CN115778929A - Use of LZ-08 for the preparation of a medicament for the treatment and/or prevention of microglial-mediated disorders - Google Patents
Use of LZ-08 for the preparation of a medicament for the treatment and/or prevention of microglial-mediated disorders Download PDFInfo
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- CN115778929A CN115778929A CN202211564530.XA CN202211564530A CN115778929A CN 115778929 A CN115778929 A CN 115778929A CN 202211564530 A CN202211564530 A CN 202211564530A CN 115778929 A CN115778929 A CN 115778929A
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Abstract
The invention relates to application of a small molecular compound LZ-08 in preparing a medicament for treating and/or preventing microglia-mediated diseases. The invention discovers that the micromolecular compound LZ-08 has an effective prevention and treatment effect on the neuroinflammation caused by the activation of microglia, and further has prevention and treatment effects on nervous system diseases caused by the neuroinflammation caused by the activation of the microglia, such as cerebral apoplexy, alzheimer disease, parkinson disease, cerebral trauma, multiple sclerosis, amyotrophic lateral sclerosis and the like. A classical EAE model was also prepared by using MOG 35-55-induced C57BL/6 mice, and it was found that neurological deficit symptoms were reduced after LZ-08 intervention. HE staining and LFB staining showed that LZ-08 can reduce brain tissue inflammatory cell infiltration and brain tissue demyelination during the peak phase of disease in EAE mice. Therefore, the compound has important significance for the development and application of medicines for treating microglial cell mediated neuroinflammatory diseases.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of a small molecular compound LZ-08 in preparing a medicine for treating and/or preventing microglia-mediated diseases.
Background
Drug development of human neurodegenerative diseases is a high risk area, and thus there is an urgent need to identify promising therapeutic drugs based on complex pathological mechanisms. Neuroinflammation occurs when the immune system reacts to various signals within the Central Nervous System (CNS), such as infection, traumatic brain injury, ischemia, autoimmunity or toxic metabolites. Therefore, neuroinflammation has attracted considerable attention due to its critical role in neurodegenerative diseases, a common risk factor. Generally, neuroinflammation is caused by microglia, and Microglia (MG), which is a type of macrophage widely distributed in the Central Nervous System (CNS), belongs to one of the glial cells, accounts for 5% -20% of the number of the whole CNS glial cells, and is a very important resident immune cell of the CNS. Microglia continually clear damaged nerves, plaques, and infectious material from the central nervous system. Numerous clinical and neuropathological studies have shown that activated microglia play a very important role in the pathogenesis of neurodegenerative diseases, such as alzheimer's disease, multiple sclerosis and parkinson's disease. But excessive activation or uncontrolled microglia can cause neurotoxicity. They are important sources of proinflammatory factors and oxidative stress, such as tumor necrosis factor, nitric oxide, interleukins and other neurotoxic substances. In this case, effective treatment by microglia inhibition may benefit patients suffering from inflammation-related neuronal disorders.
Alzheimer's Disease (AD), commonly known as senile dementia, is a neurodegenerative disease clinically manifested by memory impairment, aphasia, agnosia, visual space impairment, executive dysfunction, personality and behavioral changes, and a high incidence of older than 65 years old. The pathological phenomena of AD are complex, and the examination result of brain tissues shows that AD patients commonly have pathological phenomena such as Senile Plaques (SP) formed by a large amount of beta-amyloid protein (Abeta) deposition outside brain nerve cells, intracellular neurofibrillary tangles (NFTs) formed by tau protein abnormal phosphorylation, neuron loss, neurotrophy, synapse loss and the like. The amyloid cascade hypothesis has been a popular concept explaining the pathogenesis of AD over the past few years. However, several studies are now supporting the idea that inflammation may be a key pathological factor leading to neurodegeneration in AD. There is a large body of evidence that microglial activation plays an important role in the inflammatory signaling pathway that induces neurodegeneration. Also noteworthy, studies have shown that microglia are highly involved in the formation of Α β plaques in the brains of AD patients. Data from studies using animal models of AD also indicate the presence of activated microglia at the site of a β deposition, suggesting that microglia may physically interact with a β and modulate its levels in the brain.
Multiple Sclerosis (MS) is an immune-mediated disease characterized primarily by inflammatory demyelinating diseases of the Central Nervous System (CNS) that involve primarily white matter. Its etiology is unclear and may be related to various factors such as heredity, environment, virus infection, etc. Neuroinflammation is present in all stages of MS and is closely associated with microglia. In Experimental Autoimmune Encephalomyelitis (EAE) (MS mouse model), microglia release proteases, pro-inflammatory cytokines, ROS, and RNS, and recruit reactive T lymphocytes, thereby causing toxicity to neurons and oligodendrocyte precursor cells. Targeted deletion of Transforming Growth Factor (TGF) - β activated kinase 1 in EAE microglia reduces CNS inflammation and axonal and myelin damage by cell autonomous inhibition of NF- κ B, JNK and ERK1/2 pathways, suggesting that microglia may contribute to EAE tissue damage.
Numerous research results indicate that, in the progression of neuroinflammatory diseases such as stroke, alzheimer's disease, parkinson's disease, brain trauma, multiple sclerosis, amyotrophic lateral sclerosis and the like, chronic activation of microglia secretes a variety of proinflammatory cytokines, chemokines and neurotoxic factors including neurotoxic-inducing IL-1 β, IL-6, TNF α, MCP-1, NO, PGE2 and the like, thereby promoting neuronal death. Therefore, inhibition of microglial-mediated neuroinflammation is a potential therapeutic strategy for the treatment of these brain diseases.
Chinese patent CN104958307A, published Japanese 2015.10.07, discloses a new application of ginsenoside Rd in preparing medicine for preventing and/or treating microglia-mediated diseases, and can be used for treating diseases such as multiple sclerosis, amyotrophic lateral sclerosis, AIDS dementia, mad cow disease and the like. Another chinese patent CN104288168A, published japanese 2015.01.21, discloses an application of trillin in preparing a medicament for treating and/or preventing microglia-mediated diseases, wherein trillin can obviously inhibit the generation of inflammatory mediator NO which activates microglia, and the provided traditional Chinese medicine monomer trillin can inhibit the activation of microglia to induce cell death. Therefore, the trillin can be applied to the prevention and treatment of brain immune inflammatory related diseases such as stroke, alzheimer disease, parkinson disease, brain trauma, encephalitis, multiple sclerosis and the like.
However, no report is found on the application of the small molecule compound LZ-08 in the preparation of medicines for treating and/or preventing microglia-mediated diseases.
Disclosure of Invention
The first purpose of the invention is to provide the application of a small molecule compound LZ-08 in preparing a medicine for treating and/or preventing microglia-mediated diseases, aiming at the defects in the prior art.
It is a second object of the present invention to provide a formulation.
In order to achieve the first purpose, the invention adopts the technical scheme that:
the application of the micromolecule compound LZ-08 shown as the formula (I) in preparing the medicine for treating and/or preventing diseases mediated by microglia, wherein the micromolecule compound LZ-08 is (E) -3- (3, 4-dihydroxyphenyl) -N- (4-fluorophenethyl) acrylamide,
as a preferred example, the disease is a microglial-mediated neuroinflammatory disease.
As a preferred example, the above-mentioned microglia is a microglia line BV2 or a primary microglia.
As a preferred example, the neuroinflammatory diseases include cerebral apoplexy, alzheimer disease, parkinson disease, cerebral trauma, multiple sclerosis and amyotrophic lateral sclerosis.
In order to achieve the second purpose, the invention adopts the technical scheme that:
an agent for preventing and/or treating a microglial-mediated neuroinflammatory disease, which comprises the small molecule compound LZ-08 according to claim 1 or at least one pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
As a preferred example, the preparation comprises one or more of tablets, solutions, suspensions, emulsions, powders, granules, capsules, microcapsules, microspheres, injection, liposomes or aerosols.
The invention has the advantages that:
the micromolecule compound LZ-08 can be used for preparing medicines for treating and/or preventing microglia-mediated diseases, especially medicines for treating and/or preventing microglia-mediated neuroinflammation diseases, and has important significance for development and application of medicines for the neuroinflammation diseases.
The invention discovers that the small molecular compound LZ-08 has an effective prevention and treatment effect on the neuroinflammation caused by the activation of microglia, and further has a prevention and treatment effect on nervous system diseases caused by the neuroinflammation caused by the activation of the microglia, such as cerebral apoplexy, alzheimer disease, parkinson disease, cerebral trauma, multiple sclerosis, amyotrophic lateral sclerosis and the like. The classical EAE model is made by using MOG35-55 to induce C57BL/6 mice, and the nerve function defect symptom is relieved after the intervention of LZ-08 is found, and the conditions of brain tissue inflammatory cell infiltration and brain tissue demyelination in the disease peak stage of the EAE mice can be relieved by the LZ-08 shown by HE staining and LFB staining, so that the protection effect of the classical EAE model on the EAE mice is further verified.
Drawings
FIG. 1 shows the effect of LZ-08 on microglial survival.
FIG. 2 shows the effect of LZ-08 on the level of expression of microglial TNF-a (compared to the blank, # P<0.05; compared with the control group, the compound of the formula, * P<0.05)。
FIG. 3L shows the effect of Z-08 on microglial IL-1 β expression levels (compared to blank, # P<0.05; compared with the control group, the compound of the formula, * P<0.05)。
FIG. 4 shows the effect of LZ-08 on the level of expression of microglial TNF-a (compared to the blank, # P<0.05; compared with the control group, the compound of the formula, * P<0.05)。
figure 5 is a comparison of neurological deficit scores in mice from each group (P <0.05, P <0.01 compared to LZ-08 intervention group).
FIG. 6 shows hematoxylin-eosin staining images (. Times.200) of brain tissues of mice in each group.
FIG. 7 is a Roque fast blue staining picture (X200) of brain tissue of each group of mice.
It should be noted that the colors in the drawings are all subjected to the gray scale processing, and are actually the colors mentioned in the description of the drawings.
Detailed Description
As a preferred example, the small molecule compound LZ-08 of the following examples for treating and/or preventing microglia-mediated diseases is (E) -3- (3, 4-dihydroxyphenyl) -N- (4-fluorophenethyl) acrylamide (formula I) with the molecular formula C 17 H 16 FNO 3 Molecular mass 301.3174:
and can be synthesized by the following method:
dissolving 180mg caffeic acid (1 mmol) in 30ml tetrahydrofuran solution, sequentially adding 206mg DCC (1 mmol) and 2- (p-fluorophenyl) ethylamine (1 mmol), stirring, heating and refluxing for 2-7h, monitoring reaction degree by TLC, cooling reaction solution to room temperature after reaction is completed, precipitating a large amount of white insoluble substance, and filtering to remove insoluble substance. Distilling the filtrate under reduced pressure to remove solvent, and purifying by silica gel column chromatography to obtain product LZ-08, white powder, ESI-MS:302.1 (M + H); 1HNMR (300mhz, dmso) δ 9.36 (s, 1H), 9.12 (s, 1H), 8.04 (t, J =5.4hz, 1h), 7.27-7.18 (m, 3H), 7.10 (t, J =8.9hz, 2h), 6.92 (d, J =1.7hz, 1h), 6.81 (dd, J =8.3,1.9hz, 1h), 6.72 (d, J =8.1hz, 1h), 6.29 (d, J =15.7hz, 1h), 3.45-3.25 (m, 3H), 2.74 (t, J =7.2hz, 2h).
The invention will be further illustrated with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. In the examples, the experimental methods used were all conventional methods unless otherwise specified, and the materials, reagents and the like used were commercially available unless otherwise specified. Furthermore, it should be understood that various changes and modifications can be made by those skilled in the art after reading the disclosure of the present invention, and equivalents fall within the scope of the appended claims.
Example 1 anti-inflammatory Effect of LZ-08 in BV2 microglia
1. Pharmaceutical formulation
The LZ-08 powder is prepared into 1g/L mother liquor by using a pharmaceutically acceptable carrier.
2. Cell culture
BV2 microglial cell line (purchased from ATCC) in DMEM high-glucose complete medium (containing 10% fetal bovine serum, 100U. ML) -1 Penicillin streptomycin, 100. Mu.g. ML -1 Streptomycin) was cultured in a cell culture box containing 37 ℃ and 5% CO2 and 95% air humidity. When the cells grow to 80-90%, pouring out the culture solution in the cell bottle, washing with PBS for 1-2 times, adding pancreatin for digestion, observing most cells to shrink and become round, discarding pancreatin, and adding a proper amount of culture medium containing serum. According to the growth condition of the cells, proper cell liquid is taken for culture and passage.
3. Cell grouping and administration
BV2 cells were divided into a blank group, a control group and an experimental group, wherein the blank group was not treated, the control group was cultured for 48 hours by adding 0.1. Mu.g/ml LPS, and the experimental group was treated for 48 hours by adding 0.1. Mu.g/ml LPS and 1, 10 and 50. Mu.g/ml LZ-08, respectively.
Cell survival rate detection by CCK-8 method
(1) The experimental steps are as follows:
uniformly inoculating the logarithmic growth BV2 microglia into a 96-well plate, culturing for 24h, and then carrying out cell grouping and administration treatment according to the method. Each group was set with 6 multiple wells for 12h intervention. After the treatment, according to the specific specification of a CCK-8 kit, adding 10 mu l of CCK-8 reagent into each hole, incubating the culture plate in a cell incubator for 2h, reading OD (optical density) values at the wavelength of 450nm by using a multifunctional microplate reader, and then counting the cell survival rate of each group.
Cell survival (%) = (experimental OD-blank OD)/(control OD-blank OD) × 100%.
(2) The experimental results are as follows:
the results are shown in FIG. 1, and LZ-08 has no significant effect on microglial viability and no obvious cytotoxic effect.
ELISA method for detecting secretion of inflammatory factor
(1) Experiment step 3000r/min centrifugation 5min collect cell culture supernatant. According to the ELISA kit specification, the expression levels of inflammatory factors TNF-alpha, IL-1 beta and IL-6 in each group of culture solution are detected.
(2) Results of the experiment
Compared with a blank group, the content of TNF-alpha, IL-1 beta and IL-6 in the cell supernatant of the control group is obviously increased (P is less than 0.05) through ELISA detection. After each group of LZ-08 and LPS with different concentrations are treated together for 24 hours, TNF-alpha, IL-1 beta and IL-6 inflammatory factors secreted by microglia are remarkably reduced (P is less than 0.05) compared with a control group, and the reduction is more obvious along with the increase of the concentration of the LZ-08 (P is less than 0.05), which indicates that the LZ-08 plays a role in inhibiting TNF-alpha, IL-1 beta and IL-6 secreted by the microglia, and the figure 2, the figure 3 and the figure 4 are shown.
Example 2: effect of LZ-08 on Experimental Autoimmune Encephalomyelitis (EAE) mouse neurological deficit score
1. Laboratory animals and groups
SPF grade C57BL/6 female mice 8-10 weeks old were fed with free diet for 1 week prior to the experiment. The groups were randomly divided into a normal control group, an EAE group and an LZ-08 intervention group, 9 individuals per group.
Preparation of EAE mouse model
The induction of the EAE model was performed according to currently accepted methods. MOG35-55 polypeptide is used as a sensitizing antigen, MOG35-55 polypeptide is diluted into 2mg/ml MOG35-55 polypeptide solution by 0.01mol/L PBS, H37RA is diluted into 8mg/ml CFA solution by IFA, MOG35-55 polypeptide solution and the CFA solution with the same volume are rapidly and uniformly mixed for 10min through a three-way pipe ice bath until the mixture is in a water-in-oil state, and the antigen emulsion for inducing EAE is obtained. The two sides of the back of the model mouse are injected with 0.2ml of antigen emulsion subcutaneously by 4 points. The normal control group was injected with an equal amount of CFA solution by the same method. Immediately after immunization and at 48h, all mice (including normal control group) were given an intraperitoneal injection of PT at 500ng/0.2ml per animal. All animals were dosed equally, frequently and for the duration of treatment. Normal control group uses normal saline and CFA mixed antigen emulsion to immunize mice; in the EAE group, MOG35-55 is used for replacing physiological saline to immunize mice with CFA mixed antigen emulsion; the mice in the LZ-08 intervention group are injected with LZ-08 intraperitoneally at 20mg/kg 2 times a day for 14 days from the current day of immunization after EAE modeling. The normal control group and the EAE group were replaced with the same amount of physiological saline for LZ-08.EAE mice were sacrificed at peak disease (no increase in neurological dysfunction score, quadriplegia, or even death in 3d continuous mice) and placebo and non-diseased mice were sacrificed after 4 weeks of feeding.
3. Neurological deficit scoring
(1) Experimental procedure
Starting on the day of immunization, weighing the body mass of the mice in the morning and at the evening every day, observing the feeding condition, the onset latency and a double-blind method of the mice to score the nerve function, continuously observing that the mice are killed, and scoring by adopting a sensitive weaver15 method, wherein the standard is as follows: tail: no abnormal score 0, score 1 for tail hemiparalysis and score 2 for tail holoparalysis; four limbs: no abnormal 0 point, 1 point of gait change, 2 points of paresis, 3 points of whole paralysis (four limbs are scored and accumulated respectively), and 15 points of death.
(2) Results of the experiment
The normal control group was active normally and showed no clinical symptoms. Clinical symptoms of EAE group appear at 9d after immunization at the earliest time, the diseased mice show reduced appetite, reduced activity, dark hair color and weight loss, most of the mice show reduced tail distal tension as the first symptom, and then tail paralysis, hind limb weakness and paralysis, serious patients are combined with forelimb paralysis or even dying state, all the mice in EAE group have diseases, 6 mice in LZ-08 intervention group 9 have diseases, the rest three mice have no clinical symptoms, the disease rate is in a descending trend compared with that in EAE group, but the statistical significance is absent, the daily average neurological impairment score and the highest neurological impairment score of animals are both obviously reduced, and the difference has statistical significance (P < 0.05), which is shown in figure 5.
4. Optical observation
(1) Drawing materials and treating specimens
At peak disease, mice were anesthetized by intraperitoneal injection of 2% sodium pentobarbital (50 mg/kg,2.5 mL/kg). After successful anesthesia, 3 mice were randomly selected from the EAE model group and the LZ-08 intervention group, sacrificed after cardiac perfusion, brain tissue was rapidly excised on ice, rinsed with PBS, and placed in low-concentration sequential high-concentration alcoholic solutions, i.e., 2 hr 70% ethanol, 80% ethanol overnight, 2 hr 90% ethanol, 1 hr 100% ii ethanol, gradually dehydrated. The alcohol in the tissue mass was replaced with xylene to make the specimen transparent. Wax penetration and embedding: the tissue blocks were placed in paraffin and placed in an oven (2 hours, 60 ℃). The container is prepared in advance, and the completely waxed tissue block is placed in the container for embedding, and cooling solidification is waited. The tissue microtome takes 5 μm thick serial sections, one at 20 μm intervals, and dries the section at 60 deg.C for further use.
(2) HE staining
1) And (3) taking paraffin sections of brain tissues of each group of mice by dyeing, adding xylene for dewaxing to water, respectively placing the paraffin sections in hematoxylin staining solution and eosin staining solution for dyeing, dehydrating, sealing, and observing inflammatory focus, cell infiltration and demyelinating lesion under an optical microscope.
2) As a result, the
There was a large infiltration of inflammatory cells in the EAE model group. Compared with the EAE model group, the infiltration of inflammatory cells in the LZ-08 intervention group is reduced, which shows that the LZ-08 can reduce the infiltration of inflammatory cells in brain tissues in the peak period of disease onset of EAE mice, and the figure is 6.
(3) LFB staining
1) Taking paraffin sections of brain tissues of each group of mice, and observing the demyelination condition of white matter through dewaxing, laoks fast blue staining solution staining, dehydration sealing and microscopic examination.
2) Results
Extensive demyelinated areas were visible in the EAE model group, with blue hypopigmentation; the blue low-stained area of the LZ-08 intervention group is reduced compared with that of the EAE model group, which shows that the LZ-08 can relieve the demyelination of brain tissues in the EAE mice at the peak period of morbidity, and the figure is shown in figure 7.
The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.
Claims (6)
1. The application of the small molecular compound LZ-08 shown in the formula (I) in preparing the medicine for treating and/or preventing microglial cell mediated diseases is characterized in that the small molecular compound LZ-08 is (E) -3- (3, 4-dihydroxyphenyl) -N- (4-fluorophenethyl) acrylamide,
2. the use according to claim 1, wherein the disease is a microglial-mediated neuroinflammatory disease.
3. Use according to claim 2, characterized in that the microglia are microglial lines BV2 or primary microglia.
4. The use according to claim 2, wherein said neuroinflammatory disorder comprises stroke, alzheimer's disease, parkinson's disease, brain trauma, multiple sclerosis, amyotrophic lateral sclerosis.
5. An agent for preventing and/or treating a microglial-mediated neuroinflammatory disorder, wherein the agent comprises the small molecule compound LZ-08 according to claim 1 or at least one pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
6. The formulation of claim 5, wherein the formulation comprises one or more of a tablet, solution, suspension, emulsion, powder, granule, capsule, microcapsule, microsphere, injection, liposome, or aerosol.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104274433A (en) * | 2013-07-08 | 2015-01-14 | 中国医药大学 | application of caffeic acid amide derivative |
| CN105646439A (en) * | 2014-11-10 | 2016-06-08 | 中国人民解放军第二军医大学 | Synergist for antifungal drugs, and preparation and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104274433A (en) * | 2013-07-08 | 2015-01-14 | 中国医药大学 | application of caffeic acid amide derivative |
| CN105646439A (en) * | 2014-11-10 | 2016-06-08 | 中国人民解放军第二军医大学 | Synergist for antifungal drugs, and preparation and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| LI DAI等: "Design, synthesis, and evaluation of caffeic acid amides as synergists to sensitize fluconazole-resistant Candida albicans to fluconazole", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, pages 34 - 37 * |
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