CN114848797A - Application of PIEZO1 antagonist GsMTx-4 in preparation of medicine for treating spinal cord injury - Google Patents

Application of PIEZO1 antagonist GsMTx-4 in preparation of medicine for treating spinal cord injury Download PDF

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CN114848797A
CN114848797A CN202210570488.6A CN202210570488A CN114848797A CN 114848797 A CN114848797 A CN 114848797A CN 202210570488 A CN202210570488 A CN 202210570488A CN 114848797 A CN114848797 A CN 114848797A
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gsmtx
spinal cord
cord injury
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medicine
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赵云鹏
李魏玮
陈永坤
苏宏
宁斌
程雷
李玉华
高原
张鹏飞
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Qilu Hospital of Shandong University
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Abstract

The invention discloses application of PIEZO1 inhibitor molecule GsMTx-4 in preparation of a medicine for treating spinal cord injury. GsMTx-4 plays a protective role in spinal cord injury. In vitro cell experiments show that GsMTx-4 can antagonize the microglial inflammatory reaction process caused by mechanical injury. Meanwhile, animal models show that GsMTx-4 can relieve the occurrence of acroparalysis caused by spinal cord injury and improve the state of an illness, has no obvious toxic or side effect after long-term application, can be used in the fields of spinal cord injury and the like, and has wide application value and market prospect.

Description

Application of PIEZO1 antagonist GsMTx-4 in preparation of medicine for treating spinal cord injury
Technical Field
The invention relates to the field of medicine, in particular to application of PIEZO1 antagonist GsMTx-4 in preparation of a medicine for treating spinal cord injury.
Background
At present, the treatment of spinal cord injury is a worldwide problem and has high disability rate. At present, no specific medicine exists in the spinal cord injury repair process, the clinical application medicine effect is not good, and if the spinal cord injury degree of a patient is serious, the lethality rate is higher [1 ]. The current surgical spinal decompression or conservative treatment strategies have related risks and complications and have their own limiting factors. With the increasing number of patients with spinal cord injury, treatment for this disease has placed a tremendous burden on society and families.
The currently clinically used therapeutic drugs are mostly directed at specific symptoms, and the types of related drugs for protecting and improving the spinal cord structure are few, so that the choice of patients is small. Meanwhile, the existing drugs including hormone, mannitol and the like have limited curative effect and have certain side effect after long-term application, so the use is limited to a certain extent.
The discovery of the PIEZO1 pathway and its mechanism of action in pressure conduction received the Nobel prize in 2021. Recent studies suggest that the PIEZO1 antagonist GsMTx-4 has a potential protective function in the inhibition of macrophage inflammatory microenvironment [2 ]. Through preliminary experiments, GsMTx-4 treatment is researched, and the GsMTx-4 treatment has an improvement function on the spinal cord injury process and can provide a potential method for reducing the disability and fatality rate of the spinal cord injury after long-term use.
[1]Kathrin J.Allen,Stephen W.Leslie；Autonomic Dysreflexia In:StatPearls[Internet].Treasure Island(FL):StatPearls Publishing；2022Jan.2022Feb 14.
[2]Yun Shen,Yongchu Pan,Shuyu Guo,Lian Sun,Chi Zhang,Lin Wang；The roles of mechanosensitive ion channels and associated downstream MAPK signaling pathways in PDLC mechanotransduction Mol Med Rep 2020May；21(5):2113-2122.doi:10.3892/mmr.2020.11006.Epub 2020Feb 27.
Disclosure of Invention
The invention aims to provide application of a bone protective preparation taking PIEZO1 antagonist GsMTx-4 as an active ingredient in preparing a medicine for treating spinal cord injury.
The GsMTx-4 polypeptide is used as a component for resisting inflammatory reaction and promoting cell regeneration, has the effects of improving cell metabolism and relieving the severity of spinal cord injury, and in vitro experiments show that the GsMTx-4 has a cytotoxic effect, so that the medicine is safer after long-term use.
The technical scheme of the invention is as follows:
GsMTx-4 (purity 98.4%, CAS:1209500-46-8, molecular formula C 185 H 273 N 49 O 45 S 6 ) (Gill Biochemical Co., Ltd.) the molecular weight: 4095.85.
GsMTx-4 has good functions of maintaining stable cell metabolism and inhibiting cell inflammation, has low local dosage and low price, and is also the advantage of the GsMTx-4 compared with other spinal cord injury protective molecules. Meanwhile, the purity of the compound has already reached more than 98 percent at present, and the purity meets the requirement of medicine preparation.
The invention provides application of GsMTx-4 polypeptide in preparing a medicine for treating spinal cord injury, and particularly, in terms of application mechanism, the GsMTx-4 polypeptide is used as a cell metabolism protective factor and an apoptosis antagonistic molecule to block excessive activation of microglia and realize inflammatory reaction functions.
In particular to the application in preparing a protective medicament for spinal cord injury.
Further, especially for preparing the medicine for treating spinal cord injury caused by trauma.
Further, especially the application in preparing the medicine for alleviating traumatic acute spinal cord injury.
In particular to application of the traditional Chinese medicine composition in medicines for treating paralysis, immobility of limbs, sensory disturbance of limbs and the like caused by spinal cord injury.
The medicine also comprises pharmaceutically acceptable molecular subtypes and analogs, derivatives GsMTx-4 polypeptide salts and the like.
The medicine also comprises a pharmaceutically acceptable carrier, an auxiliary agent or a diluent.
The application form of the medicine is preferably intrathecal injection reagent or local external nanoparticles.
The results of in vitro cell experiments and in vivo animal models show that the GsMTx-4 polypeptide can antagonize the excessive activation and inflammatory reaction of microglia and play a protective role in spinal cord injury. The functional component GsMTx-4 belongs to antagonistic molecules of cell metabolic disorder and apoptosis, and can be directly extracted and purified by the prior art, so that the cost is reduced. In addition, in an animal model, the GsMTx-4 polypeptide has no obvious toxic or side effect after long-term local application, and can be used for specific diseases caused by spinal cord injury.
Therefore, the compound has predictable application in preparing the medicine for treating spinal cord injury, thereby having wide market prospect.
Drawings
FIG. 1 is BMS statistical analysis of GsMTx-4 treatment in a mouse spinal cord injury model based on hindlimb muscle force outcomes
FIG. 2 is an MRI treatment effect image of GsMTx-4 treatment in mouse spinal cord injury model
FIG. 3 is an image of HE staining of GsMTx-4 treatment in a mouse spinal cord injury model
FIG. 4 is an Iba-1 immunohistochemical stain image of GsMTx-4 treatment in a mouse spinal cord injury model
FIG. 5 is a Western Blot image of GsMTx-4 treatment of inflammatory marker molecules in a mouse spinal cord injury model
Figure 6 is the antagonistic effect of GsMTx-4 treatment on excessive mechanical stress-induced excessive inflammatory response of microglia.
Detailed Description
Sources of experimental animals, reagents, media and buffers referred to in the following examples:
the PIEZO1 channel inhibitor GsMTx-4 (molecular weight: 4095.85) (Gill Biochemical Co., Ltd.).
C57/BL6 wild type mouse (Shandong university animal center)
68100 mouse spinal cord strike device (Shenzhen RWD technology Limited)
Pressure cell culture system (Wuxi Tilia Biotech Co., Ltd.)
PBS buffer (Biyuntian biological reagent company)
COX-2 antibody, iNOS antibody, Iba-1 antibody (Thermo Fisher, Pierce)
RIPA cell protein extraction lysate (Thermo Fisher, Pierce)
Protease inhibitor (Beijing Solaibao Tech Co., Ltd.)
BCA protein quantification kit (Shanghai Yanxi Biotech Co., Ltd.)
Complete EDTA-Free (Roche biomedicine)
Xylene (national drug group chemical reagent Co., Ltd.)
Neutral gum (Shanghai Tantake skill Co., Ltd.)
Concentrated hydrochloric acid (national drug group chemical reagent Co., Ltd.)
Eosin (Shanghai Tantake skill Co., Ltd.)
Hematoxylin (Shanghai Tantake skill Co., Ltd.)
Methanol (national medicine group chemical reagent Co., Ltd.)
Citrate buffer (0.01M, pH 6.0) (Biotechnology engineering, Shanghai Co., Ltd.)
10% NGS (biological engineering Shanghai share Co., Ltd.)
Hydrogen peroxide (H2O2) (national drug group chemical Co., Ltd.)
BSA (Biotechnology Shanghai GmbH)
Absolute ethyl alcohol (national medicine group chemical reagent Co., Ltd.)
Cell counter was purchased from Thermo Fisher, USA
Microscope from Shanghai Caikang optical instruments Ltd
Centrifuge from Jinan Olaibo medical instruments Ltd
Electronic balance from medical instruments ltd, denna olabo
Enzyme-linked immunosorbent assay (ELISA) instrument purchased from Beijing Meihua apparatus science and technology Limited
Ice machine from Jinan Ou Laibo medical instruments Ltd
Ultra pure water system is commercially available from Jinan Oolabo medical instruments Ltd
Vortex mixer from Jinan Olaibo medical instruments Ltd
1. Spinal cord injury rat model construction
Pneumatic impact spinal cord injury models (15 total) were established in 10 week old wild type C57/BL6 mice. The blank group of mice (5) did not receive any treatment. The remaining 10 mice were subjected to a T10 thoracic laminectomy and spinal cord injury was created using pneumatic shock, no treatment for positive control, and local subdural injections of the PIEZO1 inhibitor GsMTx-4(280 μ g/kg body weight) 3 times per week. Spinal cord injury muscle recovery BMS scores were used at day 28 to compare recovery of spinal cord function in different groups of mice. 0 no ankle joint movement. 1 the ankle joint is slightly mobile. 2 the ankle joint is widely movable. 3 the sole is on the ground or does not stand on the sole. 4 frequent and continuous activities, and the sole of the foot stands by accident. 5 frequently and continuously standing on the sole of the foot, and some coordination. But not completely coordinated. Bilateral hind limbs were scored separately and added. After the experiment is finished, performing magnetic resonance detection on mice of all groups, performing euthanasia after the spinal cord injury repair condition is determined, collecting spinal cord specimens, performing histological and molecular biological detection on the spinal cord specimens, and analyzing the inflammatory change and regeneration process of the spinal cord.
Fig. 1-2 show the results of this experiment, with fig. 1 showing BMS scores for each group, and fig. 2 showing spinal magnetic resonance images after induction treatment (sagittal showing continuity of spinal cord injury site and axial showing integrity of spinal cord structure), all showing significant remission of spinal cord injury in mice under GsMTx-4 treatment.
2. Tissue slice preparation
Spinal cord tissues from mice from all groups were fixed in 10% formalin for at least 72 hours at room temperature. Sequentially dehydrating the tissue with 50% ethanol (60 min), 70% ethanol (60 min), 85% ethanol (60 min), 95% ethanol (60 min), 100% ethanol (30 min); sequentially treating the mixture by ethanol, dimethylbenzene (60 minutes) and dimethylbenzene (60 minutes); then clear with xylene and paraffin (60 min), paraffin (80 min); the tissue was placed in a cassette, filled with paraffin and then placed on the cold table of a paraffin embedding machine. Placing the embedded tissue paraffin block on a microtome and sectioning the tissue to a thickness of about 4 μm; the organized paraffin pieces were lightly smeared in water at 42 ℃. After the glass is completely flattened, a clean glass sheet is used for gently pulling up the slices; the sections were placed on glass slides, numbered, and baked in an oven at 68 ℃ for at least 6 hours.
3. Hematoxylin/eosin staining
The slices were dewaxed with a conventional fat-soluble solvent to water (xylene twice, 15 minutes per time; 100% alcohol for 5 minutes; 95% alcohol for 5 minutes; 75% alcohol for 5 minutes; 50% alcohol for 5 minutes), then stained with hematoxylin staining solution for 5 minutes, rinsed with clear water, stained with eosin staining solution for 5 minutes, rinsed with clear water, dehydrated (50% alcohol for 5 minutes; 75% alcohol for 5 minutes; 95% alcohol for 5 minutes; 100% alcohol for 5 minutes; xylene twice, 15 minutes per time), after which the slices were air-dried, sealed with neutral gum, and observed under an optical microscope.
FIG. 3 is a graph of the results of this section of the experiment, and HE histological staining indicates that treatment with GsMTx-4 improves the regeneration process and structural continuity of spinal cord tissue in a mouse model of spinal cord injury.
4. Immunohistochemical staining
Tissue sections were deparaffinized and hydrated. I.e., 8 minutes of xylene, 8 minutes of absolute ethanol, 8 minutes of 95% ethanol, 8 minutes of 80% ethanol, and 8 minutes of 75% ethanol in succession. After 8 minutes in 70% ethanol, the sections were rinsed 4 times for 5 minutes each; next, the deparaffinized and hydrated sections were placed in a 3% hydrogen peroxide solution and reacted at 37 ℃ for 20 minutes to block endogenous peroxidase. The antigen was repaired by washing 4 times with double distilled water each time for 5 minutes. The citrate buffer was placed in a metal heater and boiled. Boil for 15 minutes, turn off power and hold for 15 minutes. Naturally cooling to room temperature; then washing PBS 5 times each time for 5 minutes each time, wiping surrounding tissues, adding 5% goat serum, blocking non-specific antigen, reacting at room temperature for 1 hour, then adding dropwise microglial cell Iba-1 antibody to the tissue slices, and incubating overnight in a wet box at 4 ℃; the next day, sections were removed, incubated in an incubator at 37 ℃ for 1 hour, rinsed 5 times with PBS every 15 minutes, and an enhanced horseradish peroxidase-conjugated secondary antibody was added and incubated at room temperature for 2 hours. Excess secondary antibody was washed with PBS (5 times for 5 minutes each); dropwise adding a freshly prepared DAB coloring solution, observing under an optical microscope, and taking on a brown yellow color, and washing with PBS to stop color development; next, hematoxylin counterstaining was performed. The stained sections were placed in modified hematoxylin stain and stained for 5 minutes. The staining was observed under an optical microscope. The sections were then separated with 0.2% hydrochloric acid and washed with running water. Finally, the slices were sequentially rinsed with 70% alcohol for 10 minutes, 75% alcohol for 8 minutes, 80% alcohol for 8 minutes, 90% alcohol for 8 minutes, absolute ethanol for 8 minutes, xylene for 8 minutes, and xylene for 8 minutes. After dehydrating for 2 minutes, the tissue surrounding the tissue was wiped and a neutral gel was dropped, and the cover glass was placed under an optical microscope for observation.
FIG. 4 is a graph of the results of this section of the experiment, showing that the use of GsMTx-4 mitigates the process of inflammatory microglial aggregation in a mouse model caused by spinal cord injury by microglial-specific Iba-1 immunohistochemical staining.
5. Rat microglial cell culture
The rat microglia used was a stable cell line, and MC3T3-E1 cells (95% air, 5% CO2,37 ℃) were cultured simultaneously in DMEM/F-12 medium (Hyclone, Thermo CO) with the addition of 10% bovine serum (FBS, gibco, USA), 1% 100u/ml penicillin and 100mg/ml streptomycin (Hyclone, USA) at ph 7.2. The medium was changed every 3 days and passaged when the cells reached 80-90% confluence. Second or third generation cells were used for the indicated experiments. In the experiment, microglia were stimulated with 900kPa excessive mechanical stress and treated with PBS (control group) or GsMTx-4 polypeptide (experimental group).
6.Western Blot
The spinal cord tissues of each group of mice and rat microglia cells after in vitro culture and stimulation are placed on ice, and washed by ice water after treatment. After collection, proteins were extracted by adding lysis buffer (p0013c, best biotechnology), and total proteins were collected from each sample by adding cultured nucleus pulposus cells to RIPA lysis buffer (p0013c, best biotechnology). The protein in the loading buffer was heated at 100 ℃ for 10min (thermolfisher). Protein electrophoresis (30 g per lane) was performed using 10% SDS-PAGE gel (beyontime biotechnology), and after electrophoresis, the proteins were electrophoretically transferred onto nitrocellulose membranes. Blocking with Tween 20(10mm tris-HCl, ph 8.0; 150mm NaCl; 0.5% tween 20) in 5% skimmed milk for 2h, incubating with specific primary antibody (COX-2, iNOS,. beta. -Tubulin) at 37 ℃ for 1h, washing 3 times with PBS, overnight at 4 ℃, adding horseradish peroxidase secondary antibody (dilution 1:2000), and incubating at room temperature for 1 h. The membrane was removed with blunt forceps and rinsed at least three times with PBS. 1ml of working solution (p0018s, beiime Biotechnology) was added per membrane and tested (Amersham life sciences, illinton, illinois, usa). Statistical analysis of band grey values was performed using Image J software.
FIGS. 5-6 are graphs showing the results of this experiment, in which abnormal levels of inflammatory markers of spinal cord tissue and microglia in vitro caused by mechanical injury were observed using Western blot, while GsMTx-4 reduced the inflammatory response process stimulated by mechanical injury.
7. Statistical analysis
All data are expressed as mean standard deviations of at least three independent experiments. Statistical analysis for two sets of data statistical analysis using paired t-tests more than two sets of data statistical analysis using one-way analysis of variance.
Through the experiment, the GsMTx-4 polypeptide can directly antagonize spinal cord microglial cell mediated spinal cord inflammatory microenvironment disorder, has exact curative effect on a spinal cord injury animal model induced by mechanical shock, and simultaneously effectively promotes the homeostasis of the spinal cord. In addition, the GsMTx-4 polypeptide is convenient for microglial cells to absorb and utilize, and fills the blank of the current spinal cord injury prevention and treatment medicines in China.
In addition, cell experiments show that the GsMTx-4 polypeptide can relieve the microglial cell inflammatory reaction process caused by over-mechanical stress stimulation and play a protective role in the process of spinal cord injury.
More importantly, the GsMTx-4 polypeptide has simple purification process and pure and mature preparation method, and can obviously reduce the cost, thereby reducing the economic burden of patients.
While one embodiment of the present invention has been described in detail, the description is only a preferred embodiment of the present invention and should not be taken as limiting the scope of the invention. All equivalent changes and modifications made within the scope of the present invention shall fall within the scope of the present invention.

Claims (8)

  1. Application of GsMTx-4 polypeptide in preparing medicine for treating spinal cord injury.
  2. Application of GsMTx-4 polypeptide in preparing medicine for treating spinal cord injury caused by trauma.
  3. Application of GsMTx-4 polypeptide in preparing medicine for relieving traumatic acute spinal cord injury.
  4. Application of GsMTx-4 polypeptide in preparing medicine for relieving paralysis, immobility of limbs, and sensory disturbance of limbs caused by spinal cord injury.
  5. 5. Use according to claims 1-4, characterized in that: also comprises pharmaceutically acceptable GsMTx-4 polypeptide molecule subtypes, analogues and derivatives.
  6. 6. The use of claim 5, wherein: preferably a pharmaceutically acceptable salt of said GsMTx-4 polypeptide.
  7. 7. The use according to any one of claims 1 to 6, wherein: the medicament comprises a pharmaceutically acceptable carrier, adjuvant or diluent.
  8. 8. Use according to any one of claims 1 to 6, characterized in that: the application form of the medicament is selected from intrathecal injection or local external nanoparticles.
CN202210570488.6A 2022-05-24 2022-05-24 Application of PIEZO1 antagonist GsMTx-4 in preparation of medicine for treating spinal cord injury Pending CN114848797A (en)

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