8mg/kg), and was not significantly different from the control group (FIG. 4, FIG. 5). The same results were obtained in striatum (fig. 6, fig. 7). To confirm the results, we performed western blot analysis of TH protein levels in the substantia nigra and striatum, which showed a significant reduction in TH protein levels compared to controls. However, administration of ACT001 and LD enhanced expression of TH protein. It is worth mentioning that the synergistic treatment group showed a better effect in enhancing TH expression than the other treatment groups.
Furthermore, another important biochemical feature of Parkinson's Disease (PD) is the misfolding of fibrillar α -synuclein, which is associated with nigrostriatal degeneration. Therefore, we also examined the expression level of α -synuclein in substantia nigra and striatum by western blotting. MPTP significantly increases the expression of alpha-synuclein, and co-administration of ACT001 and L-DOPA inhibits MPTP-induced overexpression of alpha-synuclein, thereby protecting dopaminergic neurons. These results indicate that the parthenolide derivative ACT001 in combination with L-DOPA can treat Parkinson's disease.
The effect of co-administration of L-DOPA and ACT001 on MPTP-induced dopaminergic neurotoxicity in the nigrostriatal pathway was examined by FIGS. 4-7. (A) Immunostaining of TH-positive dopaminergic neurons in the substantia nigra. (B) Quantification of the number of TH positive neurons in substantia nigra. The number of TH positive neurons in the substantia nigra was determined by blind counting in 3 sections imaged under the microscope. (C) Immunostaining of TH positive fibers in the striatum. (D) TH positive ends were quantified in the striatum using Image Pro Premier software.
We again showed expression of Tyrosine Hydroxylase (TH) and alpha-synuclein protein levels in the substantia nigra and striatum of mice by Western blot analysis. FIGS. 8 and 9 are graphs showing the expression of the levels of Tyrosine Hydroxylase (TH) and alpha-synuclein in the substantia nigra and striatum of mice by Western blot analysis, FIG. 8 is a graph showing the results of quantitative analysis of the levels of TH and alpha-synuclein in the striatum by Western blot, and FIG. 9 is a graph showing the results of quantitative analysis of the levels of TH and alpha-synuclein in the substantia nigra by Western blot. It can be seen that co-administration of ACT001 and L-DOPA inhibited MPTP-induced overexpression of alpha-synuclein, thereby protecting dopaminergic neurons.
ACT001 in combination with L-DOPA ameliorated MPTP-induced neuroinflammation and apoptosis of the nigrostriatal pathway.
Neuroinflammation and apoptosis are the major mechanisms by which MPTP induces neuronal death. Thus, we examined the expression of the inflammatory factor IL-1 β, the pro-apoptotic signaling molecule Bax, the anti-apoptotic signaling molecule Bcl-2 and the apoptosis-activating factor clear-caspase 3 in the substantia nigra and striata (FIGS. 10 and 11). As expected, MPTP resulted in a significant increase in the protein expression of IL-1 β, Bax and Caspase3, while the protein expression of Bcl-2 was significantly reduced in the substantia nigra and striatum. However, both L-DOPA and ACT001 inhibited the increase in IL-1 β, Bax, clear-caspase 3 and the decrease in Bcl-2. Furthermore, the group receiving 8mg/kg L-DOPA alone and the group receiving ACT001 and 5mg/kg L-DOPA showed the best improvement, indicating that ACT001 and L-DOPA synergistically inhibited apoptosis and inflammation. FIGS. 10 and 11 are Western blot assays for the protein levels of IL-1 β, Bcl-2, Bax and Caspase3 in the substantia nigra and striatum. FIG. 10 is a graph showing the results of quantitative analysis of IL-1 β, Bcl-2, Bax and cleaved caspase3 expression in striatum by Western blotting, and FIG. 11 is a graph showing the results of quantitative analysis of IL-1 β, Bcl-2, Bax and cleaved caspase3 expression in substantia nigra by Western blotting.
ACT001 in combination with L-DOPA improved MPTP-induced astrocyte activation.
Furthermore, it is generally believed that activation of glial cells is indicative of neuroinflammation, and therefore we examined the extent of activation of astrocytes in the substantia nigra and striatum by GFAP immunostaining. We observed that MPTP caused a significant increase in astrocyte activation of the substantia nigra and striatum. The synergistic administration of ACT001 and L-DOPA significantly improved astrocyte activation and reduced astrocyte numbers in the substantia nigra and striatum. These results indicate that ACT001 synergistically inhibits astrocyte activation with L-DOPA. FIGS. 12-15 are graphs showing the effect of ACT001 in synergistic inhibition of astrocyte activation with L-DOPA. FIGS. 12 and 13 are immunostaining for GFAP in the substantia nigra. Fig. 14 and 15 immunostain GFAP in the striatum. Data are expressed as mean ± s.e.m. (n ═ 10). Multiple comparison test by Tukey, p <0.05, p <0.01, p <0.001, p <0.0001 compared to control. Scale bar: 100 μm and 40 μm.
ACT001 synergizes with L-DOPA to promote neuronal survival.
To further determine the ACT 001-mediated neuroprotective mechanism, we examined the expression of Akt and phosphorylated Akt (Ser473) in the substantia nigra and striatum by Western blot (fig. 16A-16D). MPTP treatment significantly reduced the ratio of p-Akt/Akt, and co-administration of ACT001 and L-DOPA significantly increased the ratio of p-Akt/Akt. These results indicate that ACT001 binding to L-DOPA can induce activation of the Akt signaling pathway to treat PD.
FIGS. 16A, 16B, 16C, 16D Western blot analysis of p-Akt/Akt protein levels in the substantia nigra and striatum. FIG. 16A is a schematic diagram of detection of expression of Akt and phosphorylated Akt (Ser473) in striatum by Western blot, FIG. 16B is a schematic diagram of protein level quantification of p-Akt/Akt of striatum, FIG. 16C is a schematic diagram of detection of expression results of Akt and phosphorylated Akt (Ser473) in substantia nigra by Western blot, and FIG. 16D is a schematic diagram of protein level results of fixed p-Akt/Akt in substantia nigra. (A) And (B) Western blotting of striatal proteins was performed to determine the protein levels of p-Akt/Akt. (C) And (D) Western blotting of substantia nigra protein to determine the protein level of p-Akt/Akt. Data are expressed as mean ± s.e.m. (n ═ 10). Multiple comparison test by Tukey, p <0.05, p <0.01, p <0.001, p <0.0001 compared to control.
Example two ACT001 reduced NLRP3 inflammasome-mediated neuroinflammation in MPTP-induced PD mice
The natural product Parthenolide (PTL) is an active ingredient in the medicinal plant, tanacetum parthenium, and has antioxidant and anti-inflammatory properties. ACT001 is a derivative of dimethylphenolactone, Dimethylaminomethane (DMAMCL) in the form of fumarate, which is comparable in effect to PTL, but shows higher stability in plasma and is available at lower cost. Evidence suggests that the pyridine domain-containing 3(NLRP3) mediated neuroinflammation of the NOD-like receptor family plays a very important role in the pathogenesis of PD. In our study, we examined whether ACT001 reduces NLRP 3-mediated neuroinflammation in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) -induced mouse Parkinson's disease. The ability to move was tested by the pole test and hind limb clasping test. Cognitive function is detected by a novel object recognition test and a circadian activity test. Dopaminergic neurodegeneration was assessed by immunostaining and western blot analysis. The oxidative stress level was determined spectrophotometrically. Expression of proinflammatory cytokines was detected by real-time quantitative PCR. Western blot analysis was used to assess the relevant proteins in the NLRP3 inflammatory-body signaling pathway. Our results indicate that ACT001 can reduce dyskinesia and cognitive deficits in PD mice. In addition, it reduces dopaminergic neurodegeneration in the substantia nigra and dopamine consumption in the striatum, and inhibits MPTP-induced oxidative stress, inflammatory responses and activation of NLRP3 inflammasome in the brain of PD mice. More importantly, it attenuates microglial activation in the nigrostriatal pathway. Overall, we first found that ACT001 reduced NLRP 3-mediated neuroinflammation in MPTP-induced PD.
1. The experimental process comprises the following steps:
group 4 mice received 0.9% physiological saline, MPTP (15mg/kg), MPTP (15mg/kg) + ACT001(20mg/kg), MPTP (15mg/kg) + ACT001(50mg/kg), respectively. Just prior to administration, MPTP, ACT001 was dissolved in 0.9% saline. MPTP was intraperitoneally administered every 24 hours for 7 days, and ACT001 was administered by gavage at a dose of 20mg/kg 1 hour before each MPTP administration, once every 24 hours for 7 days.
2. Results of the experiment
2.1 ACT001 alleviates MPTP-induced behavioral disorders.
Dyskinesia is one of the characteristics of PD. Fig. 17A is a time representation of the experimental design of example 2.A pole climbing experiment and hind limb clasping were performed to test MPTP-induced mouse dyskinesia. FIG. 17B is a graph showing the results of the pole climbing test, in which administration of MPTP significantly increased the time for the mouse to climb down the pole compared with the control group (FIG. 17B). ACT001 treatment may reduce its duration in a dose-dependent manner. Furthermore, MPTP-induced hind limb clasping behavior of mice was significantly reduced after ACT001 treatment (FIG. 17C), and FIG. 17C is a hind limb clasping severity score chart.
Next, we also performed a novel object recognition test to study MPTP-induced cognitive deficits in mice (fig. 17D), fig. 17D is a graph of mouse cognitive deficit test results. The percent recognition of new subjects in the MPTP group was significantly reduced compared to the control group. ACT001 treatment can reverse this short-term cognitive disorder.
As can be seen, ACT001 alleviates MPTP-induced behavioral disorders. (A) Schedule of experimental design. (B) Time for the mouse to climb down the pole in the pole climbing test. (C) Severity of hind limb clasping. (D) In the new object identification test, mice spend time in each area. In the new object recognition test, statistics of the time taken for the mouse to approach each object indicate that ACT001 alleviates MPTP-induced behavioral disorders. Data are expressed as mean ± s.e.m. (n-8). Multiple comparison test by Tukey, p <0.05, p <0.01, p <0.001, p <0.0001 compared to control. Compared to the MPTP treatment group, # p <0.05, # p <0.01, # p <0.001, # p < 0.0001.
ACT001 can improve circadian rhythm activity disorder caused by MPTP.
Disorders of circadian activity may lead to mild cognitive impairment, then we performed 10 days of circadian activity in 12:12h dark (LD) and 24h dark (DD) cycles, respectively, in a Clocklab biorhythm data acquisition and analysis system. During the normal 12:12 hour Light rhythm (Light: Dark, LD) phase, the circadian activity of the MPTP group was significantly reduced, while ACT001 significantly improved this state. The 24-hour Dark environment detection (Dark, DD) stage detects circadian changes in circadian activity under endogenous clock gene regulation. At this stage, the ACT 001-administered group also mitigated the MPTP-induced decrease in locomotor activity in a dose-dependent manner. The results indicate that ACT001 can restore the rhythm disorder caused by MPTP. Statistical clustering analysis was then performed on the behavioral parameters. The results divided the behavioral parameters into two groups, an exercise activity group and a rest time group. As a result, ACT001 has an improving effect on the movement/resting dysrhythmia caused by MPTP. To further analyze the differences between the behavioral parameters of each group, we also performed principal component analysis and obtained the same results.
ACT001 reduces dopaminergic neuronal degeneration in the nigrostriatal pathway.
Behavioral disorders of PD are thought to be the result of progressive degeneration of dopaminergic neurons in the substantia nigra and decreased striatal TH levels. Therefore, we examined TH levels in the substantia nigra and striatum by immunohistochemistry (fig. 18A, 18B, 18C). FIG. 18A is a graph of immunostaining of TH-positive dopaminergic neurons in the substantia nigra, and FIG. 18B is a histogram of TH-positive neuron counts, and images of 3-5 sections are counted to analyze the number of TH-positive neurons. Figure 18C is an immunostaining pattern of TH positive fibers in the striatum. The results show that mice treated with MPTP showed significant dopaminergic neuronal loss in the substantia nigra and striatum compared to the control group. ACT001 treatment reduced MPTP-induced reduction of TH levels compared to the MPTP group. In addition, the same results were obtained by detecting the expression of TH in the brain in MPTP-induced PD mice by western blotting (fig. 18D, 18E). Fig. 18D is a schematic representation of representative western blot bands for TH, and fig. 18E is a histogram showing quantitative analysis of TH. Data are expressed as mean ± s.e.m. (n-8). Multiple comparison test by Tukey, p <0.05, p <0.01, p <0.001, p <0.0001 compared to control. Compared to the MPTP treatment group, # p <0.05, # p <0.01, # p <0.001, # p < 0.0001. Scale bar: 40 μm (substantia nigra); 1mm (striatum).
2.4 ACT001 relieves MPTP-induced oxidative stress and inflammatory response in the brain in PD mice.
To investigate the effect of ACT001 on MPTP-induced lipid peroxidation, we examined the level of MDA in the brain of mice. The MDA levels in the MPTP group were significantly higher than in the control group, while ACT001 treatment reduced the MDA level increase. Moreover, SOD and CAT are important antioxidant kinases. The mice in the MPTP group showed lower SOD and CAT activities compared to the control group, whereas the ACT001 treatment significantly increased the SOD and CAT activities (FIGS. 19B, 19C), FIG. 19A is a graph showing the results of measuring the MDA level, FIG. 19B is a graph showing the results of measuring the SOD activity, and FIG. 19C is a graph showing the results of measuring the CAT activity. IL-6, TNF-alpha and IL-1 beta are key proinflammatory cytokines in the process of neuroinflammation. MPTP administration significantly upregulated mRNA levels of IL-6, TNF- α and IL-1 β in the brain of mice compared to the control group. ACT001 treatment significantly inhibited IL-6, TNF- α and IL-1 β mRNA expression in a dose-dependent manner (FIGS. 19D, 19E, 19F), FIG. 19D is a graph showing the results for IL-6 levels, FIG. 19E is a graph showing the results for TNF- α levels, and FIG. 19F is a graph showing the results for IL-1 β levels. As can be seen, ACT001 reduced MPTP-induced oxidative stress and inflammatory responses in the brain of PD mice. (A, B, C) MDA levels and SOD and CAT activities were determined spectrophotometrically. (D, E, F) Gene expression of IL-6, TNF- α and IL-1 β was determined by quantitative real-time PCR. Data are expressed as mean ± s.e.m. (n-8). Multiple comparison test by Tukey, p <0.05, p <0.01, p <0.001, p <0.0001 compared to control. Compared to the MPTP treatment group, # p <0.05, # p <0.01, # p <0.001, # p < 0.0001.
2.5 ACT001 attenuated microglial activation in the substantia nigra and striata.
Furthermore, activation of glial cells is an important factor in the progression of inflammation, and we examined the extent of activation of microglial cells in the substantia nigra and striatum by ox42 immunostaining. We observed a significant increase in microglial activation in the substantia nigra and striatum following MPTP administration. Treatment with ACT001 significantly improved microglial activation, indicating a reduction in the number of microglial cells in the substantia nigra and striatum. Fig. 20A and 20B show that ACT001 attenuates microglial activation in the nigrostriatal pathway. (A) Ox42 was immunostained in the substantia nigra. (B) Immunostaining for ox42 in the striatum. Scale bar: 100 μm and 40 μm.
ACT001 inhibits the MPTP-induced NLRP3 inflammatory-corpuscular signaling pathway in the brain of PD mice.
The NLRP3 inflammasome is reported to be involved in the development of PD. We used western blotting to detect the classical Nlrp3 activation pathway (fig. 21A, 21B, 21C and 22A, 22B). Activation of the NLRP3 inflammasome mediates the maturation and release of IL-1 β, which requires two signals. The first signal was that MPTP induced cleavage of procaspase-8 and promoted phosphorylation of p65, thereby increasing the expression of NLRP3 and proIL-1 β. As shown in FIGS. 22A and 22B, the second signal was that activated NLRP3 inflammably induced caspase-1 cleavage, promoting the conversion of pro-IL-1 β to mature IL-1 β. Treatment with ACT001 significantly inhibited the activation of the NLRP3 inflammasome in the midbrain. Fig. 21A, 21B, 21C show that ACT001 inhibits MPTP-induced activation of NLRP3 inflammasome-evoked signals in the brains of PD mice. (A) Western blot bands of caspase-8, p65, p-p 65. (B, C) histograms represent quantitative analysis of caspase-8 and p-p65 levels. Data are expressed as mean ± s.e.m. (n-8). Multiple comparison test by Tukey, p <0.05, p <0.01, p <0.001, p <0.0001 compared to control. Compared to the MPTP treatment group, # p <0.05, # p <0.01, # p <0.001, # p < 0.0001.
Fig. 22A and 22B show that ACT001 inhibits NLRP3 inflammasome activation in the brain of PD mice. (A) Western blot bands of Nlpr3, Caspase-1, ProIL-1. beta., IL-1. beta. (B) Histograms representing quantitative analysis of Nlpr3, Caspase-1, ProIL-1 β, IL-1 β levels. Data are expressed as mean ± s.e.m. (n-8). Multiple comparison test by Tukey, p <0.05, p <0.01, p <0.001, p <0.0001 compared to control. Compared to the MPTP treatment group, # p <0.05, # p <0.01, # p <0.001, # p < 0.0001.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (9)
1. Sesquiterpene lactone compound with following molecular formula in preparation of medicineThe application of the Parkinson treatment medicine comprises the following steps:
2. use of sesquiterpene lactones according to claim 1 for the preparation of a medicament for the treatment of parkinson's disease, wherein parkinson's disease is MPTP induced parkinsonism.
3. The use of sesquiterpene lactones according to claim 1 in the manufacture of a medicament for the treatment of parkinson's disease, wherein the sesquiterpene lactones are formulated with pharmaceutically acceptable excipients.
4. The use of sesquiterpene lactones according to claim 1 in the manufacture of a medicament for the treatment of parkinson's disease, wherein said medicament is in the form of a liquid, a gas, a solid or a semi-solid formulation.
5. The use of sesquiterpene lactones according to claim 4 in the manufacture of a medicament for the treatment of Parkinson's disease, wherein said medicament is in the form of an injection or an oral formulation.
6. The application of sesquiterpene lactone compounds with the following molecular formula in preparing medicines for treating neuritis mediated by NLRP3 inflammasome is disclosed:
7. the use of sesquiterpene lactones of claim 6 in the manufacture of a medicament for the treatment of NLRP3 inflammasome-mediated neuritis, characterized in that sesquiterpene lactones are formulated with pharmaceutically acceptable excipients.
8. The use of sesquiterpene lactones according to claim 6 in the manufacture of a medicament for the treatment of NLRP3 inflammasome-mediated neuritis, wherein said medicament is in the form of a liquid, gaseous, solid or semisolid formulation.
9. The use of sesquiterpene lactones according to claim 6 for the preparation of a medicament for the treatment of NLRP3 inflammasome-mediated neuritis, wherein said medicament is in the form of an injection or an oral dosage.
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