CN112546056B - Composition for treating chemotherapy-induced peripheral neuropathy and application thereof - Google Patents
Composition for treating chemotherapy-induced peripheral neuropathy and application thereof Download PDFInfo
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Abstract
The invention provides a composition for treating chemotherapy-induced peripheral neuropathy and application thereof, and belongs to the field of medicines. The composition for treating chemotherapy-induced peripheral neuropathy provided by the invention comprises ginsenoside Rg1 and fucoidin. The composition can obviously inhibit the expression of proinflammatory factors such as TNF-alpha, IL-1 beta, IL-6 and the like, thereby generating anti-inflammatory and repair promotion on peripheral nerves and enhancing the action of resistance; in addition, the composition can also obviously improve microcirculation disturbance and up-regulate SR-A expression, further enhance the phagocytosis and elimination capacity of macrophages to HMGB1, inhibit over-expression of TF, relieve microcirculation disturbance and nerve pain caused by chemotherapy drugs through A multi-target and multi-mechanism, and fundamentally inhibit the development of CIPN, thereby achieving the aim of safe and effective treatment and providing A new clinical treatment strategy.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a composition for treating chemotherapy-induced peripheral neuropathy and application thereof.
Background
Tumor is a disease seriously harming human health, and its treatment is very difficult. Although there are some targeted drug therapies, chemotherapy remains one of the most common approaches to treat malignancies. Unfortunately, chemotherapy often has serious side effects, such as pain, vomiting, dizziness, and hair loss. In particular pain, can cause the patient to become more anxious or even depressed, which can seriously affect the patient's mental state and ultimately prevent the treatment of the tumor. Among the side effects of tumors, Chemotherapy-induced Peripheral Neuropathy (CIPN) is a very painful reaction, mainly manifested as paresthesia, especially pain such as cold tactile hypersensitivity and mechanical hypersensitivity, and the sensation of such pain is sometimes so strong that Chemotherapy patients have to reduce the dose of chemotherapeutic drugs to relieve the pain, seriously hampering the therapeutic effect of Chemotherapy. It is reported that about 30-40% of patients will develop CIPN, so that the discussion of the related mechanism and treatment measures of CIPN has important clinical value and social significance.
The existing medicines for researching and treating CIPN are mainly used for protecting nerves and relieving pain symptoms, and are used for treating both symptoms and root causes, for example, neuroprotective medicines such as glutathione, calcium and magnesium, vitamin B, vitamin E, acetyl L-carnitine and the like can relieve nerve injury and improve symptoms of paraesthesia; neuropathic pain symptomatic treatment drugs include tricyclic antidepressants, 5-HT and norepinephrine reuptake inhibitors (SNRI), antiepileptic drugs and the like, and gastrointestinal adverse reactions such as nausea, dry mouth, constipation, cardiovascular adverse reactions (such as orthostatic hypotension), central nervous system toxicity (such as insomnia, anxiety, headache) and the like can occur after long-term use of the drugs. According to the american society for clinical oncology latest guidelines (ASCO2020), the use of any drug for the prevention of chemotherapy-induced peripheral neuropathy is not recommended due to the lack of high-quality, consistent evidence, and for patients with pain due to CIPN, clinicians may use duloxetine for treatment with moderate-quality evidence and moderate-intensity recommendations. Therefore, no clear effective method for preventing CIPN exists so far, and reducing the dosage and stopping the use of chemotherapeutic drugs are the main methods for treating CIPN. Due to the complex mechanism of CIPN and the limitations of existing therapeutics, the search for new therapeutics is a problem to be solved urgently in clinic.
Disclosure of Invention
In order to solve the above problems, the present invention provides a composition for treating chemotherapy-induced peripheral neuropathy and use thereof. The composition has good effect of treating CIPN, and the components of the composition are natural components, so the composition is safe and has no toxic or side effect.
In order to achieve the above purpose, the invention provides the following technical scheme:
the invention provides a composition for treating chemotherapy-induced peripheral neuropathy, which comprises ginsenoside Rg1 and fucoidin.
Preferably, the mass ratio of the ginsenoside Rg1 to the fucoidin is 1: 1-1: 5.
The invention provides application of the composition in the technical scheme in preparing a medicament for treating chemotherapy-induced peripheral neuropathy.
The invention provides application of the composition in the technical scheme in preparation of a medicine for improving microcirculation disturbance.
The invention provides application of the composition in the technical scheme in preparation of a medicine for reducing expression of tissue factor.
The invention provides application of the composition in the technical scheme in preparing a medicament for inhibiting expression of sciatic nerve inflammatory factors of peripheral neuropathy induced by chemotherapy.
The invention provides application of the composition in the technical scheme in preparation of a medicine for reducing expression of high-mobility group protein B1.
The invention provides application of the composition in the technical scheme in preparing a medicament for increasing the mechanical pain threshold of chemotherapy-induced peripheral neuropathy.
Has the advantages that:
the invention provides a composition for treating chemotherapy-induced peripheral neuropathy, which comprises ginsenoside Rg1 and fucoidin. The composition can obviously inhibit the expression of proinflammatory factors such as TNF-alpha, IL-1 beta, IL-6 and the like, thereby generating anti-inflammatory and repair promotion on peripheral nerves and enhancing the action of resistance; in addition, the composition can also obviously improve microcirculation disturbance, enhance the phagocytosis and removal capacity of macrophages to HMGB1 (high mobility group protein B1) through an SR-A mediated signal channel, inhibit over-expression of TF (tissue factor), relieve microcirculation disturbance and nerve pain caused by chemotherapeutic drugs through A multi-target multi-mechanism, and fundamentally inhibit the development of CIPN (common protein in vitro) so as to achieve the aim of safe and effective treatment and provide A new treatment strategy for clinic. The results of the examples show that: the composition provided by the invention can obviously improve the mechanical pain threshold of CIPN model mice induced by oxaliplatin, obviously improve the microcirculation disturbance condition of the CIPN model mice, and has obvious effect on the treatment of CIPN.
Drawings
FIG. 1 is a graph showing the effect of each treatment group on the plantar pain threshold in mice in example 3;
FIG. 2 is a graph of the effect of the treatment groups on the microcirculation of the sole of a mouse in example 3, wherein A is a laser Doppler blood flow graph and B is a statistical graph of the laser Doppler blood flow graph;
FIG. 3 is a graph of the effect of each treatment group on inflammatory factors in mice in example 3, wherein A is the effect of each treatment group on IL-1. beta. mRNA levels; b is the effect of each treatment group on the level of IL-6IL-6 mRNA; c is the effect of each treatment group on TNF- α mRNA levels; d is a data statistical chart of HMGB1 expression in plasma of each treatment group; # p <0.01, # p <0.001, indicating significant difference compared to the control group; p <0.05, p <0.01, p <0.001, indicating a significant difference compared to the oxaliplatin group;
FIG. 4 is the effect of each treatment group on the pain threshold and plantar blood flow in example 4, wherein A is the effect of each treatment group on the pain threshold of the sole of the mouse; b is the influence of each treatment group on the microcirculation of the soles of the mice; p <0.05, p <0.01, p <0.001, indicating significant differences compared to the control group; # p <0.05, # p <0.01, # p <0.001, indicating significant difference compared to the oxaliplatin group;
figure 5 effect of each treatment group on HMGB1 and TF in mouse plasma in example 4, where a is the effect of each treatment group on HMGB1 in mouse plasma; b is the influence of each treatment group on TF in the plasma of the mice; p <0.05, p <0.01, p <0.001, indicating significant differences compared to the control group; # p <0.05, # p <0.01, # p <0.001, indicating significant difference compared to the oxaliplatin group; & p <0.05, & & p <0.01, indicating significant differences compared to the oxaliplatin + fucoidan group.
Detailed Description
The invention provides a composition for treating chemotherapy-induced peripheral neuropathy, which comprises ginsenoside Rg1 and fucoidin. The invention has no special requirements on the sources of the ginsenoside Rg1 and the fucoidin, and can be prepared by adopting common commercial products in the field. In the invention, the ginsenoside Rg1 and the fucoidin are purchased from sigma company, and the mass ratio of the ginsenoside Rg1 to the fucoidin is preferably 1: 1-1: 5. The ginsenoside Rg1 and fucoidin compound belongs to natural compound products, and has the advantages of low toxicity, wide application, simple preparation, safety and effectiveness; the compound preparation is applied to a CIPN mouse model, not only can eliminate neuroinflammation, but also can improve sole blood flow, relieve microcirculation disturbance, and further can promote phagocytosis and clearing capacity of macrophages on harmful substances of organisms, so that CIPN is effectively relieved from multiple aspects and multiple angles, a strong superposition effect is generated, and a new effective treatment means is provided for chemotherapy-induced neuralgia, the clinical problem to be solved urgently and patients suffering from neuralgia.
The invention provides application of the composition in the technical scheme in preparing a medicament for treating chemotherapy-induced peripheral neuropathy. The composition provided by the invention can obviously improve the mechanical pain threshold of CIPN model mice induced by chemotherapy, obviously improve the microcirculation disturbance condition of CIPN model mice, and has obvious effect on CIPN treatment.
The invention provides application of the composition in the technical scheme in preparation of a medicine for improving microcirculation disturbance. The composition provided by the invention can obviously improve CIPN circulation disorder induced by chemotherapy and has obvious effect on CIPN treatment.
The invention provides application of the composition in the technical scheme in preparation of a medicine for reducing expression of tissue factors. The composition provided by the invention can obviously reduce the expression of Tissue Factor (TF), and has obvious effect on the treatment of CIPN.
The invention provides application of the composition in the technical scheme in preparing a medicament for inhibiting expression of sciatic nerve inflammatory factors of peripheral neuropathy induced by chemotherapy. The composition provided by the invention can obviously inhibit the accumulation of sciatic nerve inflammatory factors TNF-alpha, IL-1 beta and IL-6, and has obvious effect on the treatment of CIPN.
The invention provides application of the composition in the technical scheme in preparation of a medicine for reducing expression of high-mobility group protein B1(HMGB 1). The composition provided by the invention can obviously reduce the expression of HMGB1 and has an obvious effect on the treatment of CIPN.
The invention provides application of the composition in the technical scheme in preparing a medicament for increasing the mechanical pain threshold of chemotherapy-induced peripheral neuropathy. The composition can obviously increase the mechanical pain threshold of chemotherapy-induced peripheral neuropathy, relieve the neuropathic pain of CIPN and has obvious effect on the treatment of CIPN.
The invention has no special requirements on the auxiliary materials and the preparation formulation of the medicine in the technical scheme, and the conventional auxiliary materials and the preparation formulation in the field can be adopted; or directly using the mixture of the ginsenoside Rg1 and the fucoidin as a therapeutic drug without adding auxiliary materials.
In order to further illustrate the present invention, the compositions and uses thereof for the treatment of chemotherapy-induced peripheral neuropathy provided by the present invention are described in detail below with reference to the examples, which should not be construed as limiting the scope of the invention.
Example 1
A composition for treating chemotherapy-induced peripheral neuropathy comprises ginsenoside Rg1 and fucoidin, wherein the purity of ginsenoside Rg1 is not less than 95%, the purity of fucoidin is not less than 95%, and the particle and diameter have no special requirements. The mass ratio of the ginsenoside Rg1 to the fucoidin is 1: 1.
the preparation method comprises the following steps: dissolving 40mg of ginsenoside Rg1 powder and 40mg of fucoidan powder in 5ml of sterile water, shaking and vortexing to mix them uniformly and dissolve completely.
Example 2
A composition for treating chemotherapy-induced peripheral neuropathy comprises ginsenoside Rg1 and fucoidin, wherein the purity of ginsenoside Rg1 is not less than 95%, the purity of fucoidin is not less than 95%, and the particle and diameter have no special requirements. The mass ratio of the ginsenoside Rg1 to the fucoidin is 1: 5.
the preparation method comprises the following steps: dissolving 40mg of ginsenoside Rg1 powder and 200mg of fucoidan powder in 5ml of sterile water, shaking and vortexing to mix them uniformly and dissolve completely.
Example 3
A composition for treating chemotherapy-induced peripheral neuropathy comprises ginsenoside Rg1 and fucoidin, wherein the purity of ginsenoside Rg1 is not less than 95%, the purity of fucoidin is not less than 95%, and the particle and diameter have no special requirements. The mass ratio of the ginsenoside Rg1 to the fucoidin is 1: 2.5.
the preparation method comprises the following steps: dissolving 40mg of ginsenoside Rg1 powder and 100mg of fucoidan powder in 5ml of sterile water, shaking and vortexing to mix them uniformly and dissolve completely.
Evaluation of the Effect of the composition of the present invention in treating CIPN
The experimental scheme is as follows:
1 experimental animal: male C57BL/6J mice and male ICR mice, SPF grade, 6-8 weeks old in days, offered by Ministry of Experimental animals of family planning scientific institute of Shanghai, SR-A KO mice were offered as A gift from professor Chenqi of Nanjing medical university, and bred at the center of Experimental animals of Nanjing medical university. In the experiment, an animal experiment was carried out using ICR mice, C57BL/6J mice, and SR-A KO mice. All experimental animals are raised in 12h independent environment with alternating light and shade, water is freely drunk and food is eaten, the raising environment temperature is maintained at 22 +/-2 ℃, and the experiment is carried out after the experimental animals are adapted to the environment for 1 week. All experimental procedures followed the ethical committee regulations of the international association for pain research.
2, experimental method:
(1) CIPN model: adult healthy male ICR mice with SPF grade are selected, test mice are randomly divided into 7 groups (n is 6), namely a control group, an oxaliplatin group (model group), an oxaliplatin + fucoidan group, an oxaliplatin + ginsenoside Rg1 group, an oxaliplatin + fucoidan + ginsenoside Rg1(1:2.5) group, an oxaliplatin + fucoidan + ginsenoside Rg1(1:1) group and an oxaliplatin + fucoidan + ginsenoside Rg1(1:5) group.
Wherein the oxaliplatin + fucoidan group was administered fucoidan at a concentration of 200mg/kg starting 7 days before the molding, the oxaliplatin + ginsenoside Rg1 group was administered ginsenoside Rg1 at a concentration of 80mg/kg starting 7 days before the molding, the control group was administered physiological saline at 0.1ml/10g starting 7 days before the molding, the oxaliplatin + fucoidan + ginsenoside Rg1(1:2.5) group was administered 10ml/kg of the composition of example 3 starting 7 days before the molding was started, the oxaliplatin + fucoidan + ginsenoside Rg1(1:1) group was administered 10ml/kg of the composition of example 1 starting 7 days before the molding was started, the oxaliplatin + fucoidan + ginsenoside Rg1(1:5) group was administered 10ml/kg of the composition of example 2 starting 7 days before the molding was started, and the mice treated with the model group and the five groups were administered with oxaliplatin (3mg/kg) separately, the CIPN animal model was prepared for five consecutive days, during which the treatment group was concomitantly administered, and oxaliplatin was stopped at day 6 after the start of molding, and the treatment group was still continuously administered to 14 d. Behavioral determination was performed every day from the time of mouse molding, and plantar doppler blood flow was determined 14d after molding to examine the microcirculation disturbance.
(2) Mechanical foot contraction reflection threshold determination: the behavioral determination of the invention, i.e. the mechanical pain threshold measurement of mice, is carried out by von Frey hair test (cellosilk pain tester), and the references are: gu H, Wang C, Li J, Yang Y, Sun W, Jiang C, Li Y, Ni M, Liu WT, Cheng Z, Hu L.high mobility group box-1-toll-like receptor 4-phosphatability promoter 3-kinase/protein kinase B-mediated generation of matrix polypeptides kinase-9 in the vertical root proteins chemistry-induced functional nerve approach. int J cancer.2020 May 15; 146(10) 2810-2821.doi:10.1002/ijc.32652.Epub 2019 Sep 14.PMID: 31465111. The cellosilk pain measuring instrument consists of 20 VonFrey hair mechanical stimulating needles, is mainly used for evaluating the touch sense of skin, and can provide Von Frey hair stimulating force of 0.008 g-300 g. The thickness and extension of the Von Frey Hairs nylon filament determine the amount of stimulus provided. In the experiment, a Von Frey Hairs cilia mechanical stimulation needle with proper thickness is selected according to actual conditions to vertically stimulate the skin, and the stimulation force can be adjusted by adjusting and replacing the Von Frey Hairs cilia mechanical stimulation needle until the Von Frey Hairs cilia mechanical stimulation needle is bent. When the rodent paw is subjected to a mechanical stimulus, the withdrawal reflex is generated, and the rodent paw can be applied to the soles of rats and mice.
The present invention performs a pain threshold measurement of the right paw of the mouse daily according to the above method. In a quiet environment, mice were placed in transparent compartments on metal wire mesh and allowed to move freely for 20 min. After the exploration behavior of the mouse is stopped and four limbs are in contact with the wire netting, detecting, vertically stimulating sole skin of the foot of the mouse by Von-Fery fibers with different folding forces, gradually pressurizing until the filament is slightly bent, maintaining for 4s, observing whether the mouse has a foot-shrinking reaction, regarding the mouse as a positive reaction when the mouse has the actions of foot shrinking, foot licking and the like, and recording the maximum pressure causing the foot-shrinking reaction of the mouse as a mechanical stimulation foot-shrinking reflection threshold. The interval of each measurement is 3min, the 50% mechanical stimulation foot contraction reflex threshold value is calculated by adopting a sequential method, the average value is taken after 3 times of measurement, and the detection result is shown in figure 1.
(3) Doppler blood flow measurement: the blood flow velocity and flow are measured by an ultrasonic Doppler blood flow meter, ultrasonic waves are transmitted by an ultrasonic probe with a fixed position and are received by red blood cells in the blood, then the red blood cells are used as a wave source, the ultrasonic probe receives reflected waves of the red blood cells, and the blood flow velocity can be calculated according to a Doppler effect formula by utilizing the frequency difference between the transmitted waves and the reflected waves of the ultrasonic waves. The invention removes hair from the lower half body of a mouse, performs Doppler blood flow measurement, mainly observes the hindpaw of the mouse, monitors the microcirculation disturbance condition, and under the same contrast, the darker red represents the rich blood flow, the darker blue represents the certain microcirculation disturbance condition, and the blood flow is blocked, and the detection result is shown in figure 2.
(4) Real-time quantitative polymerase chain reaction (qPCR) detects mRNA levels of IL-1 β, IL-6, and TNF- α.
A. And (3) RNA extraction: after the cell administration treatment, RNA was extracted with Trizol reagent according to the procedure requirements, and the concentration was measured.
B. Reverse transcription reaction: the process is carried out by using a HiScript II Q RT Supermix kit, wherein the reaction system is as follows: 2 μ l of 5 × HiScript IIQ RT SuperMix, 500ng template RNA, and finally RNase Free ddH20 to make up the volume until the total reaction system is 10 μ l; setting a reaction program by a PCR instrument, and carrying out reverse transcription reaction at 50 ℃, 15min → 85 ℃ for 5s to obtain a cDNA sample.
Qpcr reaction: the cDNA sample is diluted 5 times, and the reaction system is as follows: mu.l of the forward primer, 2. mu.l of the reverse primer, 1. mu.l of the diluted cDNA template and 5. mu.l of 2 XSYBR qPCR Master Mix were added to the octant tube to bring the total reaction volume to 10. mu.l, vortexed and mixed, each primer was as in Table 1.
The reaction conditions were as follows: at 95 ℃ for 30 s; 40 cycles, 95 ℃, 10 sec; 60 ℃ for 30 s. The dissolution curve is 95 ℃ for 15 s; 60 ℃ for 60 s; 95 ℃ for 15 s.
The Ct value obtained is used as a result to be analyzed, and the calculation formula is as follows: 2-delta CT, delta Ct gene-CtACTIN, and delta Ct mean of delta Ct group, delta Ct-control, and are compared with internal reference ACTIN by relative quantification method.
TABLE 1 statistical tables of primer sequences
(5) Western blot detects the protein expression level of HMGB 1.
Preparing an animal sample: after 7 days of mouse CIPN modeling, mouse plasma was taken, and 190. mu.l of RIPA lysate containing a phosphatase inhibitor and a protease inhibitor PMSF was added to each sample. Adding 10ul of plasma sample, standing on ice for 30min, measuring the protein concentration in the tissue sample by BCA method, adding 5 × loading buffer in proportion, mixing uniformly by vortex, and boiling for 5min to denature the protein; samples were stored at-20 ℃.
Electrophoresis and membrane transfer: taking a plasma sample with the total protein amount of 30 mu g, carrying out SDS-PAGE electrophoresis by using 8%, 10% or 15% of gel, and stopping electrophoresis when the protein is properly separated; the gel is cut and transferred onto a PVDF membrane, the membrane is transferred under the constant current of 300mA, and the membrane transferring time is determined by the molecular weight of the target protein.
③ sealing and incubating with antibody: blocking with 10% whole milk powder (TBST dissolved) or 5% BSA + 5% milk powder solution at room temperature for 2 h; according to the following steps: the beta-actin antibody and the HMGB1 antibody were diluted at a ratio of 1000, and the bands were incubated in primary antibody dilution for 16h at 4 ℃. After incubation, the membrane was washed 3 times with TBST, 10min each time. Preparing a secondary antibody solution according to the dilution ratio of 1:5000, respectively incubating the strips and a secondary antibody corresponding to the primary antibody for 2 hours in a shaking table at room temperature, and washing the membrane for 4 times and 10min each time by TBST after the incubation is finished.
Fourthly, color development: preparing a developing solution from the solution A and the solution B in the ECL chemiluminescence kit according to the ratio of 1:1, placing the strip on an exposure platform of a gel imager, uniformly spreading the developing solution on the surface of the membrane, incubating for 1-2min, and operating a set program to perform exposure imaging.
Data analysis: the data were analyzed and counted using EXCEL, using either Gel Pro or Image J software to scan the gray levels of each set of images, and the results are shown in FIG. 3.
Figure 1 is a graph of the effect of each treatment group on pain threshold in mice. From the results shown in fig. 1, the ginsenoside Rg1 and fucoidan composition can obviously increase the mechanical pain threshold of mice, and the combined administration gradually shows advantages compared with the single administration of the two on the 10 th day, and lasts for 21 days, so that the effect of the combined administration on relieving the mechanical pain threshold of the mice is obviously better than the effect of the single administration of the two. In 2017, related literature reports that oxaliplatin is used for establishing a CIPN model, duloxetine is used for treating the CIPN model at three concentrations of 10, 30 and 60mg/kg, and von Frey membrane tests are used for measuring mechanical pain threshold of mice. The skin of the hind paw of the mouse was stimulated 10 times with a bending force of 0.4g, and the withdrawal reaction of the two paws of the mouse was scored as positive, and the total number of times was taken as 100%. The results show that 10mg/kg of duloxetine has no significant effect on alleviating mechanical Pain in mice, that a dose of 30mg/kg can alleviate Pain in about 20% of mice, and that a dose of 60mg/kg can improve Pain in about 40% of mice, but that this dose can cause partial lethargy in mice (documents: Kim W, Chung Y, Choi S, Min BI, Kim SK. Duloxetin Protects against Oxaliptin-Induced Neuropathic Pain in and Spinal neurone hypersensitivity in rodents. J Mol Sci.2017 Dec 5, (18) (2626. doi: 10.3390/ijms22626. PMID: 29206213; PMCID: PMC5751229.), there are serious adverse effects. The composition can obviously improve the mechanical pain threshold of mice and has no adverse side effect.
Fig. 2 shows the effect of each treatment group on plantar microcirculation of mice, and the results in fig. 2 show that the blood flow condition is not significantly improved when mice with oxaliplatin (L-OHP) groups are administered, but is significantly improved when mice with ginsenoside Rg1 alone are administered, and when mice with fucoidan groups are administered, the microcirculation is further improved, wherein the effect of the oxaliplatin + fucoidan + ginsenoside Rg1(1:2.5) groups is most significant.
Fig. 3 shows the effect of each treatment group on the inflammatory factors in mice, and mainly studies that the fucoidan and ginsenoside combined administration can significantly inhibit the expression of the inflammatory factors and the accumulation of HMGB 1. Wherein A is the effect of each treatment group on IL-1 β mRNA levels; b is the effect of each treatment group on IL-6mRNA levels; c is the effect of each treatment group on TNF- α mRNA levels; d is a data histogram of HMGB1 expression in plasma of each treatment group. As can be seen from FIG. 3, the ginsenoside-fucoidan combination administration group can significantly reduce the expression levels of inflammatory factors IL-1 beta, TNF-alpha and IL-6 in the blood of mice and reduce the excessive accumulation of HMGB1, wherein the oxaliplatin + fucoidan + ginsenoside Rg1(1:2.5) group has the most significant effect and can significantly relieve CIPN.
Example 4
Test protocol: the test is divided into 5 treatment groups, namely A control group, an oxaliplatin group (model group), an oxaliplatin + fucoidan group, an SR-A knockout + oxaliplatin + fucoidan group and the above n is 6, wherein C57BL/6J mice are adopted in the control group, the oxaliplatin group and the oxaliplatin + fucoidan group, SA-A knockout + oxaliplatin group and SR-A knockout + oxaliplatin + fucoidan group are adopted in the SR-A knockout + oxaliplatin + fucoidan group, the mice are injected with fucoidan (200mg/kg) from 7 days in advance, the mice are injected with oxaliplatin (3mg/kg) in the abdominal cavity from the oxaliplatin group, the oxaliplatin + fucoidan group, the SR-A knockout + oxaliplatin group and the SR-A knockout + fucoidan group starting on day 8, the CIPN animal model was prepared for five consecutive days, during which treatment groups were concomitantly administered, oxaliplatin was stopped on day 6, and treatment groups were still continuously administered to 14 d. And (3) performing behavioral determination every day from mouse molding, performing plantar Doppler blood flow determination 14 days after the molding, and inspecting the microcirculation disturbance condition and the expression level of each factor detected by Western blot, wherein the results are shown in figures 4-5.
FIG. 4 is a graph showing the effect of each treatment group on the pain threshold in mice and the microcirculation disturbance in an in vivo test, wherein A is the effect of each treatment group on the pain threshold in mice, and B is the effect of each treatment group on the circulation disturbance. The results in fig. 4 show that fucoidan can significantly reduce the pain threshold of the oxaliplatin + fucoidan group and promote the microcirculation of the mice, but the SR- A knockout + oxaliplatin + fucoidan group is not improved much, which indicates that the action of fucoidan on the labor pain and the microcirculation of CIPN mice depends on SR- A receptors, and the action of SR- A-/-completely cancels the analgesic action and the microcirculation relieving action of fucoidan, i.e., the mechanism of fucoidan relieving the pain caused by chemotherapy is that SR- A mediates the analgesic action of fucoidan and increases the blood perfusion of the feet of the mice.
Fig. 5 is a graph of the effect of treatment groups on HMGB1, TF expression in vivo experiments, where a is the effect of each treatment group on HMGB1 expression and B is the effect of each treatment group on TF expression. The results in fig. 5 show that fucoidan can significantly reduce HMGB1 and TF in the oxaliplatin + fucoidan group, but has not much improved the SR- A knockout + oxaliplatin + fucoidan group, which indicates that the inhibition effect of fucoidan on HMGB1 and TF in CIPN mice depends on SR- A receptor, and SR- A-/-completely cancels the inhibition effect of fucoidan on HMGB1 and TF, i.e., the mechanism of fucoidan relieving chemotherapeutic pain is that fucoidan reduces accumulation of HMGB1 and expression of TF in mouse plasmA through SR- A signaling pathway.
The results of the above embodiments show that the composition of ginsenoside Rg1 and fucoidin provided by the invention can significantly improve the mechanical pain threshold of CIPN model mice induced by oxaliplatin, significantly improve the microcirculation disturbance of CIPN model mice, has significant effect on CIPN treatment, is safe and reliable, has low toxicity and is easily accepted by a wide range of people, and provides a new treatment strategy for clinic.
Although the present invention has been described in detail with reference to the above embodiments, it is only a part of the embodiments of the present invention, not all of the embodiments, and other embodiments can be obtained without inventive step according to the embodiments, and the embodiments are within the scope of the present invention.
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Claims (1)
1. Use of a composition comprising ginsenoside Rg1 and fucoidan in the preparation of a medicament for the treatment of chemotherapy-induced peripheral neuropathy;
the mass ratio of the ginsenoside Rg1 to the fucoidin is 1: 1-1: 5;
the medicine for treating the chemotherapy-induced peripheral neuropathy is a medicine for inhibiting the expression of sciatic nerve inflammatory factors of the chemotherapy-induced peripheral neuropathy or a medicine for increasing the mechanical pain threshold of the chemotherapy-induced peripheral neuropathy.
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| CN202011457399.8A CN112546056B (en) | 2020-12-11 | 2020-12-11 | Composition for treating chemotherapy-induced peripheral neuropathy and application thereof |
| CN202111444654.XA CN114010653B (en) | 2020-12-11 | 2020-12-11 | Application of composition comprising ginsenoside Rg1 and fucoidin in preparation of medicine for reducing expression of tissue factor |
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| CN104383534A (en) * | 2014-10-24 | 2015-03-04 | 威海芝恩药业股份有限公司 | Immunological adjuvant containing fucosan sulfate and application of immunological adjuvant |
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| CA2817290A1 (en) * | 2010-11-11 | 2012-05-18 | Josef Penninger | Compounds and methods for treating pain |
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| WO2017113289A1 (en) * | 2015-12-31 | 2017-07-06 | 黄丽娜 | Ginsenoside rg1 vitreous cavity injection delivery system and use thereof |
| CN106692169A (en) * | 2017-02-06 | 2017-05-24 | 苏州大学附属第二医院 | Application of panaxoside Rg1 in preparing medicine for restoring spinal cord injury and method for constructing mouse spinal cord injury model |
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| CN101480222A (en) * | 2008-11-19 | 2009-07-15 | 广东海洋大学 | Complex immunopotentiator for Rachycentron canadum |
| CN104383534A (en) * | 2014-10-24 | 2015-03-04 | 威海芝恩药业股份有限公司 | Immunological adjuvant containing fucosan sulfate and application of immunological adjuvant |
| CN108685927A (en) * | 2017-04-07 | 2018-10-23 | 成都夸常科技有限公司 | Include the medical composition and its use of methylenum careuleum class compound and bioactive ingredients |
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| CN114010653B (en) | 2023-07-25 |
| CN114159460B (en) | 2023-07-14 |
| CN114028416A (en) | 2022-02-11 |
| CN114010653A (en) | 2022-02-08 |
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| CN114028416B (en) | 2023-07-25 |
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