CN115463141A - Use of ganglioside GM1 in medicine for treating hearing impairment - Google Patents
Use of ganglioside GM1 in medicine for treating hearing impairment Download PDFInfo
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- paclitaxel
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- oxaliplatin
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
The invention belongs to the technical field of medicinal application. In particular to an application of ganglioside GM1 in preparing a medicine for preventing, relieving or treating hearing loss. The ganglioside GM1 can directly improve the hearing damage caused by chemotherapy drugs such as platinum drugs, paclitaxel or paclitaxel combined with platinum drugs, especially the hearing damage caused by hair cell damage, thereby effectively improving the life quality of cancer patients after chemotherapy. The ganglioside GM1 of the invention also has the effects of preventing, relieving or treating noise deafness patients, presbycusis patients and hearing impairment patients caused by drug side effects, especially hearing impairment caused by hair cell damage, thereby improving the life quality of patients.
Description
Technical Field
The invention belongs to the technical field of medicinal application. In particular to an application of ganglioside GM1 in preparing a medicine for preventing, relieving or treating hearing loss. The hearing impairment comprises hair cell damage caused by chemotherapy drugs, and also comprises noise deafness, presbycusis, and hair cell damage caused by drug side effects.
Background
Platinum-based chemotherapeutic agents are considered to be the major cause of hearing impairment, including chemotherapy with cisplatin, oxaliplatin, and paclitaxel and its combination with platinum agents (cisplatin or oxaliplatin). Basic chemotherapeutic drugs and radiotherapy of the head and neck are the most likely cancer treatment methods causing hearing impairment. The auditory system is sensitive to chemotherapeutic drugs, mainly platinum drugs such as cisplatin, oxaliplatin, paclitaxel and platinum chemotherapy combination thereof inevitably cause hair cell damage.
In clinical treatment, the hearing impairment of tumor chemotherapy patients is lack of attention, and the main concern is the chemotherapy effect. Therefore, the treatment of the impaired acoustic function of the tumor patients caused by chemotherapy is not taken into consideration, and a great amount of impaired acoustic function of the chemotherapy patients cannot be treated. If chemotherapy or radiation therapy is necessary and the patient has developed or is likely to develop hearing loss, some prophylactic or therapeutic approach may be considered.
Currently, the clinical treatment for hearing impairment is mainly to improve the hearing function of a patient through a hearing aid, however, this method does not fundamentally repair or treat the auditory system of the patient, and even prevents the occurrence of such hearing impairment in advance. Currently, there is no preventive, palliative or therapeutic agent available for patients with hearing impairment in chemotherapy. Therefore, there is a need for a drug capable of preventing, alleviating or treating hearing loss caused by chemotherapy drugs in clinical practice, so as to improve the quality of life of cancer patients after chemotherapy.
Disclosure of Invention
The invention aims to provide the application of ganglioside GM1 in preparing medicine for preventing, relieving or treating hearing damage caused by chemotherapy.
In some preferred embodiments, the chemotherapeutic agent of the present invention is selected from the group consisting of platinum-based agents, paclitaxel, or any combination thereof; preferably, the chemotherapeutic drug is selected from cisplatin, oxaliplatin, paclitaxel, a combination of cisplatin and paclitaxel, a combination of oxaliplatin and paclitaxel; more preferably, wherein the paclitaxel is an albumin-bound paclitaxel.
The use of the invention, in some preferred embodiments, the hearing impairment comprises varying degrees of hair cell damage in the patient.
In other preferred embodiments, the hair cell damage comprises: disappearance/reduction of normal cells, increase of malformed cells, abnormality of cellular location or relative cellular location, abnormality of characteristic indicator molecules in cells (e.g., myosin7a, etc.).
The use of the invention, in some preferred embodiments, the patients comprise tumor patients selected from patients with multiple myeloma, digestive tract tumor, respiratory tract tumor, head and neck tumor, breast cancer, reproductive system tumor, and other patients suitable for chemotherapy with platinum, paclitaxel and their combination, and other patients with solid tumor and hematological tumor using various chemoradiotherapy.
In a preferred embodiment of the invention, the ganglioside GM1 is monosialotetrahexosylganglioside sodium.
In the present invention, the ganglioside GM1 is prepared in a form selected from the group consisting of an injection formulation, an oral formulation, a topical formulation or an external preparation; preferably, the formulation of the ganglioside GM1 is in the form of an injectable formulation.
In some preferred embodiments, the ganglioside GM1 of the present invention is administered before, during or after the administration of said chemotherapeutic agent.
It is also an object of the present invention to provide a use of the ganglioside GM1 in the manufacture of a medicament for use in combination with a chemotherapeutic agent for the prevention of hearing impairment in a patient suffering from a tumor, wherein said chemotherapeutic agent is selected from cisplatin, oxaliplatin, paclitaxel, a combination of cisplatin and paclitaxel, or a combination of oxaliplatin and paclitaxel, said hearing impairment comprising varying degrees of hair cell damage, comprising: disappearance/reduction of normal cells, increase of malformed cells, abnormality of cellular location or relative cellular location, abnormality of characteristic indicator molecules in cells (e.g., myosin7a, etc.).
In a third aspect of the present invention, there is provided a use of ganglioside GM1 in the preparation of a medicament for preventing, alleviating or treating hearing loss in a patient, wherein said patient is selected from the group consisting of deafness-on-noise patients, presbycusis patients, and hearing-impaired patients due to side effects of the medicament, said hearing loss comprising varying degrees of hair cell damage in the patient.
The invention has the following beneficial effects:
1. the ganglioside GM1 can obviously improve hearing impairment (particularly hearing impairment caused by hair cell injury) caused by platinum drugs or paclitaxel combined platinum drug chemotherapy, and can prevent, relieve or treat the hearing impairment of a patient caused by using chemotherapy drugs, thereby effectively improving the life quality of the cancer patient after chemotherapy.
2. Experimental data show that compared with a blank control group, the ganglioside GM1 of the invention has no obvious adverse reaction of animals and has good safety.
3. The ganglioside GM of the present invention has the effects of preventing, alleviating or treating the hearing loss caused by noise deafness patients, presbycusis patients and hearing loss patients caused by the side effects of drugs, especially the hearing loss caused by the damage of hair cells, thereby improving the life quality of patients.
Drawings
Hpf (horse post fertilization) in the context of the present invention refers to hours after fertilization (zebrafish); regarding significance of differences between groups: ns (no significan) means no significant difference in GM1 treated group compared to control group, p < 0.05; * P < 0.01; * P <0.001; * P <0.0001.
FIG. 1 is a graph of monosialotetrahexosylganglioside sodium (GM 1) ameliorating cisplatin damage to cells of the cochlear hair cell line House Ear Institute-Organ of Corti 1 (HEI-OC 1); wherein, FIG. 1A is a process of HEI-OC1 cell treatment by drug; FIGS. 1B-1D show the pre-protective effect of 0.01 mM-1 mM GM1 on 0.01 mM-1 mM cisplatin-damaged HEI-OC1 cells, respectively; in the figure, p <0.001 in the # cisplatin-damaged group compared to the control group, and p <0.001 in the GM 1-treated group compared to the cisplatin-damaged group.
FIG. 2 is a graph of monosialotetrahexosylganglioside sodium (GM 1) ameliorating cisplatin damage to zebrafish hair cells; wherein, FIG. 2A is a process of drug treatment of transgenic zebra fish; FIGS. 2B and 2C show the pre-protection effect of 0.1 mg/ml-2 mg/ml GM1 on 0.01 mg/ml-0.5 mg/ml cisplatin-damaged zebrafish hair cells in 24hpf treatment; in the figure, ns GM1 treated groups were not significantly different from the control group, and p <0.001 in the GM1 treated group compared to the cisplatin treated group.
FIG. 3 is a graph of monosialotetrahexosylganglioside sodium (GM 1) ameliorating cisplatin damage to zebrafish hair cells; wherein, fig. 3A is a process of GM1 and cisplatin treatment of transgenic zebrafish; FIGS. 3B and 3C show the pre-protection effect of 0.1 mg/ml-2 mg/ml GM1 on 0.01 mg/ml-0.5 mg/ml cis-platinum damaged zebrafish hair cells, respectively, in 8hpf treatment; in the figure, ns GM1 treated group was not significantly different compared to control group, p <0.001 compared to cisplatin treated group.
FIG. 4 is a graph of monosialotetrahexosylganglioside sodium (GM 1) ameliorating oxaliplatin damage to cells of the cochlear hair cell line House Ear Institute-Organ of Corti 1 (HEI-OC 1); wherein, fig. 4A is a processing procedure of the HEI-OC1 cells by the drug; FIGS. 4B-4D show the pre-protection effect of 0.01 mM-1mM GM1 on 0.1 mM-1.5 mM oxaliplatin-injured HEI-OC1 cells, respectively; in the figure, the # # # oxaliplatin damage group has p <0.001 compared with the control group, the ns GM1 treatment group has no significant difference compared with the oxaliplatin damage group, and the # GM1 treatment group has p <0.001 compared with the oxaliplatin damage group.
FIG. 5 is that monosialotetrahexosylganglioside sodium (GM 1) ameliorates oxaliplatin damage to zebrafish hair cells; wherein, in the figure 5A, the treatment program of the drug on the transgenic zebra fish, GM1 pre-protects the zebra fish embryo at 24 hpf; FIGS. 5B and 5C show the pre-protection effect of 0.1 mg/ml-2 mg/ml GM1 on 0.1 mg/ml-1 mg/ml oxaliplatin-damaged zebrafish hair cells respectively in 24hpf treatment; in the figure, ns GM1 treated group had no significant difference compared to control group, p <0.001 compared to oxaliplatin treated group;
FIG. 6 is that monosialotetrahexosyl ganglioside sodium (GM 1) ameliorates oxaliplatin damage to zebrafish hair cells; wherein, fig. 6A is the treatment procedure of drug on transgenic zebrafish, GM1 pre-protects zebrafish embryos at 8 hpf; FIGS. 6B and 6C show the pre-protection effect of 0.1 mg/ml-2 mg/ml GM1 on 0.1 mg/ml-1 mg/ml oxaliplatin-damaged zebrafish hair cells, respectively, in 8hpf treatment; in the figure, ns GM1 treated group had no significant difference compared to control group, p <0.001 compared to oxaliplatin treated group;
FIG. 7 is a graph of monosialotetrahexosylganglioside sodium (GM 1) ameliorating damage to zebrafish hair cells by albumin-bound paclitaxel; wherein, FIG. 7A is the treatment process of transgenic zebrafish with drugs, GM1 pre-protects zebrafish embryos at 24 hpf; FIG. 7B and FIG. 7C show the pre-protection effect of 0.1 mg/ml-2 mg/ml GM1 on 0.01 mg/ml-1 mg/ml albumin-bound paclitaxel-damaged zebrafish hair cells, respectively; in the figure, ns GM1 treated group was not significantly different from control group by p <0.001 compared to albumin bound paclitaxel treated group;
FIG. 8 is a graph of monosialotetrahexosylganglioside sodium (GM 1) ameliorating damage to zebrafish hair cells by albumin-bound paclitaxel; FIG. 8A is a treatment program of drug on transgenic zebrafish, GM1 pre-protects zebrafish embryos at 8 hpf; FIGS. 8B and 8C show the pre-protection effect of 0.1 mg/ml-2 mg/ml GM1 on 0.01 mg/ml-1 mg/ml albumin-bound paclitaxel-damaged zebrafish hair cells, respectively; in the figure, ns GM1 treated group was not significantly different from control group by p <0.001 compared to albumin bound paclitaxel treated group;
FIG. 9 is a graph of monosialotetrahexosyl ganglioside sodium (GM 1) ameliorated damage to zebrafish hair cells by albumin-bound paclitaxel in combination with cisplatin; FIG. 9A is a treatment program of drug on transgenic zebrafish, GM1 pre-protects zebrafish embryos at 8 hpf; FIGS. 9B and 9C show the pre-protection effect of 0.1 mg/ml-2 mg/ml GM1 on 0.01 mg/ml-1 mg/ml albumin-bound paclitaxel in combination with 0.01 mg/ml-0.5 mg/ml cisplatin-damaged zebrafish hair cells, respectively; in the figure, ns GM1 treated group had no significant difference compared to control group, p <0.001 compared to albumin bound paclitaxel combined cisplatin treated group;
figure 10 is a graph of monosialotetrahexosylganglioside sodium (GM 1) ameliorating damage to zebrafish hair cells by albumin-bound paclitaxel in combination with oxaliplatin; wherein, fig. 10A is the treatment procedure of drug on transgenic zebrafish, GM1 pre-protects zebrafish embryos at 8 hpf; FIGS. 10B and 10C show the pre-protection effect of 0.1 mg/ml-2 mg/ml GM1 on 0.01 mg/ml-1 mg/ml albumin-bound paclitaxel and 0.1 mg/ml-1 mg/ml oxaliplatin-damaged zebrafish hair cells, respectively; in the figure, ns GM1 treated group had no significant difference compared to control group, p <0.001 compared to albumin bound paclitaxel combined with oxaliplatin treatment group.
FIG. 11 is a graph of monosialotetrahexosyl ganglioside sodium (GM 1) ameliorated cisplatin-induced cochlear hair cell damage in mice; wherein, fig. 11A is the observation of the morphology of mouse cochlear hair cells under a fluorescence microscope; figure 11B is a hair cell phenotype count showing that cisplatin has significant cochlear capillary cytotoxicity in mice, and that GM1 pretreatment has a significant protective effect, reducing hair cell loss and number of malformations.
Figure 12 is that monosialotetrahexosylganglioside sodium (GM 1) ameliorates oxaliplatin in combination with paclitaxel induced cochlear hair cell damage in mice; wherein, fig. 12A is the observation of the morphology of mouse cochlear hair cells under a fluorescence microscope; fig. 12B is a hair cell phenotype count showing that oxaliplatin in combination with paclitaxel had significant cochlear capillary cytotoxicity in mice, with significant protective effects after GM1 pretreatment, reducing hair cell loss and number of malformations.
Figure 13 is that intervention treatment with monosialotetrahexosylganglioside sodium (GM 1) can protect cisplatin-induced hearing impairment. FIG. 13A is a photograph of immunofluorescence of mouse cochlea Corti in which Myo7a (green) marks hair cells, DAPI (blue) marks nuclei, abdominal injection of Cisplatin (Cisplatin) 3mg/kg causes hair cell loss, and abdominal injection of GM1 20mg/kg prevents hair cell loss caused by Cisplatin (Scale Bar:50 μm). Fig. 13B is a graph of the number of hair cells with Myo7a positive signals in the 200 μm region (white dashed region) of cochlea from different groups of mice, where P <0.001 and P <0.0001. FIGS. 13C-F show ABR waveforms under 24KHz stimulation in mice between different groups. Fig. 13G counts ABR reaction thresholds between different groups, respectively, where P <0.0001. Fig. 13H separately counts ABR latencies at 80dB stimulation for different groups, where P <0.0001.
Figure 14 is that monosialotetrahexosylganglioside sodium (GM 1) intervention treatment can protect against hearing damage caused by oxaliplatin. FIG. 14A is a graph of mouse cochlear Corti immunofluorescence with Myo7a (green) labeling hair cells, DAPI (blue) labeling cell nuclei, oxaliplatin (Oxa) intraperitoneally injected at 5mg/kg resulting in hair cell loss, and GM1 mg/kg intraperitoneally injected at 20mg/kg preventing hair cell loss due to Oxa. Fig. 14B counts the number of Myo7a positive signal hair cells in the 200 μm region (white dashed region) of cochlea from different groups of mice, where P <0.0001. FIGS. 14C-F show ABR waveforms under 24KHz stimulation in mice between groups. Fig. 14G counts ABR reaction thresholds between different groups, respectively, where P <0.0001. Fig. 14H separately counts ABR latencies at 80dB stimulation for different groups, where P <0.0001.
Detailed Description
The invention is further illustrated with reference to specific examples. It should be understood that the specific embodiments described herein are illustrative only and are not limiting upon the scope of the invention.
The examples do not specify particular techniques or conditions, and are to be construed in accordance with the description of the art in the literature or with the specification of the product. The reagents or instruments used are conventional products which are not indicated by manufacturers and are available from normal sources.
The experimental procedures in the following examples are conventional unless otherwise specified. The experimental materials used in the following examples are all commercially available products unless otherwise specified.
Example 1 Effect of GM1 in preventing/ameliorating cisplatin-induced cochlear hair cell and zebrafish hair cell damage/hearing impairment in mice
1. GM1 pre-protects cisplatin from damage to mouse cochlear hair cells (HEI-OC 1)
The experimental process of HEI-OC1 cells, as shown in FIG. 1A, comprises the following steps:
1. the proportion of the 10% complete medium is as follows: DMEM (45 ml) + FBS (5 ml)
Cell recovery: and (3) placing the frozen cells in a water bath kettle at 33 ℃ to quickly dissolve the cells, adding the cells into a preheated culture medium after dissolution, placing the cells into an incubator, and carrying out full-scale liquid change after 10 hours.
Cell passage: under the observation of a microscope, when the cell density is paved on 80 percent of the bottom area of the dish, the cell passage can be carried out. Medium, PBS (cell culture grade), 0.25% Trypsin-EDTA (gibco) pre-heat for 15min.
(1) Cells were removed from the incubator, the supernatant discarded and washed once with PBS, noting that: when liquid is added, the liquid is added along the dish wall, so that cells are prevented from being blown up;
(2) Removing PBS, adding 1-2ml 0.25% Trypsin-EDTA (the amount of pancreatin depends on the bottom area of dish, just covering dish bottom), digesting at 37 deg.C for 90s, and observing that the cells form a whole membrane on dish bottom;
(3) Adding fresh culture medium to terminate digestion, flushing down cells, transferring to a centrifuge tube, and adding at 1500rpm/5min;
(4) The supernatant was discarded and 1ml of medium was added to resuspend the cells. Cell count by density 1X 10 4 Passage per ml.
2. Cell plating: plate prophase digestion, heavy suspension, counting and passage are the same
(1) The plates had two different cell densities, high density 3X 10 4 Low density 1X 10 per ml 4 Per ml;
(2) Adding 100 mul of cell suspension into each hole of a 96-hole plate, and sealing the peripheral holes with sterile water;
(3) The 96-well plate seeded with the cells is returned to the incubator for culture.
3. Compound cisplatin IC 50 Measurement of
(1) After the cells are plated, putting the cells into an incubator to be cultured for 24 hours, discarding the old culture medium, adding fresh culture media containing cisplatin with different concentrations, and continuing to culture for 24 hours or 48 hours;
(2) After the culture is finished, adding 10 mu l of CCK8 into each hole, continuously culturing for 4h, and measuring the absorbance OD value by using an enzyme-labeling instrument;
(3) From the OD values, compound IC was calculated using graphpad 50 Value according to IC 50 And selecting the concentrations of a high damage group, a medium damage group and a low damage group correspondingly, and obtaining a low damage, medium damage and high damage HEI-OC1 cell model caused by cisplatin for subsequent experimental study.
4. Pre-protection of HEL-OC1 cells by GM1
(1) Culturing the cell seed plate in an incubator for 24h;
(2) Removing the old culture medium, and adding GM1 (0.01-1 mM, aqueous solution) for treatment for 24h or 48h;
(3) After 24 or 48 hours of GM1 treatment, the culture medium containing GM1 is aspirated to prepare cisplatin;
(4) Putting the culture solution containing GM1 and cisplatin into an incubator;
(5) The treatment in the incubator is continued for 24 hours or 48 hours, 10. Mu.l of CCK8 is added to each well, and after 4 hours of culture, the OD value is measured and the cell survival rate is calculated.
The results of the studies are shown in FIG. 1, panels B, C, and D, and indicate that GM1 has pre-protection effect in the concentration range of 0.01-1 mM.
2. GM1 pre-protected cisplatin from injury to Zebra fish hair cells at 24hpf treatment
Collecting Tg (Brn 3c: EGFP) transgenic zebrafish embryos of fluorescent protein labeled hair cells, incubating the embryos in an incubator at 28.5 ℃, selecting embryos with good state by 6hpf, placing the embryos in a 96-well plate, and randomly grouping the embryos: control group, GM 1-treated group, cisplatin (cissplatin) -treated group, GM1+ cisplatin-treated group, as shown in fig. 2A.
Embryos were incubated with embryo culture medium containing a concentration of GM1 (0.1 mg/ml-2 mg/ml) beginning at the 8hpf to 24hpf stage, and treatments with cisplatin (0.01 mg/ml-0.5 mg/ml) at concentrations according to the cohort were performed after 6h of GM1 treatment, as shown in FIG. 2A.
The drug treatment process is carried out in an incubator at 28.5 ℃, and after the embryo grows to 72hpf, the living body imaging is carried out on the zebra fish juvenile fish according to the time period selected as required. Transgenic zebrafish juvenile fish fluorescently labeled with hair cells were fixed in 0.8-percent LMP agarose gel containing 0.03% tricoine anesthetic, subjected to living body three-dimensional imaging under a laser confocal microscope, and analyzed for morphology and quantity indices of hair cells.
The results are shown in fig. 2B and fig. 2C, and after cisplatin treatment, hair cell alignment was disturbed, hair cell bodies were damaged, cilia were shortened or disappeared, and the number of hair cells was significantly reduced. After the GM1 pretreatment, cisplatin treatment is added, compared with the treatment only with cisplatin, the number of hair cells is obviously increased, the hair cells are arranged in a tighter cluster, and the cilia structure is improved.
3. GM1 pre-protected cisplatin from damaging zebrafish hair cells at 8hpf treatment
Collecting Tg (Brn 3c: EGFP) transgenic zebrafish embryos of fluorescent protein labeled hair cells, incubating the embryos in an incubator at 28.5 ℃, selecting embryos with good state by 6hpf, placing the embryos in a 96-well plate, and randomly grouping the embryos: control group, GM 1-treated group, cisplatin (cissplatin) -treated group, GM1+ cisplatin-treated group, as shown in fig. 3A.
Embryos were incubated with embryo culture medium containing a concentration of GM1 (0.1 mg/ml-2 mg/ml) beginning at the 8hpf to 24hpf stage, and treatments with cisplatin (0.01 mg/ml-0.5 mg/ml) at concentrations according to the cohort were performed after 6h of GM1 treatment, as shown in FIG. 3A.
The drug treatment process is carried out in an incubator at 28.5 ℃, and after the embryo grows to 72hpf, the living body imaging is carried out on the zebra fish juvenile fish according to the time period selected as required. Transgenic zebrafish juvenile fish fluorescently labeled with hair cells were fixed in 0.8-percent LMP agarose gel containing 0.03% tricoine anesthetic, subjected to living body three-dimensional imaging under a laser confocal microscope, and analyzed for morphology and quantity indices of hair cells.
The results are shown in fig. 3B and fig. 3C, and after cisplatin treatment, hair cell alignment was disturbed, hair cell bodies were damaged, cilia were shortened or disappeared, and the number of hair cells was significantly reduced. After the GM1 pretreatment, cis-platinum treatment is carried out, compared with the cis-platinum treatment, the number of hair cells is obviously increased, the hair cells are arranged in a tighter cluster, and the cilia structure is improved.
Example 2 Effect of GM1 in prevention/amelioration of oxaliplatin-induced cochlear hair cell damage/hearing impairment in mice and zebrafish
1. GM1 pre-protects oxaliplatin against damage to mouse cochlear hair cells (HEI-OC 1)
The experimental procedure for HEI-OC1 cells, as shown in Panel A of FIG. 4, includes the following steps:
1. the proportion of the 10% complete medium is as follows: DMEM (45 ml) + FBS (5 ml)
Cell recovery: and (3) placing the frozen cells in a 33 ℃ water bath kettle, quickly dissolving the cells, adding the dissolved cells into a preheated culture medium, placing the culture medium into an incubator, and performing full-scale liquid change after 10 hours.
Cell passage: under the observation of a microscope, when the cell density is paved on 80 percent of the bottom area of the dish, the cell passage can be carried out. Medium, PBS (cell culture grade), 0.25% Trypsin-EDTA (gibco) pre-heat for 15min.
(1) Cells were removed from the incubator, the supernatant discarded and washed once with PBS, noting that: when liquid is added, the liquid is added along the dish wall, so that cells are prevented from being blown up;
(2) Removing PBS, adding 1-2ml 0.25% Trypsin-EDTA (the amount of pancreatin depends on the bottom area of the dish and can be covered on the dish bottom), digesting at 37 deg.C for 90s to see that the cells form a whole membrane on the dish bottom;
(3) Adding fresh culture medium to stop digestion, flushing down cells, transferring to a centrifuge tube, and adding at 1500rpm/5min;
(4) The supernatant was discarded and 1ml of medium was added to resuspend the cells. Cell count by density 1X 10 4 Passage of one/ml.
2. Cell plating: plate prophase digestion, heavy suspension, counting and passage are the same
(1) The plates had two different cell densities, high density 3X 10 4 1 × 10 per ml, low density 4 Per ml;
(2) Adding 100 mul of cell suspension into each hole of a 96-hole plate, and sealing the peripheral holes with sterile water;
(3) The 96-well plate seeded with the cells is returned to the incubator for culture.
3. Compound oxaliplatin IC 50 Measurement of
(1) After the cell plating, putting the cell plate into an incubator to be cultured for 24 hours, discarding the old culture medium, adding a fresh culture medium containing oxaliplatin with different concentrations, and continuing to culture for 24 hours or 48 hours;
(2) After the culture is finished, adding 10 mul of CCK8 into each hole, continuing culturing for 4h, and measuring the absorbance OD value by an enzyme-labeling instrument;
(3) From the OD values, compound IC was calculated using graphpad 50 Value according to IC 50 And selecting the concentrations of a corresponding high-damage group, a middle-damage group and a low-damage group, and obtaining an HEI-OC1 cell model with low damage, middle damage and high damage caused by oxaliplatin for subsequent experimental study.
4. Pre-protection of HEL-OC1 cells by GM1
(1) Culturing the cell plate in an incubator for 24h;
(2) Removing the old culture medium, and adding GM1 (0.01-1 mM, aqueous solution) with different concentrations for treating for 24h or 48h;
(3) Sucking culture medium containing GM1 for preparing oxaliplatin after 24 or 48 hours of GM1 treatment;
(4) Putting a culture solution containing GM1 and oxaliplatin into an incubator;
(5) And then continuously treating in the incubator for 24 hours or 48 hours, adding 10 mu l of CCK8 into each hole, culturing for 4 hours, measuring the OD value, and calculating the cell survival rate.
The results of the studies are shown in FIG. 4, panels B, C and D, and indicate that GM1 has pre-protection effect in the concentration range of 0.01-1 mM.
2. GM1 pre-protects oxaliplatin from damage to zebrafish hair cells at 24hpf treatment
Collecting Tg (Brn 3c: EGFP) transgenic zebrafish embryos of fluorescent protein labeled hair cells, incubating the embryos in an incubator at 28.5 ℃, selecting embryos with good state at 6hpf, placing the embryos in a 96-well plate, and randomly grouping the embryos: control group, GM1 treated group, oxaliplatin (oxaliplatin) treated group, and GM1+ oxaliplatin treated group are shown in fig. 5A.
Embryos were incubated with embryo culture medium containing a concentration of GM1 (0.1 mg/ml to 2 mg/ml) starting at 24hpf, and a concentration of oxaliplatin (0.1 mg/ml to 1 mg/ml) was administered on a group-by-group basis after 6h of GM1 treatment, as shown in FIG. 5A.
The drug treatment process is carried out in an incubator at 28.5 ℃, and after the embryo grows to 72hpf, the living body imaging is carried out on the zebra fish juvenile fish according to the time period selected as required. The morphological, quantitative indicators of hair cells were analyzed by fixing the fluorescently labeled transgenic zebrafish juvenile fish in 0.8-th% LMP agarose gel containing 0.03% of tricaine anesthetic, live three-dimensional imaging under a laser confocal microscope.
The results are shown in fig. 5B and 5C, and after oxaliplatin treatment, the hair cells were disorganized, the hair cell bodies were damaged, cilia were shortened or disappeared, and the number of hair cells was significantly reduced. After GM1 pretreatment and oxaliplatin treatment, compared with the treatment with oxaliplatin only, the number of hair cells is obviously increased, the hair cells are arranged in a tighter cluster, and the cilia structure is improved.
3. GM1 pre-protected oxaliplatin from damage to zebrafish hair cells at 8hpf treatment
Collecting Tg (Brn 3c: EGFP) transgenic zebrafish embryos of fluorescent protein labeled hair cells, incubating the embryos in an incubator at 28.5 ℃, selecting embryos with good state at 6hpf, placing the embryos in a 96-well plate, and randomly grouping the embryos: control group, GM1 treated group, oxaliplatin (oxaliplatin) treated group, and GM1+ oxaliplatin treated group are shown in fig. 6A.
Embryos were incubated with embryo culture medium containing a concentration of GM1 (0.1 mg/ml to 2 mg/ml) starting at 8hpf, and a concentration of oxaliplatin (0.1 mg/ml to 1 mg/ml) was administered on a group-by-group basis after 6h of GM1 treatment, as shown in FIG. 6A.
The drug treatment process is carried out in an incubator at 28.5 ℃, and after the embryo grows to 72hpf, the living body imaging is carried out on the zebra fish juvenile fish according to the time period selected as required. Transgenic zebrafish juvenile fish fluorescently labeled with hair cells were fixed in 0.8-percent LMP agarose gel containing 0.03% tricoine anesthetic, subjected to living body three-dimensional imaging under a laser confocal microscope, and analyzed for morphology and quantity indices of hair cells.
As a result, as shown in fig. 6B and 6C, after oxaliplatin treatment, hair cell alignment was disturbed, hair cell bodies were damaged, cilia were shortened or disappeared, and the number of hair cells was significantly reduced. After GM1 pretreatment and oxaliplatin treatment, compared with the treatment with oxaliplatin only, the number of hair cells is obviously increased, the hair cells are arranged in a tighter cluster, and the cilia structure is improved.
Example 3 Effect of GM1 in preventing/ameliorating zebrafish hair cell damage/hearing impairment caused by paclitaxel or its platinum-based drugs
1. GM1 pre-protected paclitaxel from damage to zebrafish hair cells at 24hpf treatment
Collecting Tg (Brn 3c: EGFP) transgenic zebrafish embryos of fluorescent protein labeled hair cells, incubating the embryos in an incubator at 28.5 ℃, selecting embryos with good state by 6hpf, placing the embryos in a 96-well plate, and randomly grouping the embryos: control group, GM1 treatment group, paclitaxel (albumin-bound type, consisting of 100mg paclitaxel and 900mg human serum albumin) treatment group, and GM1+ paclitaxel (albumin-bound type) treatment group. As shown in FIG. 7A, paclitaxel (albumin bound) (0.01 mg/ml to 1mg/ml, embryo culture) treatment group started at 48 hpf. Embryos were incubated with embryo culture medium containing a certain concentration (0.1 mg/ml-2 mg/ml) of GM1 starting at 24hpf, and paclitaxel (albumin-bound type) (0.01 mg/ml-1 mg/ml, embryo culture medium) treatment at a certain concentration was performed on a group-by-group basis after 6 hours of GM1 treatment.
The drug treatment process was carried out in an incubator at 28.5 ℃. After the embryo develops to 72hpf, selecting a time period according to needs to carry out living body imaging on the zebra fish juvenile fish. In vivo three-dimensional imaging under a confocal laser confocal microscope by fixing the fluorescently-labeled hair cell-labeled transgenic zebrafish juvenile fish in 0.8-percent LMP agarose gel containing 0.03-percent tricaine anesthetic, the results are shown in FIG. 7B; the analysis of the morphology, quantity, distribution and other parameters of the hair cells shows the results in fig. 7C.
After paclitaxel (albumin-bound) treatment, hair cell arrangement is disordered, hair cell bodies are damaged, cilia are shortened or disappeared, and the number of hair cells is obviously reduced. After the GM1 pretreatment, paclitaxel (albumin bound) treatment is added, compared with the treatment only with paclitaxel (albumin bound), the number of hair cells is obviously increased, the hair cells are arranged in a tighter cluster, and the cilia structure is improved.
2. GM1 pre-treatment at 8hpf protected the damage of paclitaxel to zebrafish hair cells
Collecting Tg (Brn 3c: EGFP) transgenic zebrafish embryos of fluorescent protein labeled hair cells, incubating the embryos in an incubator at 28.5 ℃, selecting embryos with good state at 6hpf, placing the embryos in a 96-well plate, and randomly grouping the embryos: control group, GM1 treatment group, paclitaxel (albumin-bound type, consisting of 100mg paclitaxel and 900mg human serum albumin) treatment group, and GM1+ paclitaxel (albumin-bound type) treatment group. As shown in FIG. 8A, the paclitaxel (albumin bound) (0.01 mg/ml to 1mg/ml, embryo culture) treated group started at 48 hpf. Embryos were incubated with embryo culture medium containing a certain concentration (0.1 mg/ml-2 mg/ml) of GM1 starting at 8hpf, and paclitaxel (albumin-bound type) (0.01 mg/ml-1 mg/ml, embryo culture medium) treatment at a certain concentration was performed on a group-by-group basis after 6 hours of GM1 treatment.
The drug treatment process was carried out in an incubator at 28.5 ℃. After the embryo develops to 72hpf, selecting a time period according to needs to carry out living body imaging on the zebra fish juvenile fish. In vivo three-dimensional imaging by fixing the fluorescently labeled hair cells of the transgenic zebrafish juvenile fish in 0.8-th% LMP agarose gel containing 0.03% of tricaine anesthetic, under a laser confocal microscope, the results are shown in FIG. 8B; the analysis of the form, quantity, distribution and other parameters of the hair cells shows the result in fig. 8C.
After paclitaxel (albumin-bound), hair cell arrangement is disturbed, hair cell bodies are damaged, cilia are shortened or disappear, and the number of hair cells is obviously reduced. The GM1 pretreatment was followed by paclitaxel (albumin bound) treatment, which significantly increased the number of hair cells, which were more tightly clustered and improved the cilia structure compared to treatment with paclitaxel (albumin bound).
3. GM1 pre-protected damage to zebrafish hair cells from paclitaxel in combination with cisplatin at 8hpf treatment
Collecting Tg (Brn 3c: EGFP) transgenic zebrafish embryos of fluorescent protein labeled hair cells, incubating the embryos in an incubator at 28.5 ℃, selecting embryos with good state by 6hpf, placing the embryos in a 96-well plate, and randomly grouping the embryos: a control group, a GM1 treatment group, a paclitaxel (albumin bound type, comprising 100mg paclitaxel and 900mg human serum albumin) combined cisplatin treatment group, and a GM1+ paclitaxel (albumin bound type) combined cisplatin treatment group. As shown in FIG. 9A, the paclitaxel (albumin bound) (0.01 mg/ml to 1mg/ml, embryo culture) combined with cisplatin (0.01 mg/ml to 0.5mg/ml, embryo culture) treatment group was started at 48 hpf. Embryos were incubated with embryo culture medium containing a certain concentration (0.1 mg/ml-2 mg/ml) of GM1 starting at 8hpf, and paclitaxel (albumin-bound type) (0.01 mg/ml-1 mg/ml, embryo culture medium) and cisplatin (0.01 mg/ml-0.5 mg/ml, embryo culture medium) combinations at certain concentrations were performed on a group-by-group basis after 6h of GM1 treatment.
The drug treatment process was carried out in an incubator at 28.5 ℃. And after the embryo develops to 72hpf, selecting a time period as required to carry out living body imaging on the zebra fish juvenile fish. In vivo three-dimensional imaging by fixing the fluorescently labeled hair cells of the transgenic zebrafish juvenile fish in 0.8-th% LMP agarose gel containing 0.03% of tricaine anesthetic, under a laser confocal microscope, the results are shown in FIG. 9B; the analysis of the morphology, quantity, distribution and other parameters of the hair cells shows the results in fig. 9C.
After the treatment of paclitaxel (albumin-bound type) and cisplatin, hair cells are disorganized, hair cell bodies are damaged, cilia are shortened or disappear, and the number of hair cells is obviously reduced. After GM1 pretreatment, paclitaxel (albumin bound) and cisplatin combined treatment are added, compared with the paclitaxel (albumin bound) and cisplatin combined treatment, the number of hair cells is obviously increased, the hair cells are arranged in a tighter cluster, and the cilia structure is improved.
4. GM1 pre-protects damage of paclitaxel and oxaliplatin in combination with 8hpf treatment to zebra fish hair cells
Collecting Tg (Brn 3c: EGFP) transgenic zebrafish embryos of fluorescent protein labeled hair cells, incubating the embryos in an incubator at 28.5 ℃, selecting embryos with good state at 6hpf, placing the embryos in a 96-well plate, and randomly grouping the embryos: a control group, a GM1 treatment group, a paclitaxel (albumin-bound type, consisting of 100mg paclitaxel and 900mg human serum albumin) combined oxaliplatin treatment group, and a GM1+ paclitaxel (albumin-bound type) combined oxaliplatin treatment group. As shown in FIG. 10A, treatment of paclitaxel (albumin-bound) (0.01 mg/ml to 1mg/ml, embryo culture) combined with oxaliplatin (0.1 mg/ml to 1mg/ml, embryo culture) treatment groups started at 48 hpf. Embryos are incubated with an embryo culture solution containing a certain concentration (0.1 mg/ml to 2 mg/ml) of GM1 starting at 8hpf, and paclitaxel (albumin-bound type) (0.01 mg/ml to 1mg/ml, embryo culture solution) and oxaliplatin (0.1 mg/ml to 1mg/ml, embryo culture solution) can be combined at a certain concentration according to groups after 6 hours of GM1 treatment.
The drug treatment process was carried out in an incubator at 28.5 ℃. And after the embryo develops to 72hpf, selecting a time period as required to carry out living body imaging on the zebra fish juvenile fish. In vivo three-dimensional imaging under a confocal laser confocal microscope by fixing the fluorescently-labeled hair cell-labeled transgenic zebrafish juvenile fish in 0.8-percent LMP agarose gel containing 0.03-percent tricaine anesthetic, the results are shown in FIG. 10B; the analysis of the morphology, quantity, distribution and other parameters of the hair cells shows the results in fig. 10C.
After treatment with paclitaxel (albumin-bound) and oxaliplatin, hair cells are disorganized, hair cell bodies are damaged, cilia are shortened or disappeared, and the number of hair cells is obviously reduced. After GM1 pretreatment, paclitaxel (albumin bound) and oxaliplatin are added for treatment, compared with the treatment only with paclitaxel (albumin bound) and oxaliplatin, the number of hair cells is obviously increased, the hair cells are arranged in a tighter cluster, and the cilium structure is improved.
Example 4 Effect of GM1 in preventing/ameliorating mouse Hair cell Damage/Hearing impairment caused by cisplatin, oxaliplatin and paclitaxel
1. GM1 prevents/ameliorates cisplatin-induced cochlear hair cell damage in mice
Newborn mice were treated with drugs according to the experimental groups, with GM1 at a dose of 200mg/kg and cisplatin at a dose of 5mg/kg. After the drug treatment was completed, the mouse temperal bone was taken out and placed on an ice box for rapid dissection of the cochlea. The 10mm coverslips were coated with 0.5. Mu.l each slide using a separate cell-tab, formed into a 5mm diameter circle and air dried (fresh coating). The coated coverslip was placed in a petri dish with cochlea, the cochlea was attached to the slide with the face up, the attached slide was placed in a 4-well petri dish (3 ml of PBS had been added before and on ice), and after all slides were attached, 16% PFA was added to the four-well petri dish to make the solution 4% PFA. The plates were fixed for 1h, washed 3 times with PBST, blocked for 1-2h (100. Mu.l per well), incubated in PBT-1 plus primary antibody overnight at 4 ℃ and washed 3 times with PBST before adding secondary antibody at room temperature for 1h (100. Mu.l per well). PBST was washed 3 times with 6. Mu.l DAKO per sample, coverslipped and mounted with nail polish. Morphology of mouse cochlear hair cells was observed under a fluorescence microscope, and the results are shown in fig. 11A. Hair cell phenotype counts showed that cisplatin had significant cochlear capillary cytotoxicity in mice, with a significant protective effect following GM1 pretreatment, reducing hair cell loss and number of malformations (fig. 11B).
2. GM1 prevents/improves mice cochlear hair cell injury caused by oxaliplatin in and paclitaxel
The neonatal mice were treated with the drugs according to the experimental groups, with a GM1 dose of 200mg/kg and oxaliplatin and paclitaxel doses of 5mg/kg. After drug treatment was complete, the mouse temperal bone was removed and placed on an ice box for rapid dissection of the cochlea. A10 mm coverslip was coated with 0.5. Mu.l of each slide using a dispensed cell-tab, painted into a circle of 5mm diameter, and air dried (freshly painted). The coated coverslip was placed in a petri dish with the cochlea, the cochlea was adhered to the slide with the face up, the adhered slide was placed in a 4-well petri dish (3 ml of PBS had been previously added and placed on ice), and after all slides were adhered, 16% PFA was added to the four-well petri dish to make the solution finally 4% PFA. The wells were fixed for 1h, washed 3 times with PBST, blocked medium for 1-2h (100. Mu.l per well), incubated overnight at 4 ℃ in PBT-1 plus primary antibody, washed 3 times with PBST and then secondary antibody added for 1h at room temperature (100. Mu.l per well). PBST was washed 3 times with 6. Mu.l DAKO per sample, coverslipped and mounted with nail polish. Morphology of mouse cochlear hair cells was observed under a fluorescence microscope, and the results are shown in fig. 12A. Hair cell phenotype counts showed that cisplatin had significant cochlear capillary cytotoxicity in mice, with a significant protective effect following GM1 pretreatment, reducing hair cell loss and number of malformations (fig. 12B).
3. Study on prevention/improvement of cisplatin and oxaliplatin-induced cochlear hair cell damage/hearing damage in mice by GM1
Experimental Material
1. Experimental animals: c57BL/6 male mice, 8 weeks old, were provided by the university of Nantong laboratory animal center.
2. Experimental reagent:
3. experimental equipment:
experimental method
1. Grouping and administration of laboratory animals
1) Cisplatin grouping and administration
Using prospective random control experiments, the random number table method groups experimental mice into four groups of 10 mice each: control group (Vehicle), cisplatin group (Cisplatin), GM1+ cis-platinum group (GM 1& Cisplatin), GM1 group (GM 1). 3mg/kg of cisplatin is injected into the abdominal cavity of the cisplatin group mice for 7 days continuously; the mice in the GM1 group are subjected to intraperitoneal injection of GM1 of 20mg/kg for 7 days continuously; the mice in the GM1+ cisplatin group are treated 7 days in advance, GM1 mg/kg is injected into the abdominal cavity, and cisplatin 3mg/kg is injected into the abdominal cavity at the 8 th day for 7 days continuously; the control group was given only an equal amount of saline by intraperitoneal injection. Four groups were retested for Auditory Brainstem Response (ABR) one day after drug withdrawal, and after ABR examination mice were sacrificed to take out cochlea for subsequent morphological and molecular biology experiments.
2) Oxaliplatin grouping and administration
Using prospective random control experiments, the random number table method divided the animal mice into four groups of 8 mice each: control (Vehicle), oxaliplatin (Oxa), GM1+ oxaliplatin (GM 1& Oxa), and GM1 (GM 1). The mice in the oxaliplatin group are injected with oxaliplatin in the abdominal cavity for 5mg/kg continuously for 7 days; the mice in the GM1 group are injected with 20mg/kg of GM in the abdominal cavity for 7 days continuously; the GM1+ oxaliplatin group mice are treated for 7 days in advance, GM1 mg/kg is injected into the abdominal cavity, and oxaliplatin is injected into the abdominal cavity for 5mg/kg at the 8 th day for 7 days continuously; the control group was given only an equal amount of saline by intraperitoneal injection. Four groups of the mice are sacrificed after stopping taking the medicines for the ABR for one day, and the cochlea is taken out for subsequent morphological and molecular biology experiments after the ABR examination is completed.
2. ABR test
ABR is a sound-induced neural response commonly used to assess auditory function in humans and experimental animals. In mice, the ABR test will show 5 wave patterns, named wave i, wave ii, wave iii, wave iv, wave v, where wave i receives neural signals from the auditory nerve, wave ii receives neural signals from the cochlea, wave iii receives neural signals from the superior olivary nucleus, wave iv receives neural signals from the periolivary nucleus and the lateral thalamus nucleus, and wave v receives neural signals from the hypothalamus nucleus.
The ABR test is carried out in a soundproof room, before the ABR test is carried out, the weight of a mouse is weighed, 4% chloral hydrate is injected into an abdominal cavity to anaesthetize the animal, subcutaneous needle electrodes are respectively inserted into the parietal centre skin (+ electrodes), mastoid (-polar) and hind legs (grounded), click stimulation and short pure tone stimulation with different frequencies of 4KHz, 8KHz, 16KHz, 24KHz and 32KHz are respectively applied to a single sound channel of a loudspeaker, stimulation is repeated with the decrement of 10dB from the sound pressure level of 90dB, and an ABR waveform diagram is recorded. After the experiment is finished, the response threshold value and the latency change of the recorded wave II are counted.
3. Mouse cochlea Corti immunofluorescence staining
After the ABR experiment was completed, 5 mice were randomly selected from each group for immunofluorescence staining. Mouse inner ear was carefully stripped under microscope after 4% pfa fixation and EDTA decalcification. Dissecting the basement membrane of the mouse in precooled PBS; coating a cover glass with the diameter of 10mm with a cell-tab, forming a circle with the diameter of 5mm, and airing (fresh coating); putting the coated cover glass into a culture dish with a mouse cochlea basilar membrane, and adhering the cochlea on the glass, wherein the front side of the cochlea faces upwards (the front side of the cochlea has a bulge) during adhesion; the well-adhered slide was placed in a 4-well petri dish (3 ml of PBS was added in advance, placed on ice), and washed three times with PBS; after blocking for one hour at room temperature, the hair cell marker Myosin7a (Myo 7 a) primary antibody was added and incubated overnight at 4 ℃; rinsing with PBS for 3 times, and incubating the corresponding secondary antibodies at room temperature for 2 hours according to the proportion within 5 minutes each time; PBS rinse 3 times for 5 minutes, add 10. Mu.l of a mounting medium containing DAPI (4', 6-diamidino-2-phenylindole, a fluorescent dye capable of binding strongly to DNA) to each slide, cover with 10mm coverslips, and mount with nail polish; pictures were taken using a confocal microscope.
4. Data processing
Images taken by laser confocal imaging were analyzed and processed by Imaris × 64.0. A software. Data obtained by experiments are processed by Graphpad Prism8, one-way ANOVA is used for comparing single-factor and multi-group differences, two-way ANOVA is used for comparing Two groups and multi-factor, and P <0.05 shows that the differences have statistical significance.
Results and conclusions of the experiment
1. GM1 prevents cisplatin-induced Corti hair cell damage and ABR threshold response abnormalities
The organ Corti is a helix located on the basilar membrane of the cochlear duct membrane, consisting of inner and outer hair cells, supporting cells and a mantle membrane (protective membrane), and is a major component of auditory receptors. There are a single row of Inner Hair Cells (IHCs) near the modiolus and 3 or more rows of Outer Hair Cells (OHCs) outside. The hair cells at different parts of the basement membrane are different in height, and gradually become higher from the bottom of the cochlea to the top of the cochlea. The hair cells at the bottom of the cochlea have short static cilia, the static cilia near the top of the cochlea are gradually lengthened, and the sensitive wavelength is also gradually lengthened. The height of these cochlear hair cells, as well as the gradient of the length of the resting cilia, are the morphological basis for the generation of cochlear wavelength alignment and wave modulation functions. In order to investigate whether GM1 has a preventive protection effect on hair cell damage caused by cisplatin, after cisplatin is injected into an abdominal cavity, cochlear Corti hair cells of a mouse are detected by immunofluorescence staining. The experimental results are shown in fig. 13 (a-B) and table 1, and the numbers of hair cells with Myo7a positive signals at the top (Apex), middle (Middle) and Base (Base) of the left and right cochlear of the mouse are counted respectively, and the results show that the cochlear hair cells of the mouse are reduced by injecting cisplatin 3mg/kg into the abdominal cavity compared with the control group, while GM1 can prevent hair cell reduction caused by cisplatin.
Since wave II of the ABR test receives a nerve signal of a cochlear nucleus, the change of response threshold and latency of wave II among different groups is recorded in experimental statistics, and the experimental result is shown in figure 13 (C-H) and tables 2 and 3, cisplatin can cause the abR response threshold and the abR response latency of a mouse to be abnormal, the response threshold is increased and the latency is prolonged, and GM1 can prevent the hearing behavior of the mouse from being abnormal. The results suggest that pretreatment with GM1 can prevent cisplatin hearing impairment.
Tables 1-3 illustrate: tables 1-3 are data relating to 10 mice per group, not in sequence.
TABLE 1GM1 prevention of cisplatin-Hearing impairment — number of Myo7a positive hair cells from Corti apparatus
TABLE 2 GM1 prevention of cisplatin induced hearing impairment ABR behavioral Experimental latency (ms)
TABLE 3 GM1 prevention of cisplatin induced hearing impairment-ABR behavioral experiment Hearing threshold (dB)
4. GM1 prevents oxaliplatin-induced hearing impairment-Corti hair cell damage and ABR threshold of response abnormality
After 5mg/kg of oxaliplatin is intraperitoneally injected, cochlear Corti hair cells of a mouse are detected by immunofluorescence staining, and the experimental results are shown in fig. 14 (A-B) and table 4, wherein oxaliplatin causes the number of cochlear hair cells of the mouse to be reduced, and GM1 can prevent the hair cells caused by oxaliplatin from being reduced. The ABR test also shows that the experimental result is as shown in figure 14 (C-H) and tables 5 and 6, oxaliplatin can cause the abR reaction threshold and the ABR reaction latency of the mice to be abnormal, the reaction threshold is increased, the latency is prolonged, and GM1 can prevent the abnormal hearing behavior of the mice. The experimental results suggest that pretreatment with GM1 can prevent oxaliplatin hearing impairment.
Tables 4-6 illustrate: table 4 presents data relating to 10 mice per group, without precedence. Tables 5 and 6 show the data for 8 mice per group, without any sequence.
TABLE 4 GM1 prevention of hearing impairment due to oxaliplatin-number of Myo7a positive hair cells of Corti apparatus
TABLE 5 GM1 prevention of hearing impairment caused by oxaliplatin-ABR behavioral Experimental incubation period (ms)
TABLE 6 GM1 prevention of hearing impairment due to oxaliplatin-ABR behavioral experiments Hearing threshold (dB)
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. Use of the ganglioside GM1 in the manufacture of a medicament for the prevention, alleviation or treatment of hearing loss induced by a chemotherapeutic drug.
2. The use of claim 1, wherein the chemotherapeutic drug is selected from a platinum-based drug, paclitaxel, or any combination thereof; preferably, the chemotherapeutic is selected from cisplatin, oxaliplatin, paclitaxel, a combination of cisplatin and paclitaxel, a combination of oxaliplatin and paclitaxel; more preferably, wherein the paclitaxel is an albumin-bound paclitaxel.
3. The use of claim 1, wherein the hearing impairment comprises varying degrees of hair cell damage in the patient.
4. The use of claim 3, wherein the hair cell damage comprises: disappearance/reduction of normal cells, increase of malformed cells, abnormality of cellular location or relative cellular location, abnormality of characteristic indicator molecules in cells.
5. The use according to claim 3, said patient comprising a tumor patient selected from the group consisting of patients with multiple myeloma, digestive tract tumors, respiratory tract tumors, head and neck tumors, breast cancer, tumors of the reproductive system.
6. The use according to claim 1, the ganglioside GM1 being monosialotetrahexosyl ganglioside sodium.
7. The use according to claim 1, wherein the ganglioside GM1 is in a formulation selected from the group consisting of an injectable formulation, an oral formulation, a topical formulation or an external formulation; preferably, the formulation of the ganglioside GM1 is in the form of an injectable formulation.
8. The use according to claim 1, the ganglioside GM1 being administered before, during or after the administration of said chemotherapeutic drug.
9. Use of ganglioside GM1 in the manufacture of a medicament for use in combination with a chemotherapeutic agent for the prevention of hearing impairment in a patient suffering from a tumor, wherein said chemotherapeutic agent is selected from cisplatin, oxaliplatin, paclitaxel, a combination of cisplatin and paclitaxel, or a combination of oxaliplatin and paclitaxel, said hearing impairment comprising varying degrees of hair cell damage, comprising: disappearance/reduction of normal cells, increase of malformed cells, abnormality of cellular location or relative cellular location, abnormality of characteristic marker molecules in cells.
10. Use of the ganglioside GM1 in the manufacture of a medicament for the prevention, alleviation or treatment of a hearing impairment in a patient selected from the group consisting of a patient with noise deafness, a patient with presbycusis, and a patient with hearing impairment due to drug side effects, said hearing impairment comprising a varying degree of hair cell damage in the patient.
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